ERC FUNDED PROJECTS

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: 2022-05-31

Quantum optics, the study of how discrete packets of light (photons) and matter interact, has led to the development of remarkable new technologies which exploit the bizarre properties of quantum mechanics. These quantum technologies are primed to revolutionize the fields of communication, information processing, and metrology in the coming years. Similar to contemporary technologies, the future quantum machinery will likely consist of a semiconductor platform to create and process the quantum information. However, to date the demanding requirements on a quantum photonic platform have yet to be satisfied with conventional bulk (three-dimensional) semiconductors. To surmount these well-known obstacles, a new paradigm in quantum photonics is required. Initiated by the recent discovery of single photon emitters in atomically flat (two-dimensional) semiconducting materials, 2DQP aims to be at the nucleus of a new approach by realizing quantum optics with ultra-stable (coherent) quantum states integrated into devices with electronic and photonic functionality. We will characterize, identify, engineer, and coherently manipulate localized quantum states in this two-dimensional quantum photonic platform. A vital component of 2DQP’s vision is to go beyond the fundamental science and achieve the ideal solid-state single photon device yielding perfect extraction - 100% efficiency - of on-demand indistinguishable single photons. Finally, we will exploit this ideal device to implement the critical building block for a photonic quantum computer.

1 999 135 €

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

Despite their amazing success, we believe that computer vision algorithms have only scratched the surface of what can be done in terms of modeling and understanding our world from images. We believe that novel image analysis techniques will be a major enabler and driving force behind next-generation technologies, enhancing everyday life and opening up radically new possibilities. And we believe that the key to achieving this is to develop algorithms for reconstructing and analyzing the 3D structure of our world. In this project, we will focus on three lines of research: A) We will develop algorithms for 3D reconstruction from standard color cameras and from RGB-D cameras. In particular, we will promote real-time-capable direct and dense methods. In contrast to the classical two-stage approach of sparse feature-point based motion estimation and subsequent dense reconstruction, these methods optimally exploit all color information to jointly estimate dense geometry and camera motion. B) We will develop algorithms for 3D shape analysis, including rigid and non-rigid matching, decomposition and interpretation of 3D shapes. We will focus on algorithms which are optimal or near-optimal. One of the major computational challenges lies in generalizing existing 2D shape analysis techniques to shapes in 3D and 4D (temporal evolutions of 3D shape). C) We will develop shape priors for 3D reconstruction. These can be learned from sample shapes or acquired during the reconstruction process. For example, when reconstructing a larger office algorithms may exploit the geometric self-similarity of the scene, storing a model of a chair and its multiple instances only once rather than multiple times. Advancing the state of the art in geometric reconstruction and geometric analysis will have a profound impact well beyond computer vision. We strongly believe that we have the necessary competence to pursue this project. Preliminary results have been well received by the community.

2 000 000 €

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

The realization of high-performance micro-supercapacitors is currently a big challenge but the ineluctable applications requiring such miniaturized energy storage devices are continuously emerging, from wearable electronic gadgets to wireless sensor networks. Although they store less energy than micro-batteries, micro-supercapacitors can be charged and discharged very rapidly and exhibit a quasi-unlimited lifetime. The global scientific research is consequently largely focused on the improvement of their capacitance and energetic performances. However, to date, they are still far from being able to power sensors or electronic components. Here I propose a 3D paradigm shift of micro-supercapacitor design to ensure increased energy storage capacities. Hydrous ruthenium dioxide (RuO2) is a pseudocapacitive material for supercapacitor electrode well-known for its high capacitance. A thin-film of ruthenium will be deposited by atomic layer deposition (ALD), followed by an electrochemical oxidation process, onto a high-surface-area 3D current collector prepared via an ingenious dynamic template built with hydrogen bubbles. The structural features of these 3D architectures will be controllably tailored by the processing methodologies. These electrodes will be combined with an innovative electrolyte in solid form (a protic ionogel) able to operate over an extended cell voltage. In a parallel investigation, we will develop a fundamental understanding of electrochemical reactions occurring at the nanoscale with a FIB-patterned (Focused Ion Beam) RuO2 nano-supercapacitor. The resulting 3D micro-supercapacitors should display extremely high power, long lifetime and – for the first time – energy densities competing or even exceeding that of micro-batteries. As a key achievement, prototypes will be designed using a new concept based on a self-adaptative micro-supercapacitors matrix, which arranges itself according to the global amount of energy stored.

1 673 438 €

Start date: 2018-04-01, End date: 2023-03-31

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

My vision is to establish, within the framework of an ERC CoG, a multidisciplinary group which will work in concert towards pioneering the integration of novel 2-Dimensional nanomaterials with novel additive fabrication techniques to develop a unique class of energy storage devices. Batteries and supercapacitors are two very complementary types of energy storage devices. Batteries store much higher energy densities; supercapacitors, on the other hand, hold one tenth of the electricity per unit of volume or weight as compared to batteries but can achieve much higher power densities. Technology is currently striving to improve the power density of batteries and the energy density of supercapacitors. To do so it is imperative to develop new materials, chemistries and manufacturing strategies. 3D2DPrint aims to develop micro-energy devices (both supercapacitors and batteries), technologies particularly relevant in the context of the emergent industry of micro-electro-mechanical systems and constantly downsized electronics. We plan to use novel two-dimensional (2D) nanomaterials obtained by liquid-phase exfoliation. This method offers a new, economic and easy way to prepare ink of a variety of 2D systems, allowing to produce wide device performance window through elegant and simple constituent control at the point of fabrication. 3D2DPrint will use our expertise and know-how to allow development of advanced AM methods to integrate dissimilar nanomaterial blends and/or “hybrids” into fully embedded 3D printed energy storage devices, with the ultimate objective to realise a range of products that contain the above described nanomaterials subcomponent devices, electrical connections and traditional micro-fabricated subcomponents (if needed) ideally using a single tool.

2 499 942 €

Start date: 2016-10-01, End date: 2021-09-30

"Bridging the fields of Computer Animation and Computational Fabrication, this proposal will establish the foundations for algorithmic design of physical structures that can generate lifelike movements. Driven by embedded actuators, these types of structures will enable an abundance of possibilities for a wide array of real-world technologies: animatronic characters whose organic motions will enhance their ability to awe, entertain and educate; soft robotic creatures that are both skilled and safe to be around; patient-specific prosthetics and wearable devices that match the soft touch of the human body, etc. Recent advances in additive manufacturing (AM) technologies are particularly exciting in this context, as they allow us to create designs of unparalleled geometric complexity using a constantly expanding range of materials. And if past developments are an indication, within the next decade we will be able to fabricate physical structures that approach, at least at the macro scale, the functional sophistication of their biological counterparts. However, while this unprecedented capability enables fascinating opportunities, it also leads to an explosion in the dimensionality of the space that must be explored during the design process. As AM technologies keep evolving, the gap between ""what we can produce"" and ""what we can design"" is therefore rapidly growing. To effectively leverage the extraordinary design possibilities enabled by AM, 3DPBio will develop the computational and mathematical foundations required to study a fundamental scientific question: how are physical deformations, mechanical movements and overall functional capabilities governed by geometric shape features, material compositions and the design of compliant actuation systems? By enabling computers to reason about this question, our work will establish new ways to algorithmically create digital designs that can be turned into mechanical lifeforms at the push of a button."

