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

RNA viruses have extreme mutation frequencies. When a RNA virus replicates, nucleotide mutations are generated resulting in a population of variants. This genetic diversity creates a cloud of mutations that are potentially beneficial to viral survival, but the majority of mutations are detrimental to the virus. By increasing the mutation rate of a RNA virus, viral fitness is reduced because it generates more errors, and attenuates the virus during in vivo infection. Another feature that affects RNA virus fitness is mutational robustness. Mutational robustness is the ability to buffer the negative effects of mutation. The attenuation of RNA viruses for vaccine production faces problems of genetic instability and reversion to a pathogenic phenotype. The conventional method for attenuation is mostly empirical and specific to the particular RNA virus species.
Hence, it cannot be universally applied to a variety of virus types. We've developed a non-empirical, rational means of attenuating RNA viruses, targeting mutational robustness as modifiable trait.
 We demonstrate that mutational robustness of RNA viruses can be modified without changing a virus' physical and biological properties for vaccine production; yet the virus is attenuated as it becomes victim of its naturally high mutation rate. Specifically, the genome of RNA viruses are modified so that a larger proportion of mutations become lethal Stop mutations. Our technology places the virus one step away from these Stop mutations (1-to-Stop). We succeeded in attenuating two RNA viruses from very different viral families, confirming the broad applicability of this approach. These viruses were attenuated in vivo, generated high levels of neutralizing antibody and protected mice from lethal challenge infection. The proposal now seeks to complete proof of concept studies and develop commercialization strategies to scale up this new technology to preclinical testing with industrial partners.

150 000 €

Start date: 2016-09-01, End date: 2018-02-28

The suite of graphene’s unique properties and applications can be enormously enhanced by its functionalization. As non-covalently functionalized graphenes do not target all graphene’s properties and may suffer from limited stability, covalent functionalization represents a promising way for controlling graphene’s properties. To date, only a few well-defined graphene derivatives have been introduced. Among them, fluorographene (FG) stands out as a prominent member because of its easy synthesis and high stability. Being a perfluorinated hydrocarbon, FG was believed to be as unreactive as the two-dimensional counterpart perfluoropolyethylene (Teflon®). However, our recent experiments showed that FG is not chemically inert and can be used as a viable precursor for synthesizing graphene derivatives. This surprising behavior indicates that common textbook grade knowledge cannot blindly be applied to the chemistry of 2D materials. Further, there might be specific rules behind the chemistry of 2D materials, forming a new chemical discipline we tentatively call 2D chemistry. The main aim of the project is to explore, identify and apply the rules of 2D chemistry starting from FG. Using the knowledge gained of 2D chemistry, we will attempt to control the chemistry of various 2D materials aimed at preparing stable graphene derivatives with designed properties, e.g., 1-3 eV band gap, fluorescent properties, sustainable magnetic ordering and dispersability in polar media. The new graphene derivatives will be applied in sensing, imaging, magnetic delivery and catalysis and new emerging applications arising from the synergistic phenomena are expected. We envisage that new applications will be opened up that benefit from the 2D scaffold and tailored properties of the synthesized derivatives. The derivatives will be used for the synthesis of 3D hybrid materials by covalent linking of the 2D sheets joined with other organic and inorganic molecules, nanomaterials or biomacromolecules.

1 831 103 €

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

I propose to investigate the nanometer scale organization of delicate 2-dimensional molecular materials using nanoscale vibrational spectroscopy. 2D structures are of great scientific and technological importance, for example as novel materials (graphene, MoS2, WS2, etc.), and in the form of biological membranes and synthetic 2D-polymers. Powerful methods for their analysis and imaging with molecular selectivity and sufficient spatial resolution, however, are lacking. Tip-enhanced Raman spectroscopy (TERS) allows label-free spectroscopic identification of molecular species, with ≈10 nm spatial resolution, and with single molecule sensitivity for strong Raman scatterers. So far, however, TERS is not being carried out in liquids, which is the natural environment for membranes, and its application to poor Raman scatterers such as components of 2D polymers, lipids, or other membrane compounds (proteins, sugars) is difficult. TERS has the potential to overcome the restrictions of other optical/spectroscopic methods to study 2D materials, namely (i) insufficient spatial resolution of diffraction-limited optical methods; (ii) the need for labelling for all methods relying on fluorescence; and (iii) the inability of some methods to work in liquids. I propose to address a number of scientific questions associated with the spatial organization, and the occurrence of defects in sensitive 2D molecular materials. The success of these studies will also rely critically on technical innovations of TERS that notably address the problem of energy dissipation. This will for the first time allow its application to study of complex, delicate 2D molecular systems without photochemical damage.

2 311 696 €

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

Some 50% of human melanoma tumors have activating mutations in the BRAF gene. BRAF inhibitor drugs given either alone or in combination with MEK inhibitors have improved progression-free and overall survival in patients with BRAF mutant metastatic melanoma. However, drug resistance invariably limits the duration of clinical benefit of such treatments and is almost always associated with re-activation of signaling through the MAP kinase pathway in the presence of drug due to secondary mutations in the pathway. This highlights the urgent need to develop strategies to treat melanomas that have developed resistance to BRAF and/or MEK inhibitors. As part of an ERC advanced grant, my laboratory has shown that BRAF inhibitor withdrawal in melanomas that have developed resistance to BRAF inhibitors leads to a transient growth arrest that is the consequence of temporary hyperactivation of signaling through the MAP kinase pathway, explaining the so called “drug holiday effect”. We have also found that subsequent treatment of such BRAF inhibitor resistant melanomas with Histone DeACetylase inhibitor drugs (HDACi) leads to persistent hyperactivation of MAP kinase signaling, causing both chronic proliferation arrest and cell death, ultimately leading to complete regression of BRAF-inhibitor resistant melanomas in mice. We propose here to perform a proof of concept study in at least 10 evaluable melanoma patients that, after proven initial tumor response, have developed resistance to BRAF inhibitors to validate that subsequent treatment of such patients with an HDACi drug will result in durable responses. Translational studies on tumor biopsies taken before, during and after HDACi treatment will be performed to study the cellular effects of HDACi treatment. Our goal is to provide initial proof of concept in patients for use of this sequential BRAFi-HDACi therapy as the treatment of choice for the some 40,000 BRAF mutant melanomas that are diagnosed in the EU annually.

