ERC FUNDED PROJECTS

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

148 021 €

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

The applicant will collaborate with Irish, European and U.S.-based colleagues to develop a sustainable biorefinery and bioenergy industry in Ireland and Europe. The focus of this ERC Starting Grant will be the application of classical microbiological, physiological and real-time polymerase chain reaction (PCR)-based assays, to qualitatively and quantitatively characterize microbial communities underpinning novel and innovative, low-temperature, anaerobic waste (and other biomass) conversion technologies, including municipal wastewater treatment and, demonstration- and full-scale biorefinery applications. Anaerobic digestion (AD) is a naturally-occurring process, which is widely applied for the conversion of waste to methane-containing biogas. Low-temperature (<20 degrees C) AD has been applied by the applicant as a cost-effective alternative to mesophilic (c. 35C) AD for the treatment of several waste categories. However, the microbiology of low-temperature AD is poorly understood. The applicant will work with microbial consortia isolated from anaerobic bioreactors, which have been operated for long-term experiments (>3.5 years), and include organic acid-oxidizing, hydrogen-producing syntrophic microbes and hydrogen-consuming methanogens. A major focus of the project will be the ecophysiology of psychrotolerant and psychrophilic methanogens already identified and cultivated by the applicant. The project will also investigate the role(s) of poorly-understood Crenarchaeota populations and homoacetogenic bacteria, in complex consortia. The host organization is a leading player in the microbiology of waste-to-energy applications. The applicant will train a team of scientists in all aspects of the microbiology and bioengineering of biomass conversion systems.

1 499 797 €

Start date: 2011-05-01, End date: 2016-04-30

Making accurate predictions is a crucial factor in many systems (such as in modelling energy consumption, power load forecasting, traffic networks, process industry, environmental modelling, biomedicine, brain-machine interfaces) for cost savings, efficiency, health, safety and organizational purposes. In this proposal we aim at realizing a new generation of more advanced black-box modelling techniques for estimating predictive models from measured data. We will study different optimization modelling frameworks in order to obtain improved black-box modelling approaches. This will be done by specifying models through constrained optimization problems by studying different candidate core models (parametric models, support vector machines and kernel methods) together with additional sets of constraints and regularization mechanisms. Different candidate mathematical frameworks will be considered with models that possess primal and (Lagrange) dual model representations, functional analysis in reproducing kernel Hilbert spaces, operator splitting and optimization in Banach spaces. Several aspects that are relevant to black-box models will be studied including incorporation of prior knowledge, structured dynamical systems, tensorial data representations, interpretability and sparsity, and general purpose optimization algorithms. The methods should be suitable for handling larger data sets and high dimensional input spaces. The final goal is also to realize a next generation software tool (including symbolic generation of models and handling different supervised and unsupervised learning tasks, static and dynamic systems) that can be generically applied to data from different application areas. The proposal A-DATADRIVE-B aims at getting end-users connected to the more advanced methods through a user-friendly data-driven black-box modelling tool. The methods and tool will be tested in connection to several real-life applications.

2 485 800 €

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

I intend to investigate what cognitive mechanisms give us combinatorial speech. Combinatorial speech is the ability to make new words using pre-existing speech sounds. Humans are the only apes that can do this, yet we do not know how our brains do it, nor how exactly we differ from other apes. Using new experimental techniques to study human behavior and new computational techniques to model human cognition, I will find out how we deal with combinatorial speech. The experimental part will study individual and cultural learning. Experimental cultural learning is a new technique that simulates cultural evolution in the laboratory. Two types of cultural learning will be used: iterated learning, which simulates language transfer across generations, and social coordination, which simulates emergence of norms in a language community. Using the two types of cultural learning together with individual learning experiments will help to zero in, from three angles, on how humans deal with combinatorial speech. In addition it will make a methodological contribution by comparing the strengths and weaknesses of the three methods. The computer modeling part will formalize hypotheses about how our brains deal with combinatorial speech. Two models will be built: a high-level model that will establish the basic algorithms with which combinatorial speech is learned and reproduced, and a neural model that will establish in more detail how the algorithms are implemented in the brain. In addition, the models, through increasing understanding of how humans deal with speech, will help bridge the performance gap between human and computer speech recognition. The project will advance science in four ways: it will provide insight into how our unique ability for using combinatorial speech works, it will tell us how this is implemented in the brain, it will extend the novel methodology of experimental cultural learning and it will create new computer models for dealing with human speech.