2 000 000 €

Start date: 2020-02-01, End date: 2025-01-31

How does the inside of the proton look like? What generates its spin?
3DSPIN will deliver essential information to answer these questions at the frontier of subnuclear physics. At present, we have detailed maps of the distribution of quarks and gluons in the nucleon in 1D (as a function of their momentum in a single direction). We also know that quark spins account for only about 1/3 of the spin of the nucleon. 3DSPIN will lead the way into a new stage of nucleon mapping, explore the distribution of quarks in full 3D momentum space and obtain unprecedented information on orbital angular momentum. Goals 1. extract from experimental data the 3D distribution of quarks (in momentum space), as described by Transverse-Momentum Distributions (TMDs); 2. obtain from TMDs information on quark Orbital Angular Momentum (OAM). Methodology 3DSPIN will implement state-of-the-art fitting procedures to analyze relevant experimental data and extract quark TMDs, similarly to global fits of standard parton distribution functions. Information about quark angular momentum will be obtained through assumptions based on theoretical considerations. The next five years represent an ideal time window to accomplish our goals, thanks to the wealth of expected data from deep-inelastic scattering experiments (COMPASS, Jefferson Lab), hadronic colliders (Fermilab, BNL, LHC), and electron-positron colliders (BELLE, BABAR). The PI has a strong reputation in this field. The group will operate in partnership with the Italian National Institute of Nuclear Physics and in close interaction with leading experts and experimental collaborations worldwide. Impact Mapping the 3D structure of chemical compounds has revolutionized chemistry. Similarly, mapping the 3D structure of the nucleon will have a deep impact on our understanding of the fundamental constituents of matter. We will open new perspectives on the dynamics of quarks and gluons and sharpen our view of high-energy processes involving nucleons.

1 509 000 €

Start date: 2015-07-01, End date: 2020-12-31

Goal of the 4DPHOTON project is the development and construction of a photon imaging detector with unprecedented performance. The proposed device will be capable of detecting fluxes of single-photons up to one billion photons per second, over areas of several square centimetres, and will measure - for each photon - position and time simultaneously with resolutions better than ten microns and few tens of picoseconds, respectively. These figures of merit will open many important applications allowing significant advances in particle physics, life sciences or other emerging fields where excellent timing and position resolutions are simultaneously required. Our goal will be achieved thanks to the use of an application-specific integrated circuit in 65 nm complementary metal-oxide-semiconductor (CMOS) technology, that will deliver a timing resolution of few tens of picoseconds at the pixel level, over few hundred thousand individually-active pixel channels, allowing very high rates of photons to be detected, and the corresponding information digitized and transferred to a processing unit. As a result of the 4DPHOTON project we will remove the constraints that many light imaging applications have due to the lack of precise single-photon information on four dimensions (4D): the three spatial coordinates and time simultaneously. In particular, we will prove the performance of this detector in the field of particle physics, performing the reconstruction of Cherenkov photon rings with a timing resolution of ten picoseconds. With its excellent granularity, timing resolution, rate capability and compactness, this detector will represent a new paradigm for the realisation of future Ring Imaging Cherenkov detectors, capable of achieving high efficiency particle identification in environments with very high particle multiplicities, exploiting time-association of the photon hits.

1 975 000 €

Start date: 2019-12-01, End date: 2024-11-30

This project aims at a better understanding of the philosophical richness of ninth century thought using the unprecedented and highly innovative method of the synchronic approach. The hypothesis directing this synchronic approach is that studying together in parallel the four main philosophical traditions of the century – i.e. Latin, Greek, Syriac and Arabic – will bring results that the traditional enquiry limited to one tradition alone can never reach. This implies pioneering a new methodology to overcome the compartmentalization of research which prevails nowadays. Using this method is only possible because the four conditions of applicability – comparable intellectual environment, common text corpus, similar methodological perspective, commensurable problems – are fulfilled. The ninth century, a time of cultural renewal in the Carolingian, Byzantine and Abbasid empires, possesses the remarkable characteristic – which ensures commensurability – that the same texts, namely the writings of Aristotelian logic (mainly Porphyry’s Isagoge and Aristotle’s Categories) were read and commented upon in Latin, Greek, Syriac and Arabic alike. Logic is fundamental to philosophical enquiry. The contested question is the human capacity to rationalise, analyse and describe the sensible reality, to understand the ontological structure of the world, and to define the types of entities which exist. The use of this unprecedented synchronic approach will allow us a deeper understanding of the positions, a clear identification of the a priori postulates of the philosophical debates, and a critical evaluation of the arguments used. It provides a unique opportunity to compare the different traditions and highlight the heritage which is common, to stress the specificities of each tradition when tackling philosophical issues and to discover the doctrinal results triggered by their mutual interactions, be they constructive (scholarly exchanges) or polemic (religious controversies).

1 998 566 €

Start date: 2015-09-01, End date: 2021-02-28

In todays advanced technological world, we can track the exact movement of individuals, analyse their genetic makeup and predict predisposition to certain diseases. However, we are unable to accurately assess an individual’s dietary intake. This is without a doubt one of the main stumbling blocks in assessing the link between diet and disease/health. The present proposal (A-DIET) will address this issue with the overarching objective to develop novel strategies for assessment of dietary intake. Using approaches to (1) identify biomarkers of specific foods (2) classify people into dietary patterns (nutritypes) and (3) develop a tool for integration of dietary and biomarker data, A-DIET has the potential to dramatically enhance our ability to accurately assess dietary intake. The ultimate output from A-DIET will be a dietary assessment tool which can be used to obtain an accurate assessment of dietary intake by combining dietary and biomarker data which in turn will allow investigations into relationships between diet, health and disease. New biomarkers of specific foods will be identified and validated using intervention studies and metabolomic analyses. Methods will be developed to classify individuals into dietary patterns based on biomarker/metabolomic profiles thus demonstrating the novel concept of nutritypes. Strategies for integration of dietary and biomarker data will be developed and translated into a tool that will be made available to the wider scientific community. Advances made in A-DIET will enable nutrition epidemiologist’s to properly examine the relationship between diet and disease and develop clear public health messages with regard to diet and health. Additionally results from A-DIET will allow researchers to accurately assess people’s diet and implement health promotion strategies and enable dieticians in a clinical environment to assess compliance to therapeutic diets such as adherence to a high fibre diet or a gluten free diet.