149 750 €

Start date: 2016-05-01, End date: 2017-10-31

Computational Electromagnetics (CEM) is the scientific field at the origin of all new modeling and simulation tools required by the constantly arising design challenges of emerging and future technologies in applied electromagnetics. As in many other technological fields, however, the trend in all emerging technologies in electromagnetic engineering is going towards miniaturized, higher density and multi-scale scenarios. Computationally speaking this translates in the steep increase of the number of degrees of freedom. Given that the design cost (the cost of a multi-right-hand side problem dominated by matrix inversion) can scale as badly as cubically with these degrees of freedom, this fact, as pointed out by many, will sensibly compromise the practical impact of CEM on future and emerging technologies. For this reason, the CEM scientific community has been looking for years for a FFT-like paradigm shift: a dynamic fast direct solver providing a design cost that would scale only linearly with the degrees of freedom. Such a fast solver is considered today a Holy Grail of the discipline. The Grand Challenge of 321 will be to tackle this Holy Grail in Computational Electromagnetics by investigating a dynamic Fast Direct Solver for Maxwell Problems that would run in a linear-instead-of-cubic complexity for an arbitrary number and configuration of degrees of freedom. The failure of all previous attempts will be overcome by a game-changing transformation of the CEM classical problem that will leverage on a recent breakthrough of the PI. Starting from this, the project will investigate an entire new paradigm for impacting algorithms to achieve this grand challenge. The impact of the FFT’s quadratic-to-linear paradigm shift shows how computational complexity reductions can be groundbreaking on applications. The cubic-to-linear paradigm shift, which the 321 project will aim for, will have such a rupturing impact on electromagnetic science and technology.

2 000 000 €

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

Photonics, in recognition of its strategic significance and pervasiveness throughout many industrial sectors, has been identified as one of the Key Enabling Technologies for Europe. Photonics in combination with quantum information science has great potential to facilitate, transform and innovate future technologies for the better. The Proof of Concept (PoC) project intends to contribute to this by developing and testing a communication platform prototype, comprised of single photon detectors, which are efficiently coupled to single mode fibers using an innovative laser written device. This enables the integration of single photon detectors on innovative glass waveguides. These glass integrated photonic circuits offer excellent specifics for on-chip quantum optics implementations in terms of scattering losses, offering flexibility of the waveguide geometry and ensuring high coupling efficiency with optical fibers. The device developed and tested in the PoC, directly addresses a market need for an integrated and efficient on-chip communication systems. Current available systems have limitations involving high costs, complex production, and inefficient coupling of detectors to optical fibers. The proposed platform will offer 1.) a simplified production process, 2.) high optical fiber coupling efficiency 3.) improved performance levels, 4.) high cost efficiency, and 5.) compactness. Such systems can be applied in a wide range of communication and non-communication applications, such as free-space optical communication, quantum communication, quantum cryptography, DNA sequencing, single molecule detection and material analysis. Moreover, the future commercialisation of quantum computing is expected to create a vast demand for these communication systems. In addition to the technology PoC, the project carries out IPR strategy considerations through patenting actions, determines the market potential, seeks market feedback, and plans for post-PoC commercialisation paths.

150 000 €

Start date: 2016-02-01, End date: 2017-07-31

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

1 999 750 €

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

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

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

1 203 627 €

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

The architecture of DNA in the cell nucleus is an emerging epigenetic key contributor to genome function. We recently developed 4C technology, a high-throughput technique that combines state-of-the-art 3C technology with tailored micro-arrays to uniquely allow for an unbiased genome-wide search for DNA loci that interact in the nuclear space. Based on 4C technology, we were the first to provide a comprehensive overview of long-range DNA contacts of selected loci. The data showed that active and inactive chromatin domains contact many distinct regions within and between chromosomes and genes switch long-range DNA contacts in relation to their expression status. 4C technology not only allows investigating the three-dimensional structure of DNA in the nucleus, it also accurately reconstructs at least 10 megabases of the one-dimensional chromosome sequence map around the target sequence. Changes in this physical map as a result of genomic rearrangements are therefore identified by 4C technology. We recently demonstrated that 4C detects deletions, balanced inversions and translocations in patient samples at a resolution (~7kb) that allowed immediate sequencing of the breakpoints. Excitingly, 4C technology therefore offers the first high-resolution genomic approach that can identify both balanced and unbalanced genomic rearrangements. 4C is expected to become an important tool in clinical diagnosis and prognosis. Key objectives of this proposal are: 1. Explore the functional significance of DNA folding in the nucleus by systematically applying 4C technology to differentially expressed gene loci. 2. Adapt 4C technology such that it allows for massive parallel analysis of DNA interactions between regulatory elements and gene promoters. This method would greatly facilitate the identification of functionally relevant DNA elements in the genome. 3. Develop 4C technology into a clinical diagnostic tool for the accurate detection of balanced and unbalanced rearrangements.

1 225 000 €

Start date: 2008-09-01, End date: 2013-08-31

The focus of this project is the development of algorithms that allow one to capture and analyse dynamic events taking place in the real world. For this, we intend to develop smart camera networks that can perform a multitude of observation tasks, ranging from surveillance and tracking to high-fidelity, immersive reconstructions of important dynamic events (i.e. 4D videos). There are many fundamental questions in computer vision associated with these problems. Can the geometric, topologic and photometric properties of the camera network be obtained from live images? What is changing about the environment in which the network is embedded? How much information can be obtained from dynamic events that are observed by the network? What if the camera network consists of a random collection of sensors that happened to observe a particular event (think hand-held cell phone cameras)? Do we need synchronization? Those questions become even more challenging if one considers active camera networks that can adapt to the vision task at hand. How should resources be prioritized for different tasks? Can we derive optimal strategies to control camera parameters such as pan, tilt and zoom, trade-off resolution, frame-rate and bandwidth? More fundamentally, seeing cameras as points that sample incoming light rays and camera networks as a distributed sensor, how does one decide which rays should be sampled? Many of those issues are particularly interesting when we consider time-varying events. Both spatial and temporal resolution are important and heterogeneous frame-rates and resolution can offer advantages. Prior knowledge or information obtained from earlier samples can be used to restrict the possible range of solutions (e.g. smoothness assumption and motion prediction). My goal is to obtain fundamental answers to many of those question based on thorough theoretical analysis combined with practical algorithms that are proven on real applications.