1 276 620 €

Start date: 2012-02-01, End date: 2017-01-31

The amazing rate of progress in the computer technologies and telecommunications presents many new challenges for Optimization Theory. New problems are usually very big in size, very special in structure and possibly have a distributed data support. This makes them unsolvable by the standard optimization methods. In these situations, old theoretical models, based on the hidden Black-Box information, cannot work. New theoretical and algorithmic solutions are urgently needed. In this project we will concentrate on development of fast optimization methods for problems of big and very big size. All the new methods will be endowed with provable efficiency guarantees for large classes of optimization problems, arising in practical applications. Our main tool is the acceleration technique developed for the standard Black-Box methods as applied to smooth convex functions. However, we will have to adapt it to deal with different situations. The first line of development will be based on the smoothing technique as applied to a non-smooth functions. We propose to substantially extend this approach to generate approximate solutions in relative scale. The second line of research will be related to applying acceleration techniques to the second-order methods minimizing functions with sparse Hessians. Finally, we aim to develop fast gradient methods for huge-scale problems. The size of these problems is so big that even the usual vector operations are extremely expensive. Thus, we propose to develop new methods with sublinear iteration costs. In our approach, the main source for achieving improvements will be the proper use of problem structure. Our overall aim is to be able to solve in a routine way many important problems, which currently look unsolvable. Moreover, the theoretical development of Convex Optimization will reach the state, when there is no gap between theory and practice: the theoretically most efficient methods will definitely outperform any homebred heuristics.

2 090 038 €

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

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

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

150 000 €

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

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

1 088 386 €

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

Space exploration is one of boldest and most exciting endeavors that humanity has undertaken, and it holds enormous promise for the future. Our next challenges for the spatial conquest include bringing back samples to Earth by means of robotic missions and continuing the manned exploration program, which aims at sending human beings to Mars and bring them home safely. Inaccurate prediction of the heat-flux to the surface of the spacecraft heat shield can be fatal for the crew or the success of a robotic mission. This quantity is estimated during the design phase. An accurate prediction is a particularly complex task, regarding modelling of the following phenomena that are potential “mission killers:” 1) Radiation of the plasma in the shock layer, 2) Complex surface chemistry on the thermal protection material, 3) Flow transition from laminar to turbulent. Our poor understanding of the coupled mechanisms of radiation, ablation, and transition leads to the difficulties in flux prediction. To avoid failure and ensure safety of the astronauts and payload, engineers resort to “safety factors” to determine the thickness of the heat shield, at the expense of the mass of embarked payload. Thinking out of the box and basic research are thus necessary for advancements of the models that will better define the environment and requirements for the design and safe operation of tomorrow’s space vehicles and planetary probes for the manned space exploration. The three basic ingredients for predictive science are: 1) Physico-chemical models, 2) Computational methods, 3) Experimental data. We propose to follow a complementary approach for prediction. The proposed research aims at: “Integrating new advanced physico-chemical models and computational methods, based on a multidisciplinary approach developed together with physicists, chemists, and applied mathematicians, to create a top-notch multiphysics and multiscale numerical platform for simulations of planetary atmosphere entries, crucial to the new challenges of the manned space exploration program. Experimental data will also be used for validation, following state-of-the-art uncertainty quantification methods.”

1 494 892 €

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

Rates of domestic violence and the relative risk of premature death for women are higher in sub-Saharan Africa than in any other region. Yet we know remarkably little about the economic forces, incentives and constraints that drive discrimination against women in this region, making it hard to identify policy levers to address the problem. This project will help fill this gap. I will investigate gender discrimination from two complementary perspectives. First, through the lens of economic history, I will investigate the forces driving trends in women’s relative well-being since slavery. To quantify the evolution of well-being of sub-Saharan women relative to men, I will use three types of historical data: anthropometric indicators (relative height), vital statistics (to compute numbers of missing women), and outcomes of formal and informal family law disputes. I will then investigate how major economic developments and changes in family laws differentially affected women’s welfare across ethnic groups with different norms on women’s roles and rights. Second, using intra-household economic models, I will provide new insights into domestic violence and gender bias in access to crucial resources in present-day Africa. I will develop a new household model that incorporates gender identity and endogenous outside options to explore the relationship between women’s empowerment and the use of violence. Using the notion of strategic delegation, I will propose a new rationale for the separation of budgets often observed in African households and generate predictions of how improvements in women’s outside options affect welfare. Finally, with first hand data, I will investigate intra-household differences in nutrition and work effort in times of food shortage from the points of view of efficiency and equity. I will use activity trackers as an innovative means of collecting high quality data on work effort and thus overcome data limitations restricting the existing literature