1 995 548 €

Start date: 2015-08-01, End date: 2020-07-31

"I propose an ambitious, yet feasible 5-year research project that will fill an important gap in global health. Specifically, I will develop and validate novel approaches for anthelmintic drug discovery and development. My proposal pursues the following five research questions: (i) Is a chip calorimeter suitable for high-throughput screening in anthelmintic drug discovery? (ii) Is combination chemotherapy safe and more efficacious than monotherapy against strongyloidiasis and trichuriasis? (iii) What are the key pharmacokinetic parameters of praziquantel in preschool-aged children and school-aged children infected with Schistosoma mansoni and S. haematobium using a novel and validated technology based on dried blood spotting? (iv) What are the metabolic consequences and clearance of praziquantel treatment in S. mansoni-infected mice and S. mansoni- and S. haematobium-infected children? (v) Which is the ideal compartment to study pharmacokinetic parameters for intestinal nematode infections and does age, nutrition, co-infection and infection intensity influence the efficacy of anthelmintic drugs? My proposed research is of considerable public health relevance since it will ultimately result in improved treatments for soil-transmitted helminthiasis and pediatric schistosomiasis. Additionally, at the end of this project, I have generated comprehensive information on drug disposition of anthelmintics. A comprehensive database of metabolite profiles following praziquantel treatment will be available. Finally, the proof-of-concept of chip calorimetry in anthelmintic drug discovery has been established and broadly validated."

1 927 350 €

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

In order to tackle some of the prime societal challenges of this century, science has to urgently provide effective tools addressing the redesign of chemical value chains through the exploitation of novel, bio-based raw materials, and the discovery and implementation of more resource-efficient production platforms. Nature will inevitably play a pivotal role in the imminent transformation of industrial strategies, and the recent bioeconomy approaches can only be regarded as initial step towards a sustainable future. Operating at the interface between chemistry and life sciences, my ABIONYS will fundamentally challenge the widely held distinction separating chemical from biosynthesis, and will deliver the first proof-of-concept where abiotic reactions act as productive puzzle pieces in biosynthetic arrangements. On the basis of our previous ground-breaking discoveries on artificial enzyme functions, I will create a significantly extended toolbox of biocatalysis modules by applying protein-based interpretations of synthetically crucial but non-natural reactions i.e. transformations that are in no way biosynthetically encoded in living organisms. My research will exploit these tools in multi-enzyme cascades for the preparation of complex organic target structures, not only to highlight the great synthetic potential of these approaches, but also to lay the groundwork for in vivo implementations. Eventually, the knowledge gathered from enzyme discovery and cascade design will enable to create an unprecedented class of bioproduction systems, where the genetic incorporation of artificial enzyme functions into recombinant microbial host organisms will yield tailor-made cellular factories. Combining classical organic synthesis strategies with the power of modern biotechnology, ABIONYS is going to transform the way we synthesize complex and functional building blocks by allowing us to encode organic chemistry thinking into living production platforms.

1 995 707 €

Start date: 2020-11-01, End date: 2025-10-31

Due to antibiotic resistance, there is now great interest in the development of antibody-based therapies against bacterial infections, for instance via antibodies that boost the host immune system. In order to kill bacteria, antibodies should trigger activation of the complement cascade, which forms bactericidal Membrane Attack Complex (MAC) pores and strongly enhances phagocytosis. Although the power of complement could be exploited for antibody therapies, such developments are hampered by our limited insights into the mechanisms underlying antibody-dependent complement activation on bacteria. My team has developed unique assays to study complement activation on bacteria. In this proposal, we will combine our function-driven approaches with novel B cell sequencing methods to identify anti-bacterial antibodies with strong complement-activating potential. We will develop novel approaches to identify the variable (VH:VL) sequences of human antibodies that recognize whole bacterial cells. After FACS sorting of memory B cells or yeast Fab display, we will use multi-well functional assays to select monoclonal antibodies driving potent complement activation and subsequent killing of E. coli (via neutrophils or MAC). Thanks to our unique tools and unprecedented insights, we are in an unique position to decipher basic mechanisms by which antibodies induce bacterial killing via neutrophils or MAC. We will combine live-cell imaging and structural approaches to determine how bactericidal antibodies assemble lethal MAC pores in the bacterial cell envelope. Finally, we will explore the design of potent antibody combinations and study the mechanisms by which antibodies steer different effector functions, both in the context of clinical and non-pathogenic E. coli strains. Altogether, this grant will lead to fundamental knowledge about the functioning of the immune system and provide a biological basis for the development of antibody-based therapies against bacteria.

2 000 000 €

Start date: 2021-06-01, End date: 2026-05-31

A central problem in developmental biology is to understand how tissues are patterned in time and space - how do identical cells differentiate to form the adult body plan? Patterns often arise from prior asymmetries in developing embryos, but there is also increasing evidence for self-organizing mechanisms that can break the symmetry of an initially homogeneous cell population. These patterning processes are mediated by a small number of signaling molecules, including the TGF-β superfamily members BMP and Nodal. While we have begun to analyze how biophysical properties such as signal diffusion and stability contribute to axis formation and tissue allocation during vertebrate embryogenesis, three key questions remain. First, how does signaling cross-talk control robust patterning in developing tissues? Opposing sources of Nodal and BMP are sufficient to produce secondary zebrafish axes, but it is unclear how the signals interact to orchestrate this mysterious process. Second, how do signaling systems self-organize to pattern tissues in the absence of prior asymmetries? Recent evidence indicates that axis formation in mammalian embryos is independent of maternal and extra-embryonic tissues, but the mechanism underlying this self-organized patterning is unknown. Third, what are the minimal requirements to engineer synthetic self-organizing systems? Our theoretical analyses suggest that self-organizing reaction-diffusion systems are more common and robust than previously thought, but this has so far not been experimentally demonstrated. We will address these questions in zebrafish embryos, mouse embryonic stem cells, and bacterial colonies using a combination of quantitative imaging, optogenetics, mathematical modeling, and synthetic biology. In addition to providing insights into signaling and development, this high-risk/high-gain approach opens exciting new strategies for tissue engineering by providing asymmetric or temporally regulated signaling in organ precursors.

1 997 750 €

Start date: 2020-07-01, End date: 2025-06-30

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

"Children learn any language that they grow up with, adapting to any of the ca. 7000 languages of the world, no matter how divergent or complex their structures are. What cognitive processes make this extreme flexibility possible? This is one of the most burning questions in cognitive science and the ACQDIV project aims at answering it by testing and refining the following leading hypothesis: Language acquisition is flexible and adaptive to any kind of language because it relies on a small set of universal cognitive processes that variably target different structures at different times during acquisition in every language. The project aims at establishing the precise set of processes and at determining the conditions of variation across maximally diverse languages. This project focuses on three processes: (i) distributional learning, (ii) generalization-based learning and (iii) interaction-based learning. To investigate these processes I will work with a sample of five clusters of languages including longitudinal data of two languages each. The clusters were determined by a clustering algorithm seeking the structurally most divergent languages in a typological database. The languages are: Cluster 1: Slavey and Cree, Cluster 2: Indonesian and Yucatec, Cluster 3: Inuktitut and Chintang, Cluster 4: Sesotho and Russian, Cluster 5: Japanese and Turkish. For all languages, corpora are available, except for Slavey where fieldwork is planned. The leading hypothesis will be tested against the acquisition of aspect and negation in each language of the sample and also against the two structures in each language that are most salient and challenging in them (e. g. complex morphology in Chintang). The acquisition processes also depend on statistical patterns in the input children receive. I will examine these patterns across the sample with respect to repetitiveness effects, applying data-mining methods and systematically comparing child-directed and child-surrounding speech."