1 757 422 €

Start date: 2008-08-01, End date: 2013-11-30

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

2 349 898 €

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

"Antibodies are among the most widely monitored class of diagnostic biomarkers. Immunoassays market now covers about 1/3 of the global market of in-vitro diagnostics (about $50 billion). However, current methods for the detection of diagnostic antibodies are either qualitative or require cumbersome, resource-intensive laboratory procedures that need hours to provide clinicians with diagnostic information. A new method for fast and low-cost detection of antibodies will have a strong economic impact in the market of in-vitro diagnostics and Immunoassays. During our ERC Starting Grant project ""Nature Nanodevices"" we have developed a novel diagnostic technology for the detection of clinically relevant antibodies in serum and other body fluids. The platform (here named Ab-switch) supports the fluorescent detection of diagnostic antibodies (for example, HIV diagnostic antibodies) in a rapid (<3 minutes), single-step and low-cost fashion. The goal of this Proof of Concept project is to bring our promising platform to the proof of diagnostic market and exploit its innovative features for commercial purposes. We will focus our initial efforts in the development of rapid kits for the detection of antibodies diagnostic of HIV. We will 1) Fully characterize the Ab-switch product in terms of analytical performances (i.e. sensitivity, specificity, stability etc.) with direct comparison with other commercial kits; 2) Prepare a Manufacturing Plan for producing/testing the Ab-switch; 3) Establish an IP strategy for patent filing and maintenance; 4) Determine a business and commercialization planning."

150 000 €

Start date: 2017-02-01, End date: 2018-07-31

The main objective of this research project is to contribute at bridging the gap between the two main branches of financial theory, namely corporate finance and asset pricing. It is motivated by the conviction that these two aspects of financial activity should and can be analyzed within a unified framework. This research will borrow from these two approaches in order to construct theoretical models that allow one to analyze the design and issuance of financial securities, as well as the dynamics of their valuations. Unlike asset pricing, which takes as given the price of the fundamentals, the goal is to derive security price processes from a precise description of firm’s operations and internal frictions. Regarding the latter, and in line with traditional corporate finance theory, the analysis will emphasize the role of agency costs within the firm for the design of its securities. But the analysis will be pushed one step further by studying the impact of these agency costs on key financial variables such as stock and bond prices, leverage, book-to-market ratios, default risk, or the holding of liquidities by firms. One of the contributions of this research project is to show how these variables are interrelated when firms and investors agree upon optimal financial arrangements. The final objective is to derive a rich set of testable asset pricing implications that would eventually be brought to the data.

1 000 000 €

Start date: 2008-11-01, End date: 2014-10-31

The centriole is the largest evolutionary conserved macromolecular structure responsible for building centrosomes and cilia or flagella in many eukaryotes. Centrioles are critical for the proper execution of important biological processes ranging from cell division to cell signaling. Moreover, centriolar defects have been associated to several human pathologies including ciliopathies and cancer. This state of facts emphasizes the importance of understanding centriole biogenesis. The study of centriole formation is a deep-rooted question, however our current knowledge on its molecular organization at high resolution remains fragmented and limited. In particular, exquisite details of the overall molecular architecture of the human centriole and in particular of its central core region are lacking to understand the basis of centriole organization and function. Resolving this important question represents a challenge that needs to be undertaken and will undoubtedly lead to groundbreaking advances. Another important question to tackle next is to develop innovative methods to enable the nanometric molecular mapping of centriolar proteins within distinct architectural elements of the centriole. This missing information will be key to unravel the molecular mechanisms behind centriolar organization. This research proposal aims at building a cartography of the human centriole by elucidating its molecular composition and architecture. To this end, we will combine the use of innovative and multidisciplinary techniques encompassing spatial proteomics, cryo-electron tomography, state-of-the-art microscopy and in vitro assays and to achieve a comprehensive molecular and structural view of the human centriole. All together, we expect that these advances will help understand basic principles underlying centriole and cilia formation as well as might have further relevance for human health.

1 498 965 €

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

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

Nanowires based on group III–nitride semiconductors exhibit outstanding potential for emerging applications in energy-efficient lighting, optoelectronics and solar energy harvesting. Nitride nanowires, tailored at the nanoscale, should overcome many of the challenges facing conventional planar nitride materials, and also add extraordinary new functionality to these materials. However, progress towards III–nitride nanowire devices has been hampered by the challenges in quantifying nanowire electrical properties using conventional contact-based measurements. Without reliable electrical transport data, it is extremely difficult to optimise nanowire growth and device design. This project aims to overcome this problem through an unconventional approach: advanced contact-free electrical measurements. Contact-free measurements, growth studies, and device studies will be cross-correlated to provide unprecedented insight into the growth mechanisms that govern nanowire electronic properties and ultimately dictate device performance. A key contact-free technique at the heart of this proposal is ultrafast terahertz conductivity spectroscopy: an advanced technique ideal for probing nanowire electrical properties. We will develop new methods to enable the full suite of contact-free (including terahertz, photoluminescence and cathodoluminescence measurements) and contact-based measurements to be performed with high spatial resolution on the same nanowires. This will provide accurate, comprehensive and cross-correlated feedback to guide growth studies and expedite the targeted development of nanowires with specified functionality. We will apply this powerful approach to tailor nanowires as photoelectrodes for solar photoelectrochemical water splitting. This is an application for which nitride nanowires have outstanding, yet unfulfilled, potential. This project will thus harness the true potential of nitride nanowires and bring them to the forefront of 21st century technology.

1 499 195 €

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

In tissues, cells have their physical space constrained by neighbouring cells and extracellular matrix. In the PROMICO ERC project, our team proposed to specifically address the effect of physical confinement on normal and cancer cells that are dividing and migrating, using new pathophysiologically relevant in vitro approaches based on innovative micro-fabrication techniques. One of the devices we developed was meant to quantitatively control two key parameters of the cell environment: its geometry and its surface chemical properties. The main technical breakthrough was achieved using micro-fabricated elastomeric structures bound to a hard substrate (Le Berre Integrative Biology, 2012). The method led to important fundamental discoveries in cell biology (Lancaster Dev Cell 2013, Le Berre PRL 2013, Liu Cell 2015, Raab Science 2016). In part based on our findings, the notion that confinement is a crucial parameter for cell physiology has spread through the cell biology. Based on this, our idea is that cell confinement could be used as a powerfull cell conditioning technology, to change the cell state and offer new opportunities for fundamental research in cell biology, but also in cell therapies and drug screening. However, our current method to confine cells is not adapted to large scale cell conditioning applications, because the throughput and reliability of the device is still too low and because the recovery of cells after confinement remain poorly controlled. It is thus now timely to develop a robust and versatile cell confiner adapted to use in any cell biology lab, in academy and in industry, with no prior experience in micro-fabrication. Achieving this goal involves a complete change of technology compared to the ‘homemade’ PDMS device we have been using so far. We will also perform proofs of concept of its use for its application in cell based therapies, such as cancer immunotherapy, by testing the possibility to mechanically activate dendritic cells.