1 998 438 €

Start date: 2014-09-01, End date: 2019-08-31

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

2 349 603 €

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

The two biggest challenges in solving practical optimization problems are computational intractability, and the presence of uncertainty: most problems are either NP-hard, or have incomplete input data which makes an exact computation impossible. Recently, there has been a huge progress in our understanding of intractability, based on spectacular algorithmic and lower bound techniques. For several problems, especially those with only local constraints, we can design optimum approximation algorithms that are provably the best possible. However, typical optimization problems usually involve complex global constraints and are much less understood. The situation is even worse for coping with uncertainty. Most of the algorithms are based on ad-hoc techniques and there is no deeper understanding of what makes various problems easy or hard. This proposal describes several new directions, together with concrete intermediate goals, that will break important new ground in the theory of approximation and online algorithms. The particular directions we consider are (i) extend the primal dual method to systematically design online algorithms, (ii) build a structural theory of online problems based on work functions, (iii) develop new tools to use the power of strong convex relaxations and (iv) design new algorithmic approaches based on non-constructive proof techniques. The proposed research is at the cutting edge of algorithm design, and builds upon the recent success of the PI in resolving several longstanding questions in these areas. Any progress is likely to be a significant contribution to theoretical computer science and combinatorial optimization.

1 519 285 €

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

Previous efforts to raise living standards have been based on relentlessly increasing combustion, causing environmental destruction at all scales. In addition to climate-warming CO2, fossil fuel combustion also produces a large number of organic compounds and particulate matter, which deteriorate air quality. The atmosphere is cleansed from such pollutants by gas-phase oxidation reactions, which are invariably mediated by peroxy radicals (RO2). Oxidation transforms initially volatile and water-insoluble hydrocarbons into water-soluble forms (ultimately CO2), enabling scavenging by liquid droplets. A minor but crucially important alternative oxidation pathway leads to oxidative molecular growth, and formation of atmospheric aerosols. Aerosols impart a huge influence on the atmosphere, from local air quality issues to global climate forcing, yet their formation mechanisms and structures of organic aerosol precursors remains elusive. In a paradigm change, RO2 was recently found to undergo autoxidation, enabling rapid aerosol precursor formation even at sub-second time-scales – in stark contrast to the long processing times (days - weeks) previously assumed to be necessary. We have shown how abundant biogenic hydrocarbons (BVOC) autoxidize, but due to key structural differences, the same pathways are not available for anthropogenic hydrocarbons (AVOC), and thus they were not expected to autoxidize. My preliminary experiments reveal that AVOCs do autoxidize, but the mechanism enabling this remain unknown. Crucially, the co-reactants shown to inhibit BVOC seem to enforce AVOC autoxidation – potentially explaining the recent mysterious discovery of new-particle formation in polluted megacities. In ADAPT, I will use a combination of novel mass spectrometric detection methods fortified by theoretical calculations, to solve the mechanism of AVOC autoxidation. This will directly assist both air quality management, and the design of cleaner fuels and engines.

2 689 147 €

Start date: 2021-02-01, End date: 2026-01-31

Today, our daily diet typically contains dozens of food additives (e.g. colours, emulsifiers, sweeteners: ~350 substances allowed on the EU market). Safety assessment is performed by health agencies to protect consumers against potential adverse effects of each additive, yet such an assessment is only based on current available evidence, i.e., for most additives, only in-vitro/in-vivo toxicological studies and exposure simulations. Meanwhile, the long-term health impact of additives intake and any potential ‘cocktail’ effects remain largely unknown and have become a source of serious concern. Growing evidence link the consumption of ultra-processed foods, containing numerous additives, to adverse health outcomes, in particular our recent results on cancer (Fiolet BMJ 2018). While most additives allowed in the EU are likely to be neutral for health and some may even be beneficial, recent animal and cell-based studies have suggested detrimental effects of several such compounds. In humans, data is lacking. No epidemiological study has ever assessed individual-level exposure to a wide range of food additives and its association with health, hampered by unsuited traditional dietary assessment tools facing the high additive content variability across commercial brands. Hence, a major breakthrough will come from the novel and unique tools I developed with my team, notably within the NutriNet-Santé cohort (n=164,000), collecting precise and repeated data on foods and beverages usually consumed, including names and brands of industrial products. With this unique resource, I propose a project at the forefront of international research to provide answers to a question of major importance for public health. Built as a combination of epidemiological studies and in-vitro/in-vivo experiments, this project will shed light on individual exposure to food additive 'cocktails' in relation to obesity, cancer, cardiovascular diseases and mortality, while depicting underlying mechanisms.

2 000 000 €

Start date: 2020-05-01, End date: 2025-04-30

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

2 000 000 €

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

Communication networks have become a critical infrastructure of our digital society. However, with the explosive growth of data-centric applications and the resulting increasing workloads headed for the world’s datacenter networks, today’s static and demand-oblivious network architectures are reaching their capacity limits. The AdjustNet project proposes a radically different perspective, envisioning demand-aware networks which can dynamically adapt their topology to the workload they currently serve. Such self-adjusting networks hence allow to exploit structure in the demand, and thereby reach higher levels of efficiency and performance. The vision of AdjustNet is timely and enabled by recent innovations in optical technologies which allow to flexibly reconfigure the physical network topology. The goal of AdjustNet is to lay the theoretical foundations for self-adjusting networks. We will identify metrics that serve as yardstick of what can and cannot be achieved in a self-adjusting network for a given demand, devise algorithms for online adaption, and validate our framework through case studies. Our novel methodology is motivated by an intriguing connection of self-adjusting networks to known datastructures and to information theory. AdjustNet comes with significant challenges since, similar to self-driving cars, self-adjusting networks require human network operators to give away control, and since more autonomous network operations may lead to instabilities. AdjustNet will overcome these risks and achieve its objectives by pursuing a rigorous approach, devising a theoretical well-founded framework for self-adjusting networks which come with provable guarantees and incorporate self–protection mechanisms. The PI is well-equipped for this project and recently obtained first promising results. As the community is currently re-architecting communication networks, there is a unique opportunity to bridge the gap between theory and practice, and have impact.

1 670 823 €

Start date: 2020-03-01, End date: 2025-02-28

"The proposed research program has three main objectives. The first and second objectives are to seek extreme precisions in optical atomic spectroscopy and optical clocks, and to use this quest as a mean of exploration in atomic physics. The third objective is to explore new possibilities that stem from extreme precision. These goals will be pursued via three complementary activities: #1: Search for extreme precisions with an Hg optical lattice clock. #2: Explore and exploit the rich Hg system, which is essentially unexplored in the cold and ultra-cold regime. #3: Identify new applications of clocks with extreme precision to Earth science. Clocks can measure directly the gravitational potential via Einstein’s gravitational redshift, leading to the idea of “clock-based geodesy”. The 2 first activities are experimental and build on an existing setup, where we demonstrated the feasibility of an Hg optical lattice clock. Hg is chosen for its potential to surpass competing systems. We will investigate the unexplored physics of the Hg clock. This includes interactions between Hg atoms, lattice-induced light shifts, and sensitivity to external fields which are specific to the atomic species. Beyond, we will explore the fundamental limits of the optical lattice scheme. We will exploit other remarkable features of Hg associated to the high atomic number and the diversity of stable isotopes. These features enable tests of fundamental physical laws, ultra-precise measurements of isotope shifts, measurement of collisional properties toward evaporative cooling and quantum gases of Hg, investigation of forbidden transitions promising for measuring the nuclear anapole moment of Hg. The third activity is theoretical and is aimed at initiating collaborations with experts in modelling Earth gravity. With this expertise, we will identify the most promising and realistic approaches for clocks and emerging remote comparison methods to contribute to geodesy, hydrology, oceanography, etc."

1 946 432 €

Start date: 2014-04-01, End date: 2019-03-31

Digital technology has fundamentally changed the action repertoire of political campaigning and advocacy in the last decade. Despite its fundamental role in contemporary political strategy and potential to affect the quality of democracy, there is still little systematic evidence to assess and compare the real effects of online and offline advocacy tools. ADVODID will implement the first large-scale quantitative project designed to provide rich correlational and causal evidence on the effects of advocacy on citizens and policymakers, in both online and offline settings. It sets out to address - theoretically and empirically - the potentials and challenges for modern democracies that arise from digital advocacy tools. Its novelty lies in analyzing the use, impact and democratic consequences of digital advocacy strategies by assessing interactions of advocacy groups with both citizens and political representatives in a diverse set of eight countries (Australia, Chile, Denmark, India, the Netherlands, Spain, the UK, and the US). ADVODID will collect data on the advocacy agenda and strategy use of at least 400 carefully sampled advocates in these countries, and will assess agenda congruence with political and public agendas, and their dynamic development over time. Correlational analyses of different measures of advocacy success will be complemented by field experiments in cooperation with advocates in two countries, to supply causal evidence on how advocacy affects the positions and actions of policymakers and citizens. The project’s rich datasets will be used to assess and refine theories of democratic representation and the role of digital advocacy across different types of policy issues. ADVODID will greatly advance understanding of how modern advocacy impacts its target audiences and potentially changes participatory democracy. Its findings will have interdisciplinary and social relevance and inform ways to strengthen representative democracy in an online age.

1 986 922 €

Start date: 2021-08-01, End date: 2026-07-31

Densities in neutron star (NS) cores can reach up to ten times the density of a normal atomic nucleus, and the stabilising effect of gravitational confinement permits long-timescale weak interactions. This generates nucleonic matter that is extremely neutron-rich, and the exciting possibility of stable states of strange matter (hyperons or deconfined quarks). Our uncertainty about the nature of cold ultradense matter is encoded in the Equation of State (EOS), which can be mapped via the stellar structure equations to quantities like mass M and radius R that determine the exterior space-time. One very promising technique for measuring the EOS exploits hotspots that form on the NS surface due to the pulsar mechanism, accretion streams, or during thermonuclear explosions in the stellar ocean. As the NS rotates, the hotspot gives rise to a pulsation and relativistic effects encode information about the EOS into the pulse profile. Pulse Profile Modelling (PPM), which employs relativistic ray-tracing and Bayesian inference codes to measure M-R and the EOS, is being pioneered by NASA’s NICER telescope, which is poised to deliver its first results in 2019. Complexities, that have only become apparent with exposure to real data, mean that there is work to be done if we are to have confidence in the nominal 5-10% accuracy of NICER’s M-R results. AEONS will deliver this. The project will also look ahead to the next generation of large-area X-ray timing telescopes, since it is only then that PPM will place tight constraints on dense matter models. The sources these missions target, accreting neutron stars, pose challenges for PPM such as variability, surface pattern uncertainty, and polarimetric signatures. AEONS will develop a robust pipeline for accreting NS PPM and embed it in a multi-messenger EOS inference framework with radio and gravitational wave constraints. This will ensure that PPM delivers major advances in our understanding of the nature of matter.

2 425 000 €

Start date: 2020-06-01, End date: 2025-05-31

Gas turbines are an essential ingredient in the long-term energy and aviation mix. They are flexible, offer fast start-up and the ability to burn renewable-generated fuels. However, they generate NOx emissions, which cause air pollution and damage human health, and reducing these is an air quality imperative. A major hurdle to this is that lean premixed combustion, essential for further NOx emission reductions, is highly susceptible to thermoacoustic instability. This is caused by a two-way coupling between unsteady combustion and acoustic waves, and the resulting large pressure oscillations can cause severe mechanical damage. Computational methods for predicting thermoacoustic instability, fast and accurate enough to be used as part of the industrial design process, are urgently needed. The only computational methods with the prospect of being fast enough are those based on coupled treatment of the acoustic waves and unsteady combustion. These exploit the amenity of the acoustic waves to analytical modelling, allowing costly simulations to be directed only at the more complex flame. They show real promise: my group recently demonstrated the first accurate coupled predictions for lab-scale combustors. The method does not yet extend to industrial combustors, the more complex flow-fields in these rendering current acoustic models overly-simplistic. I propose to comprehensively overhaul acoustic models across the entirety of the combustor, accounting for real and important acoustic-flow interactions. These new models will offer the breakthrough prospect of extending efficient, accurate predictive capability to industrial combustors, which has a real chance of facilitating future, instability free, very low NOx gas turbines.