150 000 €

Start date: 2017-06-01, End date: 2018-11-30

Robot-assisted and minimally invasive medical procedures are impacting medical care by increasing accuracy, reducing cost, and minimizing patient discomfort and recovery times after interventions. Developers of commercial robotic surgical systems and medical device manufacturers look for realistic phantoms that can be used in place of animal experiments or cadavers to test procedures and to train medical personnel. Existing phantoms are either made from hard materials, or they lack anatomical detail, and they are mainly passive and thus unrealistic. Here, we use recently developed fabrication know-how and expertise within our ERC-funded research to develop the first active artificial urinary tract model that includes a kidney, a bladder, and a prostate. Rapid prototyping is combined with a fabrication step that we have developed to permit the incorporation of active elements, such as a peristaltic system and fluidic valves in the phantom. We have developed smart material composites that reproduce the mechanical and haptic properties, and that give ultrasound contrast indistinguishable from real organs, while permitting anatomical details to be reproduced with a mean error of as little as 500 microns. Feedback from a major medical device company indicates that ours is a unique phantom with unprecedented accuracy for which there is a market. Within this POC grant we want to develop a complete prototype, and to demonstrate a series of medical interventions on the phantom, including endoscopic diagnostic procedures (cystoscopy and ureterorenoscopy) and endoscopic treatment procedures (laser lithotripsy). The grant will allow us to protect our know-how, identify further markets, and develop a commercialization strategy. Overall, this project will generate the first active phantom system that permits the testing of surgical instruments and procedures, with a sizeable market potential.

150 000 €

Start date: 2017-03-01, End date: 2018-08-31

Alzheimer’s disease (AD) is the most common form of dementia in the Western World, representing an economic and social cost of billions of euros a year. Given the changing demographics of society, these costs will only increase over the coming decades. Amyloid plaques, composed of amyloid beta peptide (Abeta), are a defining characteristic of AD. Evidence now suggests that Abeta is central to disease pathogenesis due to its toxicity, which leads to cell loss and eventual cognitive decline. Abeta is generated by proteolytic cleavage of amyloid precursor protein, a process that involves the protein BACE1. Knock-down of BACE1 is sufficient to prevent amyloid pathology and cognitive deficits in transgenic mouse models of AD, so BACE1 is an attractive target for therapeutic intervention. Although many small molecule inhibitors of BACE1 have been developed, many have problems with imperfect selectivity, posing a substantial risk for off-target toxicity in vivo. In contrast, antibody-based therapeutics provide an attractive alternative given their excellent molecular selectivity. However, the success of antibody therapies in AD is limited by the blood brain barrier, which limits antibody entry into the brain from the systemic circulation. Recent studies have shown that adeno-associated virus serotype 9 (AAV9) effectively crosses the blood brain barrier. Here, we propose evaluating the use of AAV9 as a delivery system for a highly specific and potent inhibitory nanobody targeted against BACE1 as a treatment for AD.

150 000 €

Start date: 2016-12-01, End date: 2018-05-31

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

1 607 105 €

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

Recent technological advances in optical microscopy have vastly broadened the possibilities for applications in the biomedical sciences. Fluorescence microscopy is the central tool for investigation of molecular structures and dynamics that take place in the cellular and tissue environment. Coupled with progress in labeling methods, these microscopes permit observation of biological structures and processes with unprecedented sensitivity and resolution. This work has been enabled by the engineering development of diverse optical systems that provide different capabilities for the imaging toolkit. All such methods rely upon high fidelity optics to provide optimal resolution and efficiency, but they all suffer from aberrations caused by refractive index variations within the specimen. It is widely accepted that in many applications this fundamental problem prevents optimum operation and limits capability. Adaptive optics (AO) has been introduced to overcome these limitations by correcting aberrations and a range of demonstrations has shown clearly its potential. Indeed, it shows great promise to improve virtually all types of research or commercial microscopes, but significant challenges must still be met before AO can be widely implemented in routine imaging. Current advances are being made through development of bespoke AO solutions to individual imaging tasks. However, the diversity of microscopy methods means that individual solutions are often not translatable to other systems. This proposal is directed towards the creation of theoretical and practical frameworks that tie together AO concepts and provide a suite of scientific tools with broad application. This will be achieved through a systems approach that encompasses theoretical modelling, optical engineering and the requirements of biological applications. Additional outputs will include practical designs, operating protocols and software algorithms that will support next generation AO microscope systems.

3 234 789 €

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

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

2 192 500 €

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

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

In many situations experts act adequately, yet without deliberation. Architects e.g, immediately sense opportunities offered by the site of a new project. One could label these manifestations of expert intuition as ‘higher-level’ cognition, but still these experts act unreflectively. The aim of my project is to develop the Skilled Intentionality Framework (SIF), a new conceptual framework for the field of embodied/enactive cognitive science (Chemero, 2009; Thompson, 2007). I argue that affordances - possibilities for action provided by our surroundings - are highly significant in cases of unreflective and reflective ‘higher’ cognition. Skilled Intentionality is skilled coordination with multiple affordances simultaneously. The two central ideas behind this proposal are (a) that episodes of skilled ‘higher’ cognition can be understood as responsiveness to affordances for ‘higher’ cognition and (b) that our surroundings are highly resourceful and contribute to skillful action and cognition in a far more fundamental way than is generally acknowledged. I use embedded philosophical research in a particular practice of architecture to shed new light on the ways in which affordances for ‘higher’ cognition support creative imagination, anticipation, explicit planning and self-reflection. The Skilled Intentionality Framework is groundbreaking in relating findings established at several complementary levels of analysis: philosophy/phenomenology, ecological psychology, affective science and neurodynamics. Empirical findings thought to be exclusively valid for everyday unreflective action can now be used to explain skilled ‘higher’ cognition as well. Moreover, SIF brings both the context and the social back into cognitive science. I will show SIF’s relevance for Friston’s work on the anticipating brain, and apply it in the domain of architecture and public health. SIF will radically widen the scope of the increasingly influential field of embodied cognitive science.

1 499 850 €

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

This research will create a new theoretical vision of the importance of marriage as an agent of transformation in human sociality. Marriage globally is undergoing profound change, provoking intense debate and anxiety. These concerns refract wider instabilities in political, economic, and familial institutions. They signal the critical role of marriage in bringing together - and separating - intimate, personal, and familial life with wider state institutions. But we have little up to date comparative research or general theory of how marriage changes or the long-term significance of such change. Paradoxically, social scientific and public discourse emphasise the conservative and normative aspects of marriage. This underlines the need for a new theoretical frame that takes account of cultural and historical specificity to grasp the importance of marriage as both vehicle of and engine for transformation. AGATM overturns conventional understandings by viewing marriage as inherently transformative, indeed at the heart of social and cultural change. The research will investigate current transformations of marriage in two distinct senses. First, it will undertake an ethnographic investigation of new forms of marriage in selected sites in Europe, N. America, Asia, and Africa. Second, it will subject ‘marriage’ to a rigorous theoretical critique that will denaturalise marriage and reintegrate it into the new anthropology of kinship. Research on five complementary and contrastive sub-projects examining emerging forms of marriage in different locations will be structured through the themes of care, property, and ritual forms. The overarching analytic of temporality will frame the theoretical vision of the research and connect the themes. The resulting six monographs, journal articles, and exhibition will together revitalise the study of kinship by placing the moral, practical, political, and imaginative significance of marriage over time at its centre.

2 297 584 €

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

Which brain mechanisms are responsible for the faith of the memories we make with age, whether they wither or stay, and in what form? Episodic memory function does decline with age. While this decline can have multiple causes, research has focused almost entirely on encoding and retrieval processes, largely ignoring a third critical process– consolidation. The objective of AgeConsolidate is to provide this missing link, by combining novel experimental cognitive paradigms with neuroimaging in a longitudinal large-scale attempt to directly test how age-related changes in consolidation processes in the brain impact episodic memory decline. The ambitious aims of the present proposal are two-fold: (1) Use recent advances in memory consolidation theory to achieve an elaborate model of episodic memory deficits in aging (2) Use aging as a model to uncover how structural and functional brain changes affect episodic memory consolidation in general The novelty of the project lies in the synthesis of recent methodological advances and theoretical models for episodic memory consolidation to explain age-related decline, by employing a unique combination of a range of different techniques and approaches. This is ground-breaking, in that it aims at taking our understanding of the brain processes underlying episodic memory decline in aging to a new level, while at the same time advancing our theoretical understanding of how episodic memories are consolidated in the human brain. To obtain this outcome, I will test the main hypothesis of the project: Brain processes of episodic memory consolidation are less effective in older adults, and this can account for a significant portion of the episodic memory decline in aging. This will be answered by six secondary hypotheses, with 1-3 experiments or tasks designated to address each hypothesis, focusing on functional and structural MRI, positron emission tomography data and sleep experiments to target consolidation from different angles.

1 999 482 €

Start date: 2017-05-01, End date: 2022-04-30

Parameterized mathematical models have been central to the understanding and design of communication, networking, and radar systems. However, they often lack the ability to model intricate interactions innate in complex systems. On the other hand, data-driven approaches do not need explicit mathematical models for data generation and have a wider applicability at the cost of flexibility. These approaches need labelled data, representing all the facets of the system interaction with the environment. With the aforementioned systems becoming increasingly complex with intricate interactions and operating in dynamic environments, the number of system configurations can be rather large leading to paucity of labelled data. Thus there are emerging networks of systems of critical importance whose cognition is not effectively covered by traditional approaches. AGNOSTIC uses the process of exploration through system probing and exploitation of observed data in an iterative manner drawing upon traditional model-based approaches and data-driven discriminative learning to enhance functionality, performance, and robustness through the notion of active cognition. AGNOSTIC clearly departs from a passive assimilation of data and aims to formalize the exploitation/exploration framework in dynamic environments. The development of this framework in three applications areas is central to AGNOSTIC. The project aims to provide active cognition in radar to learn the environment and other active systems to ensure situational awareness and coexistence; to apply active probing in radio access networks to infer network behaviour towards spectrum sharing and self-configuration; and to learn and adapt to user demand for content distribution in caching networks, drastically improving network efficiency. Although these cognitive systems interact with the environment in very different ways, sufficient abstraction allows cross-fertilization of insights and approaches motivating their joint treatment.

2 499 595 €

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

Taking inspiration from natural carriers, such as viruses, a new technology has been developed in our laboratories part of an ongoing ERC starting grant project, Molecular Engineering of Virus-like Carriers (MEViC). We created synthetic viruses using polymers and thus safer materials. They are able of delivering high payload of specific drugs into cells with no detrimental effect. While testing for anticancer therapies, we identified a synthetic virus capable of targeting almost exclusively macrophages. We performed preliminary work showing that this can be successfully applied to deliver antibiotics to rid of intracellular pathogens. This has now open a completely new possibility whereas we can expand our technology for the treatment of several infections as well as to contribute to the ongoing efforts in tackling antibiotic resistance.

149 062 €

Start date: 2017-07-01, End date: 2018-12-31

This project will develop the principles required to enable bond-modifying redox catalysis based on aluminium by preparing and studying new Al(I) compounds capable of reversible oxidative addition. Catalytic processes are involved in the synthesis of 75 % of all industrially produced chemicals, but most catalysts involved are based on precious metals such as rhodium, palladium or platinum. These metals are expensive and their supply limited and unstable; there is a significant need to develop the chemistry of non-precious metals as alternatives. On toxicity and abundance alone, aluminium is an attractive candidate. Furthermore, recent work, including in our group, has demonstrated that Al(I) compounds can perform a key step in catalytic cycles - the oxidative addition of E-H bonds. In order to realise the significant potential of Al(I) for transition-metal style catalysis we urgently need to: - establish the principles governing oxidative addition and reductive elimination reactivity in aluminium systems. - know how the reactivity of Al(I) compounds can be controlled by varying properties of ligand frameworks. - understand the onward reactivity of oxidative addition products of Al(I) to enable applications in catalysis. In this project we will: - Study mechanisms of oxidative addition and reductive elimination of a range of synthetically relevant bonds at Al(I) centres, establishing the principles governing this fundamental reactivity. - Develop new ligand frameworks to support of Al(I) centres and evaluate the effect of the ligand on oxidative addition/reductive elimination at Al centres. - Investigate methods for Al-mediated functionalisation of organic compounds by exploring the reactivity of E-H oxidative addition products with unsaturated organic compounds.