1 985 288 €

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

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

Understanding how proteins respond to mutations is of paramount importance to biology and disease. While protein stability and misfolding have been instrumental in rationalizing the impact of mutations, we recently discovered that an alternative route is also frequent, where mutations at the surface of symmetric proteins trigger novel self-interactions that lead to infinite self-assembly. This mechanism can be involved in disease, as in sickle-cell anemia, but may also serve in adaptation. Importantly, it differs fundamentally from aggregation, because misfolding does not drive it. Thus, we term it “agglomeration”. The ease with which agglomeration can occur, even by single point mutations, shifts the paradigm of how quickly new protein assemblies can emerge, both in health and disease. This prompts us to determine the basic principles of protein agglomeration and explore its implications in cell physiology and human disease. We propose an interdisciplinary research program bridging atomic and cellular scales to explore agglomeration in three aims: (i) Map the landscape of protein agglomeration in response to mutation in endogenous yeast proteins; (ii) Characterize how yeast physiology impacts agglomeration by changes in gene expression or cell state, and, conversely, how protein agglomerates impact yeast fitness. (iii) Analyze agglomeration in relation to human disease via two approaches. First, by predicting single nucleotide polymorphisms that trigger agglomeration, prioritizing them using knowledge from Aims 1 & 2, and characterizing them experimentally. Second, by providing a proof-of-concept that agglomeration can be exploited in drug design, whereby drugs induce its formation, like mutations can do. Overall, through this research, we aim to establish agglomeration as a paradigm for protein assembly, with implications for our understanding of evolution, physiology, and disease.

2 574 819 €

Start date: 2019-04-01, End date: 2024-09-30

The goal of the AI4REASON project is a breakthrough in what is considered a very hard problem in AI and automation of reasoning, namely the problem of automatically proving theorems in large and complex theories. Such complex formal theories arise in projects aimed at verification of today's advanced mathematics such as the Formal Proof of the Kepler Conjecture (Flyspeck), verification of software and hardware designs such as the seL4 operating system kernel, and verification of other advanced systems and technologies on which today's information society critically depends. It seems extremely complex and unlikely to design an explicitly programmed solution to the problem. However, we have recently demonstrated that the performance of existing approaches can be multiplied by data-driven AI methods that learn reasoning guidance from large proof corpora. The breakthrough will be achieved by developing such novel AI methods. First, we will devise suitable Automated Reasoning and Machine Learning methods that learn reasoning knowledge and steer the reasoning processes at various levels of granularity. Second, we will combine them into autonomous self-improving AI systems that interleave deduction and learning in positive feedback loops. Third, we will develop approaches that aggregate reasoning knowledge across many formal, semi-formal and informal corpora and deploy the methods as strong automation services for the formal proof community. The expected outcome is our ability to prove automatically at least 50% more theorems in high-assurance projects such as Flyspeck and seL4, bringing a major breakthrough in formal reasoning and verification. As an AI effort, the project offers a unique path to large-scale semantic AI. The formal corpora concentrate centuries of deep human thinking in a computer-understandable form on which deductive and inductive AI can be combined and co-evolved, providing new insights into how humans do mathematics and science.

1 499 500 €

Start date: 2015-09-01, End date: 2020-10-31

The Type 6 secretion system (T6SS) allows Gram-negative bacteria to deliver toxins into both eukaryotic and bacterial target cells and thus cause disease or kill competitors. T6SS is composed of four main parts: a membrane complex, a baseplate and a long spring-like sheath wrapped around an inner tube. Sheath contraction generates a large amount of energy to push the tube with associated toxins through the baseplate and membrane complex out of the cell. However, the reach of the T6SS tube is limited and thus a direct contact with the target membrane and precise positioning of T6SS assembly is required for protein translocation. In this proposal, we will unravel principles of spatial and temporal coordination of T6SS assembly that we have recently observed in several bacterial species. We will study how cells sense attacks from neighboring bacteria to dynamically localize its T6SS. We will describe how bacteria initiate and position T6SS assembly in response to physical cell-cell interactions. We will identify the principles and the role of T6SS localization in intracellular pathogens. Using genetic and biochemical approaches, we will identify and characterize proteins interacting with the core components of T6SS and test their role in initiation and positioning of T6SS assembly. We will search for peptidoglycan remodeling enzymes required for T6SS assembly. We will use advanced microscopy techniques to describe dynamic localization of proteins upon T6SS activation to establish the order of their assembly. We will quantify how much T6SS aiming increases efficiency of protein delivery and T6SS function during bacterial competition and pathogenesis. Overall, we will unravel novel principles of spatial and temporal control of localization of protein complexes and show how this allows bacteria to quickly respond to external cues and interact with their environment.

2 493 650 €

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

"The AlchemEast project is devoted to the study of alchemical theory and practice as it appeared and developed in distinct, albeit contiguous (both chronologically and geographically) areas: Graeco-Roman Egypt, Byzantium, and the Near East, from Ancient Babylonian times to the early Islamic Period. This project combines innovative textual investigations with experimental replications of ancient alchemical procedures. It uses sets of historically and philologically informed laboratory replications in order to reconstruct the actual practice of ancient alchemists, and it studies the texts and literary forms in which this practice was conceptualized and transmitted. It proposes new models for textual criticism in order to capture the fluidity of the transmission of ancient alchemical writings. AlchemEast is designed to carry out a comparative investigation of cuneiform tablets as well as a vast corpus of Greek, Syriac and Arabic writings. It will overcome the old, pejorative paradigm that dismissed ancient alchemy as a ""pseudo-science"", by proposing a new theoretical framework for comprehending the entirety of ancient alchemical practices and theories. Alongside established forms of scholarly output, such as critical editions of key texts, AlchemEast will provide an integrative, longue durée perspective on the many different phases of ancient alchemy. It will thus offer a radically new vision of this discipline as a dynamic and diversified art that developed across different technical and scholastic traditions. This new representation will allow us to connect ancient alchemy with medieval and early modern alchemy and thus fully reintegrate ancient alchemy in the history of pre-modern alchemy as well as in the history of ancient science more broadly."

1 997 000 €

Start date: 2017-12-01, End date: 2022-11-30

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

1 999 823 €

Start date: 2014-12-01, End date: 2020-11-30

Present-day financial markets are turning algorithmic, as market orders are increasingly being executed by fully automated computer algorithms, without any direct human intervention. Although algorithmic finance seems to fundamentally reshape the central dynamics in financial markets, and even though it prompts core sociological questions, it has not yet received any systematic attention. In a pioneering contribution to economic sociology and social studies of finance, ALGOFINANCE aims to understand how and with what consequences the turn to algorithms is changing financial markets. The overall concept and central contributions of ALGOFINANCE are the following: (1) on an intra-firm level, the project examines how the shift to algorithmic finance reshapes the ways in which trading firms operate, and does so by systematically and empirically investigating the reconfiguration of organizational structures and employee subjectivity; (2) on an inter-algorithmic level, it offers a ground-breaking methodology (agent-based modelling informed by qualitative data) to grasp how trading algorithms interact with one another in a fully digital space; and (3) on the level of market sociality, it proposes a novel theorization of how intra-firm and inter-algorithmic dynamics can be conceived of as introducing a particular form of sociality that is characteristic to algorithmic finance: a form of sociality-as-association heuristically analyzed as imitation. None of these three levels have received systematic attention in the state-of-the-art literature. Addressing them will significantly advance the understanding of present-day algorithmic finance in economic sociology. By contributing novel empirical, methodological, and theoretical understandings of the functioning and consequences of algorithms, ALGOFINANCE will pave the way for other research into digital sociology and the broader algorithmization of society.