1 493 679 €

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

Mathematical proofs have always been prone to error. Today, proofs can be hundreds of pages long and combine results from many specialisms, making them almost impossible to check. One solution is to deploy modern verification technology. Interactive theorem provers have demonstrated their potential as vehicles for formalising mathematics through achievements such as the verification of the Kepler Conjecture. Proofs done using such tools reach a high standard of correctness. However, existing theorem provers are unsuitable for mathematics. Their formal proofs are unreadable. They struggle to do simple tasks, such as evaluating limits. They lack much basic mathematics, and the material they do have is difficult to locate and apply. ALEXANDRIA will create a proof development environment attractive to working mathematicians, utilising the best technology available across computer science. Its focus will be the management and use of large-scale mathematical knowledge, both theorems and algorithms. The project will employ mathematicians to investigate the formalisation of mathematics in practice. Our already substantial formalised libraries will serve as the starting point. They will be extended and annotated to support sophisticated searches. Techniques will be borrowed from machine learning, information retrieval and natural language processing. Algorithms will be treated similarly: ALEXANDRIA will help users find and invoke the proof methods and algorithms appropriate for the task. ALEXANDRIA will provide (1) comprehensive formal mathematical libraries; (2) search within libraries, and the mining of libraries for proof patterns; (3) automated support for the construction of large formal proofs; (4) sound and practical computer algebra tools. ALEXANDRIA will be based on legible structured proofs. Formal proofs should be not mere code, but a machine-checkable form of communication between mathematicians.

2 430 140 €

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

Osteoarthritis (OA) is a common joint disease affecting over 40 million Europeans. Most common consequences of OA are pain, disability and social isolation. What is alarming, the number of patients will increase 50% in developed countries during the next 20 years. Moreover, the economic costs of OA are considerable since 1) direct healthcare (hospital admissions, medical examinations, drug therapy, etc.) and 2) productivity costs due to reduced performance while at work and absence from work have been estimated to be between 1% and 2.5% of the gross domestic product (GDP) in Western countries. We have developed an algorithm that is able to predict the progression of OA for overweight subjects while healthy subjects do not develop OA. When employed in clinical use, preventive and personalised treatments can be started before clinically significant symptoms are observed. This marks a major breakthrough in improving the life quality of OA patients and patients prone to OA. Our discovery will directly lead to longer working careers and lesser absence from work, and will result subsequently increased productivity. Moreover, the patients are expected to live longer due to reduced disability and social isolation. Moreover, the discovery provides economic long-term relief for the health care system, which is burdened by increasing geriatric population and stringent economic environment. With our tool, as an example, by eliminating 25% of medical examinations annually due to overweight or obesity in Finland (150.000 patients), we estimate to decrease annual direct costs by 140M€ and indirect costs by 185M€. In the PoC project we will carry out technical proof-of-concept and perform pre-commercialisation actions to shorten the time to market. The ultimate goal after the project is to develop our innovation towards a software product, aiding the OA diagnostics in hospitals and having commercialisation potential amongst medical device companies.

150 000 €

Start date: 2018-01-01, End date: 2019-06-30

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

2 500 000 €

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

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

1 222 329 €

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

In most European countries social insurance programs, like welfare, unemployment insurance and disability insurance are characterized by low reemployment rates. Therefore, governments spend huge amounts of money on active labour market programs, which should help individuals in finding work. Recent surveys indicate that programs which aim at intensifying job search behaviour are much more effective than schooling programs for improving human capital. A second conclusion from these surveys is that despite the size of the spendings on these programs, evidence on its effectiveness is limited. This research proposal aims at developing an economic framework that will be used to evaluate the effectiveness of popular programs like offering reemployment bonuses, fraud detection, workfare and job search monitoring. The main innovation is that I will combine economic theory with recently developed econometric techniques and detailed administrative data sets, which have not been explored before. While most of the literature only focuses on short-term outcomes, the available data allow me to also consider the long-term effectiveness of programs. The key advantage of an economic model is that I can compare the effectiveness of the different programs, consider modifications of programs and combinations of programs. Furthermore, using an economic model I can construct profiling measures to improve the targeting of programs to subsamples of the population. This is particularly relevant if the effectiveness of programs differs between individuals or depends on the moment in time the program is offered. Therefore, the results from this research will not only be of scientific interest, but will also be of great value to policymakers.

550 000 €

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

DNA repair pathways evolved as an intricate network that senses DNA damage and resolves it in order to minimise genetic lesions and thus preventing tumour formation. Gaining in recognition the last few years, the alternative end-joining (alt-EJ) DNA repair pathway was recently shown to be up-regulated and required for cancer cell viability in the absence of homologous recombination-mediated repair (HR). Despite this integral role, the alt-EJ repair pathway remains poorly characterised in humans. As such, its molecular composition, regulation and crosstalk with HR and other repair pathways remain elusive. Additionally, the contribution of the alt-EJ pathway to tumour progression as well as the identification of a mutational signature associated with the use of alt-EJ has not yet been investigated. Moreover, the clinical relevance of developing small-molecule inhibitors targeting players in the alt-EJ pathway, such as the polymerase Pol Theta (Polθ), is of importance as current anticancer drug treatments have shown limited effectiveness in achieving cancer remission in patients with HR-deficient (HRD) tumours. Here, we propose a novel, multidisciplinary approach that aims to characterise the players and mechanisms of action involved in the utilisation of alt-EJ in cancer. This understanding will better elucidate the changing interplay between different DNA repair pathways, thus shedding light on whether and how the use of alt-EJ contributes to the pathogenic history and survival of HRD tumours, eventually paving the way for the development of novel anticancer therapeutics. For all the abovementioned reasons, we are convinced this project will have important implications in: 1) elucidating critical interconnections between DNA repair pathways, 2) improving the basic understanding of the composition, regulation and function of the alt-EJ pathway, and 3) facilitating the development of new synthetic lethality-based chemotherapeutics for the treatment of HRD tumours.

1 498 750 €

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

This interdisciplinary project investigates the transformation of Shii Islam in the Middle East and Europe since the 1950s. The project examines the formation of modern Shii communal identities and the role Shii clerical authorities and their transnational networks have played in their religio-political mobilisation. The volatile situation post-Arab Spring, the rise of militant movements such as ISIS and the sectarianisation of geopolitical conflicts in the Middle East have intensified efforts to forge distinct Shii communal identities and to conceive Shii Muslims as part of an alternative umma (Islamic community). The project focusses on Iran, Iraq and significant but unexplored diasporic links to Syria, Kuwait and Britain. In response to the rise of modern nation-states in the Middle East, Shii clerical authorities resorted to a wide range of activities: (a) articulating intellectual responses to the ideologies underpinning modern Middle Eastern nation-states, (b) forming political parties and other platforms of socio-political activism and (c) using various forms of cultural production by systematising and promoting Shii ritual practices and utilising visual art, poetry and new media. The project yields a perspectival shift on the factors that led to Shii communal mobilisation by: - Analysing unacknowledged intellectual responses of Shii clerical authorities to the secular or sectarian ideologies of post-colonial nation-states and to the current sectarianisation of geopolitics in the Middle East. - Emphasising the central role of diasporic networks in the Middle East and Europe in mobilising Shii communities and in influencing discourses and agendas of clerical authorities based in Iraq and Iran. - Exploring new modes of cultural production in the form of a modern Shii aesthetics articulated in ritual practices, visual art, poetry and new media and thus creating a more holistic narrative on Shii religio-political mobilisation.

1 952 374 €

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

Alzheimer's disease, the most common cause of dementia in older people, is a devastating condition that is becoming a public health crisis as our population ages. Despite great progress recently in Alzheimer’s disease research, we have no disease modifying drugs and a decade with a 99.6% failure rate of clinical trials attempting to treat the disease. This project aims to develop relevant therapeutic targets to restore brain function in Alzheimer’s disease by integrating human and model studies of synapses. It is widely accepted in the field that alterations in amyloid beta initiate the disease process. However the cascade leading from changes in amyloid to widespread tau pathology and neurodegeneration remain unclear. Synapse loss is the strongest pathological correlate of dementia in Alzheimer’s, and mounting evidence suggests that synapse degeneration plays a key role in causing cognitive decline. Here I propose to test the hypothesis that the amyloid cascade begins at the synapse leading to tau pathology, synapse dysfunction and loss, and ultimately neural circuit collapse causing cognitive impairment. The team will use cutting-edge multiphoton and array tomography imaging techniques to test mechanisms downstream of amyloid beta at synapses, and determine whether intervening in the cascade allows recovery of synapse structure and function. Importantly, I will combine studies in robust models of familial Alzheimer’s disease with studies in postmortem human brain to confirm relevance of our mechanistic studies to human disease. Finally, human stem cell derived neurons will be used to test mechanisms and potential therapeutics in neurons expressing the human proteome. Together, these experiments are ground-breaking since they have the potential to further our understanding of how synapses are lost in Alzheimer’s disease and to identify targets for effective therapeutic intervention, which is a critical unmet need in today’s health care system.

2 000 000 €

Start date: 2016-11-01, End date: 2021-10-31

Compound semiconductor solar cells are providing the highest photovoltaic conversion efficiency, yet their performance lacks far behind the theoretical potential. This is a position we will challenge by engineering advanced III-V optoelectronics materials and heterostructures for better utilization of the solar spectrum, enabling efficiencies approaching practical limits. The work is strongly motivated by the global need for renewable energy sources. To this end, AMETIST framework is based on three vectors of excellence in: i) material science and epitaxial processes, ii) advanced solar cells exploiting nanophotonics concepts, and iii) new device fabrication technologies. Novel heterostructures (e.g. GaInNAsSb, GaNAsBi), providing absorption in a broad spectral range from 0.7 eV to 1.4 eV, will be synthesized and monolithically integrated in tandem cells with up to 8-junctions. Nanophotonic methods for light-trapping, spectral and spatial control of solar radiation will be developed to further enhance the absorption. To ensure a high long-term impact, the project will validate the use of state-of-the-art molecular-beam-epitaxy processes for fabrication of economically viable ultra-high efficiency solar cells. The ultimate efficiency target is to reach a level of 55%. This would enable to generate renewable/ecological/sustainable energy at a levelized production cost below ~7 ¢/kWh, comparable or cheaper than fossil fuels. The work will also bring a new breath of developments for more efficient space photovoltaic systems. AMETIST will leverage the leading position of the applicant in topical technology areas relevant for the project (i.e. epitaxy of III-N/Bi-V alloys and key achievements concerning GaInNAsSb-based tandem solar cells). Thus it renders a unique opportunity to capitalize on the group expertize and position Europe at the forefront in the global competition for demonstrating more efficient and economically viable photovoltaic technologies.

2 492 719 €

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

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

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

1 991 743 €

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

Our ability to predict adaptation and the response of populations to selection is limited. Solving this issue is a fundamental challenge of evolutionary ecology with implications for applied sciences such as conservation, and agronomy. Non genetic inheritance (NGI; e.g., ecological niche transmission) is suspected to play a foremost role in adaptive evolution but such hypothesis remains untested. Using quantitative genetics in wild plant populations, experimental evolution, and epigenetics, we will assess the role of NGI in the adaptive response to selection of plant populations. The ANGI project will follow the subsequent research program: (1) Using long-term survey data, we will measure natural selection in wild populations of Antirrhinum majus within its heterogeneous array of micro-habitats. We will calculate the fitness gain provided by multiple traits and stem elongation to plants growing in bushes where they compete for light. Stem elongation is known to depend on epigenetic variation. (2) Using a statistical approach that we developed, we will estimate the quantitative genetic and non genetic heritability of traits. (3) We will identify phenotypic changes caused by fitness that are based on genetic variation and NGI and assess their respective roles in adaptive evolution. (4) In controlled conditions, we will artificially select for increased stem elongation in clonal lineages, thereby excluding DNA variation. We will quantify the non genetic response to selection and test for a quantitative epigenetic signature of selection. (5) We will build on our results to generate an inclusive theory of genetic and non genetic natural selection. ANGI builds on a confirmed expertise in selection experiments, quantitative genetics and NGI. In addition, the availability of survey data provides a solid foundation for the achievement of this project. Our ambition is to shed light on original mechanisms underlying adaptation that are an alternative to genetic selection.