1 590 036 €

Start date: 2017-05-01, End date: 2021-04-30

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

1 923 060 €

Start date: 2015-07-01, End date: 2020-12-31

Brain and spinal cord diseases affect 38% of the European population and cost over 800 billion € annually; representing by far the largest health challenge. ALS is a prevalent neurological disease caused by motor neuron death with an invariably fatal outcome. I contributed to ALS research with the groundbreaking discovery of TDP-43 mutations, functionally characterized these mutations in the first vertebrate model and demonstrated a genetic interaction with another major ALS gene FUS. Emerging evidence indicates that four major causative factors in ALS, C9orf72, TDP-43, FUS & SQSTM1, genetically interact and could function in common cellular mechanisms. Here, I will develop zebrafish transgenic lines for all four genes, using state of the art genomic editing tools to combine simultaneous gene knockout and expression of the mutant alleles. Using these innovative disease models I will study the functional interactions amongst these four genes and their converging effect on key ALS pathogenic mechanisms: autophagy degradation, stress granule formation and RNA regulation. These studies will permit to pinpoint the molecular cascades that underlie ALS-related neurodegeneration. We will further expand the current ALS network by proposing and validating novel genetic interactors, which will be further screened for disease-causing variants and as pathological markers in patient samples. The power of zebrafish as a vertebrate model amenable to high-content phenotype-based screens will enable discovery of bioactive compounds that are neuroprotective in multiple animal models of disease. This project will increase the fundamental understanding of the relevance of C9orf72, TDP-43, FUS and SQSTM1 by developing animal models to characterize common pathophysiological mechanisms. Furthermore, I will uncover novel genetic, disease-related and pharmacological modifiers to extend the ALS network that will facilitate development of therapeutic strategies for neurodegenerative disorders

2 000 000 €

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

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

AMI aims to provide a novel interpretation of social links between humans and animals in hunter-gatherer cemeteries in North-East Europe, c. 9000–7500 years ago. AMI brings together cutting-edge developments in bioarchaeological science and the latest understanding of how people’s identities form in order to study the relationships between humans and animals. Grave materials and human remains will be studied from the viewpoint of process rather than as isolated objects, and will be interpreted through their histories. The main objectives are 1) Synthesize the animal related bioarchaeological materials in mortuary contexts in North-East Europe, 2) Conduct a systematic multimethodological analysis of the animal-derived artefacts and to study them as actors in human social identity construction, 3) Reconstruct the individual life histories of humans, animals, and animal-derived artefacts in the cemeteries, and 4) Produce models for the reconstruction of social identities based on the data from the bioanalyses, literature, and GIS. Various contextual, qualitative and quantitative biodata from animals and humans will be analysed and compared. Correlations and differences will be explored. Intra-site spatial analyses and data already published on cemeteries will contribute significantly to the research. Ethnographic information about recent hunter-gatherers from circumpolar regions gathered from literature will support the interpretation of the results from these analyses. The research material derives from almost 300 burials from eight sites in North-East Europe and includes, for example, unique materials from Russia that have not previously been available for modern multidisciplinary research. The project will make a significant contribution to our understanding of how humans living in the forests of North-East Europe adapted the animals they shared their environment with into their social and ideological realities and practices.

1 992 839 €

Start date: 2020-04-01, End date: 2025-03-31

Mitochondria are often referred to as the “power houses” of eukaryotic cells. All eukaryotes were thought to have mitochondria of some form until 2016, when the first eukaryote thriving without mitochondria was discovered by our laboratory – a flagellate Monocercomonoides. Understanding cellular functions of these cells, which represent a new functional type of eukaryotes, and understanding the circumstances of the unique event of mitochondrial loss are motivations for this proposal. The first objective focuses on the cell physiology. We will perform a metabolomic study revealing major metabolic pathways and concentrate further on elucidating its unique system of iron-sulphur cluster assembly. In the second objective, we will investigate in details the unique case of mitochondrial loss. We will examine two additional potentially amitochondriate lineages by means of genomics and transcriptomics, conduct experiments simulating the moments of mitochondrial loss and try to induce the mitochondrial loss in vitro by knocking out or down genes for mitochondrial biogenesis. We have chosen Giardia intestinalis and Entamoeba histolytica as models for the latter experiments, because their mitochondria are already reduced to minimalistic “mitosomes” and because some genetic tools are already available for them. Successful mitochondrial knock-outs would enable us to study mitochondrial loss in ‘real time’ and in vivo. In the third objective, we will focus on transforming Monocercomonoides into a tractable laboratory model by developing methods of axenic cultivation and genetic manipulation. This will open new possibilities in the studies of this organism and create a cell culture representing an amitochondriate model for cell biological studies enabling the dissection of mitochondrial effects from those of other compartments. The team is composed of the laboratory of PI and eight invited experts and we hope it has the ability to address these challenging questions.

1 935 500 €

Start date: 2018-05-01, End date: 2023-04-30

The current trend in biophotonics is to try and replicate the same ease and precision that our hands, eyes and ears offer at the macroscopic level, e.g. to hold, observe, squeeze and pull, rotate, cut and probe biological specimens in microfluidic environments. The bidding to get closer and closer to the object of interest has prompted the development of extremely advanced manipulation techniques at scales comparable to that of the wavelength of light. However, the fact that the optical beam can only access the microfluidic chip from the narrow aperture of a microscopic objective limits the versatility of the photonic function that can be realized. With this project, the applicant proposes to introduce a new biophotonic platform based on the all optical manipulation of flexible photonic metasurfaces. These artificial two-dimensional materials have virtually arbitrary photonic responses and have an intrinsic exceptional mechanical stability. This cross-disciplinary project, bridging photonics, material sciences and biology, will enable the adoption of the most modern and advanced photonic designs in microfluidic environments, with transformative benefits for microscopy and biophotonic applications at the interface of molecular and cell biology.

1 999 524 €

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

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: 2023-09-30

Molecular structure elucidation is of great importance in synthetic chemistry, pharmacy, life sciences, energy and environmental sciences, and technology applications. To date structure elucidation by atomic force microscopy (AFM) has been demonstrated for a few, small and mainly planar molecules. In this project high-risk, high-impact scientific questions will be solved using structure elucidation with the AFM employing a novel tool and novel methodologies. A combined low-temperature scanning tunneling microscope/atomic force microscope (LT-STM/AFM) with high throughput and in situ electrospray deposition method will be developed. Chemical resolution will be achieved by novel measurement techniques, in particular the usage of different and novel tip functionalizations and combination with Kelvin probe force microscopy. Elements will be identified using substructure recognition provided by a database that will be erected and by refined theory and simulations. The developed tools and techniques will be applied to molecules of increasing fragility, complexity, size, and three-dimensionality. In particular samples that are challenging to characterize with conventional methods will be studied. Complex molecular mixtures will be investigated molecule-by-molecule taking advantage of the single-molecule sensitivity. The absolute stereochemistry of molecules will be determined, resolving molecules with multiple stereocenters. The operation of single molecular machines as nanocars and molecular gears will be investigated. Reactive intermediates generated with atomic manipulation will be characterized and their on-surface reactivity will be studied by AFM.