1 999 970 €

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

Many anti-angiogenic drugs are clinically used in several types of cancer to block angiogenesis, impair tumor growth, progression and dissemination. Nevertheless, clinical trials report emergence of resistance to treatment and a failure in long-lasting effects of these therapies. To date, resistant patients do not currently have any established, proven alternative therapeutic possibility and the medical field is moving towards a careful selection of subgroups or subtypes of patients that have to be treated with each one of the available second-line targeted drugs. For this relevant unmet medical need, many laboratories and pharmaceutical companies have focused on developing new biomarkers and new drugs to fight anti-angiogenic resistance, but up to date, there is no proven established biomarker or method to predict which patient’s tumor is resistant to antiangiogenic therapies and which drug is capable of blocking this resistance to therapy. AngioResist PoC aims at solving the existing patient selection gap in the treatment of cancer that is therapeutically resistant to antiangiogenic drugs. Based on data generated from our ERC project and two filed European Patent applications, AngioResist PoC will transform the acquired basic knowledge into an Innovation project, to validate a novel biomarker of response/resistance to antiangiogenics together with a new inhibitor for the treatment of these selected patients. The project will coordinately perform the preclinical phases of development of the drug compound and the biomarker, with the final aim of licensing them both to a selected partner during the clinical phases. Together with our licensee, we aim at the final distribution of a therapeutic drug that will be delivered with a biomarker kit for the selection and treatment of cancer patients resistant to antiangiogenic drugs.

149 932 €

Start date: 2016-09-01, End date: 2018-02-28

Vaccines and immunodiagnostics have been vital for public health and medicine, however a quantitative molecular understanding of vaccine-induced antibody responses is lacking. Antibody research is currently going through a big-data driven revolution, largely due to progress in next-generation sequencing (NGS) and bioinformatic analysis of antibody repertoires. A main advantage of high-throughput antibody repertoire analysis is that it provides a wealth of quantitative information not possible with other classical methods of antibody analysis (i.e., serum titers); this information includes: clonal distribution and diversity, somatic hypermutation patterns, and lineage tracing. In preliminary work my group has established standardized methods for antibody repertoire NGS, including an experimental-bioinformatic pipeline for error and bias correction that enables highly accurate repertoire sequencing and analysis. The overall goal of this proposal will be to apply high-throughput antibody repertoire analysis for quantitative vaccine profiling and discovery of next-generation immunodiagnostics. Using mouse subunit vaccination as our model system, we will answer for the first time, a fundamental biological question within the context of antibody responses - what is the link between genotype (antibody repertoire) and phenotype (serum antibodies)? We will expand upon this approach for improved rational vaccine design by quantitatively determining the impact of a comprehensive set of subunit vaccination parameters on complete antibody landscapes. Finally, we will develop advanced bioinformatic methods to discover immunodiagnostics based on antibody repertoire sequences. In summary, this proposal lays the foundation for fundamentally new approaches in the quantitative analysis of antibody responses, which long-term will promote the development of next-generation vaccines and immunodiagnostics.

1 492 586 €

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

Anxiety, a state of apprehension or fear, may provoke cognitive or behavioural disorders and eventually lead to serious medical illnesses. The high prevalence of anxiety disorders in our society sharply contrasts with the lack of clear factual knowledge about the corresponding brain mechanisms at the origin of this profound change in the appraisal of the environment. Little is known about how the psychopathological state of anxiety ultimately turns to a medical condition. The core of this proposal is to gain insight in the neural underpinnings of anxiety and disorders related to anxiety using modern human brain-imaging such as scalp EEG and fMRI. I propose to enlighten how anxiety transforms and shapes human cognition and what the neural correlates and time-course of this modulatory effect are. The primary innovation of this project is the systematic use scalp EEG and fMRI in human participants to better understand the neural mechanisms by which anxiety profoundly influences specific cognitive functions, in particular selective attention and decision-making. The goal of this proposal is to precisely determine the exact timing (using scalp EEG), location, size and extent (using fMRI) of anxiety-related modulations on selective attention and decision-making in the human brain. Here I propose to focus on these two specific processes, because they are likely to reveal selective effects of anxiety on human cognition and can thus serve as powerful models to better figure out how anxiety operates in the human brain. Another important aspect of this project is the fact I envision to help bridge the gap in Health Psychology between fundamental research and clinical practice by proposing alternative revalidation strategies for human adult subjects affected by anxiety-related disorders, which could directly exploit the neuro-scientific discoveries generated in this scientific project.

812 986 €

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

Cold atmospheric pressure plasmas (APP) have been reported to selectively kill cancer cells without damaging the surrounding tissues. Studies have been conducted on a variety of cancer types but to the best of our knowledge not on any kind of bone cancer. Treatment options for bone cancer include surgery, chemotherapy, etc. and may involve the use of bone grafting biomaterials to replace the surgically removed bone. APACHE brings a totally different and ground-breaking approach in the design of a novel therapy for bone cancer by taking advantage of the active species generated by APP in combination with biomaterials to deliver the active species locally in the diseased site. The feasibility of this approach is rooted in the evidence that the cellular effects of APP appear to strongly involve the suite of reactive species created by plasmas, which can be derived from a) direct treatment of the malignant cells by APP or b) indirect treatment of the liquid media by APP which is then put in contact with the cancer cells. In APACHE we aim to investigate the fundamentals involved in the lethal effects of cold plasmas on bone cancer cells, and to develop improved bone cancer therapies. To achieve this we will take advantage of the highly reactive species generated by APP in the liquid media, which we will use in an incremental strategy: i) to investigate the effects of APP treated liquid on bone cancer cells, ii) to evaluate the potential of combining APP treated liquid in a hydrogel vehicle with/wo CaP biomaterials and iii) to ascertain the potential three directional interactions between APP reactive species in liquid medium with biomaterials and with chemotherapeutic drugs. The methodological approach will involve an interdisciplinary team, dealing with plasma diagnostics in gas and liquid media; with cell biology and the effects of APP treated with bone tumor cells and its combination with biomaterials and/or with anticancer drugs.

1 499 887 €

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