2 000 000 €

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

Action potentials are not all equal. Despite shared biophysical principles and even similar action-potential shape, neurons with different spike generators can encode vastly different aspects of a stimulus and result in radically different behaviors of the embedding network. Differences between spike generators may be hard to discern because the information content of a spike train is not obvious to the naked eye. This is where computational analysis comes into play: theoretical research has shown that spike generation can be classified into a few dynamical types with qualitatively distinct computational properties. Among these, so-called homoclinic spikes – unlike the other commonly considered types – have been largely ignored. Yet, homoclinic spike generators are special because only they react with high sensitivity to inputs during the refractory period. Indeed, it is directly after a spike when homoclinic spikers “listen” best. As we recently demonstrated, this unique property has computationally exciting consequences: it can provoke a dramatic increase in network synchronization in response to minimal changes in physiological parameters, without requiring alterations in synaptic strength or connectivity. Supported by in-vitro evidence for homoclinic spiking in the rodent brain, ANewSpike explores the intriguing hypothesis that this “forgotten“ spike generator provides a unifying framework for the induction of epileptic activity by a wide range of physiological trigger parameters, from temperature to energy deprivation. Using a theory-experiment approach, we explore (i) the prevalence of homoclinic spiking in the brain, (ii) its ability to promote the transmission of high frequencies, and (iii) its ability to boost network synchronization. Our multi-scale study aims to add a novel dimension to our understanding of neural dynamics at the cellular and network level by revealing homoclinic spiking as an integral part of brain dynamics in both health and pathology.

2 000 000 €

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

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: 2022-02-28

Finite automata are fundamental objects in Computer Science, of great importance on one hand for theoretical aspects (formal language theory, decidability, complexity) and on the other for practical applications (parsing). In number theory, finite automata are mainly used as simple devices for generating sequences of symbols over a finite set (e.g., digital representations of real numbers), and for recognizing some sets of integers or more generally of finitely generated abelian groups or monoids. One of the main features of these automatic structures comes from the fact that they are highly ordered without necessarily being trivial (i.e., periodic). With their rich fractal nature, they lie somewhere between order and chaos, even if, in most respects, their rigidity prevails. Over the last few years, several ground-breaking results have lead to a great renewed interest in the study of automatic structures in arithmetics. A primary objective of the ANT project is to exploit this opportunity by developing new directions and interactions between automata and number theory. In this proposal, we outline three lines of research concerning fundamental number theoretical problems that have baffled mathematicians for decades. They include the study of integer base expansions of classical constants, of arithmetical linear differential equations and their link with enumerative combinatorics, and of arithmetics in positive characteristic. At first glance, these topics may seem unrelated, but, surprisingly enough, the theory of finite automata will serve as a natural guideline. We stress that this new point of view on classical questions is a key part of our methodology: we aim at creating a powerful synergy between the different approaches we propose to develop, placing automata theory and related methods at the heart of the subject. This project provides a unique opportunity to create the first international team focusing on these different problems as a whole.

1 438 745 €

Start date: 2015-10-01, End date: 2020-09-30

The frightening increase in antibiotic drug resistance is threatening global healthcare as we know it. To this extent the World Health Organisation that has classes M. tuberculosis and Gram-negative nosocomial infections as the highest priority for novel R&D strategies. A major obstacle to drug discovery programs is to design inhibitors that can efficiently enter into bacteria. One such stealth strategy is exemplified by natural siderophore-antibiotics conjugates (sideromycins) that piggyback the bacterial iron acquisition machinery to enter bacteria. This Trojan-horse strategy has inspired the chemical synthesis of numerous sideromycin conjugates, with cefiderocol a current preclinical candidate. Despite the advances in this field, natural examples of sideromycins are still scarce, and finding new examples may provide further insight into siderophore antibiotic formation and delivery. ANTIBIOCLICKS will investigate a unique bioinspired conjugation chemistry that has been uncovered from a newly discovered natural sideromycin. This natural “click” chemistry is ideal for the coupling of catecholate containing siderophores (such as those of the WHO prioritised M. tuberculosis, A. baumannii, E. coli, P. aeruginosa and K. pneumonia) to antibiotics or other molecules. This project will aim to define the exact chemical mechanism behind this novel and surprisingly simple conjugation reaction, and use this unique and facile chemistry to generate a combinatorial library of siderophores with antibiotics and fluorophores. These products will subsequently be used to probe the exact mechanism of bacterial sideromycin uptake, potential intracellular decoupling and target engagement. Finally, the antibiotic and diagnostic potential of the generated siderophore conjugates will be evaluated. To this extent, ANTIBIOCLICKS will provide illuminating insight into new bioinspired conjugation chemistry, and evaluate its potential for novel bacterial therapeutics and diagnostics.

2 000 000 €

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

Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.

1 999 770 €

Start date: 2018-05-01, End date: 2023-04-30

Antarctic sea ice is a critical component of Earth’s climate system. Seasonal fluctuations support unique ecosystems and impact planetary albedo, ocean-atmosphere exchanges of heat and climatically-active gases (e.g. CO2), and formation of intermediate and deep water masses which create the world’s largest sink of heat and carbon. The properties of the sea-ice pack are complex: despite its climatic significance, Antarctic sea ice is challenging to observe and to model, leading to low confidence in future projections in a warming climate. The geological record offers a longer-term context for recent trends. At the last glacial maximum (LGM) a likely doubling of Antarctic sea-ice extent relative to today is hypothesised to have driven an ocean drawdown of atmospheric CO2. However, a combination of sparse empirical datasets and uncertainties in sea-ice modelling means that the properties and climatic impacts of the LGM Antarctic sea-ice pack are poorly understood. The narrow focus of the geological record on key primary producers and grazers further limits our understanding of Antarctic ecosystem responses to changes in sea ice. ANTSIE will exploit a unique biological archive of Antarctic sea-ice conditions to generate a novel ecosystem perspective on the patterns and properties of sea ice during and since the LGM. ‘Antarctic mumiyo’ sequences are preserved remains of regurgitated stomach contents from snow petrels, which feed within and at the edges of the sea-ice pack. A network of mumiyo sequences, which sample across the climatically important Weddell Sea region, will be geochemically analysed to determine snow petrel diet and sea-ice properties with unprecedented century-scale resolution. The results will be used to evaluate new state-of-the-art simulations of the LGM sea-ice pack. By integrating multi-disciplinary perspectives, ANTSIE will provide new understanding of Antarctic sea-ice controls and impacts, to facilitate improved confidence in future project.

1 999 929 €

Start date: 2020-06-01, End date: 2025-11-30