1 499 313 €

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

"Ageing is the gradual and irreversible breakdown of living systems associated with the advancement of time, which leads to an increase in vulnerability and eventual mortality. Despite recent advances in ageing research, the intrinsic complexity of the ageing process has prevented a full understanding of this process, therefore, ageing remains a grand challenge in contemporary biology. In AGELESS, we will tackle this challenge by uncovering the molecular mechanisms of halted ageing in a unique model system, the bats. Bats are the longest-lived mammals relative to their body size, and defy the ‘rate-of-living’ theories as they use twice as much the energy as other species of considerable size, but live far longer. This suggests that bats have some underlying mechanisms that may explain their exceptional longevity. In AGELESS, we will identify the molecular mechanisms that enable mammals to achieve extraordinary longevity, using state-of-the-art comparative genomic methodologies focused on bats. We will identify, using population transcriptomics and telomere/mtDNA genomics, the molecular changes that occur in an ageing wild population of bats to uncover how bats ‘age’ so slowly compared with other mammals. In silico whole genome analyses, field based ageing transcriptomic data, mtDNA and telomeric studies will be integrated and analysed using a networks approach, to ascertain how these systems interact to halt ageing. For the first time, we will be able to utilize the diversity seen within nature to identify key molecular targets and regions that regulate and control ageing in mammals. AGELESS will provide a deeper understanding of the causal mechanisms of ageing, potentially uncovering the crucial molecular pathways that can be modified to halt, alleviate and perhaps even reverse this process in man."

1 499 768 €

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

This research project is based on the notion that, because of their specific interaction with space, people with particular dis-abilities are able to appreciate spatial qualities or detect misfits in the environment that most architects—or other designers—are not even aware of. This notion holds for sensory dis-abilities such as blindness or visual impairment, but also for mental dis-abilities like autism or Alzheimer’s dementia. The experiences and subsequent insights of these dis-abled people, so it is argued, represent a considerable knowledge resource that would complement and enrich the professional expertise of architects and designers in general. This argument forms the basis for a methodological and theoretical exploration of a multi-sensorial design approach in architecture. On the one hand, a series of retrospective case studies will be conducted to identify and describe the motives and elements that trigger or stimulate architects’ attention for the multi-sensorial spatial experiences of people with dis-abilities when designing spaces. On the other hand, the research project will investigate experimentally in real time to what extent design processes and products in architecture can be enriched by establishing a dialogue between the multi-sensorial ‘knowing-in-action’ of people with dis-abilities and the expertise of professional architects/designers. In this way, the research project aims to develop a more profound understanding of how the concept of Design for All can be realised in architectural practice. At least as important, however, is its contribution to innovation in architecture tout court. The research results are expected to give a powerful impulse to quality improvement of the built environment by stimulating and supporting the development of innovative design concepts.

1 195 385 €

Start date: 2008-05-01, End date: 2013-10-31

ALUFIX proposes an original strategy for the development of aluminium-based materials involving damage mitigation and extrinsic self-healing concepts exploiting the new opportunities of the solid-state friction stir process. Friction stir processing locally extrudes and drags material from the front to the back and around the tool pin. It involves short duration at moderate temperatures (typically 80% of the melting temperature), fast cooling rates and large plastic deformations leading to far out-of-equilibrium microstructures. The idea is that commercial aluminium alloys can be locally improved and healed in regions of stress concentration where damage is likely to occur. Self-healing in metal-based materials is still in its infancy and existing strategies can hardly be extended to applications. Friction stir processing can enhance the damage and fatigue resistance of aluminium alloys by microstructure homogenisation and refinement. In parallel, friction stir processing can be used to integrate secondary phases in an aluminium matrix. In the ALUFIX project, healing phases will thus be integrated in aluminium in addition to refining and homogenising the microstructure. The “local stress management strategy” favours crack closure and crack deviation at the sub-millimetre scale thanks to a controlled residual stress field. The “transient liquid healing agent” strategy involves the in-situ generation of an out-of-equilibrium compositionally graded microstructure at the aluminium/healing agent interface capable of liquid-phase healing after a thermal treatment. Along the road, a variety of new scientific questions concerning the damage mechanisms will have to be addressed.

1 497 447 €

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

Osteoarthritis (OA), the most common form of arthritis, is a serious disease of the joints affecting nearly 10% of the population worldwide. The onset of OA has been associated with defects to articular cartilage that lines the bones of synovial joints. Current strategies to treat articular cartilage defects are ineffective and/or prohibitively expensive. The aim of ANCHOR is to develop and commercialise a new medicinal product for articular cartilage regeneration that recruits endogenous bone marrow derived stem cells into an extracellular matrix derived scaffold anchored to the subchondral bone by 3D printed polymeric supports. By recruiting endogenous cells into a supporting scaffold, ANCHOR will obviate the need for pre-seeding scaffolds with cells prior to implantation into cartilage defects, thereby dramatically reducing the cost and complexity of the repair procedure. It will also overcome the need for suturing of a scaffold into a cartilage defect, which is a very time consuming and technically challenging surgical procedure. Finally, the inherent chondro-inductivity of the cartilage ECM derived scaffolds developed by the applicant will maximise the potential for hyaline cartilage regeneration. The project will leverage the applicants extensive experience in ECM derived biomaterials and 3D printing to develop a new product with significant commercial potential. The impact of ANCHOR will be multi-faceted: it will transform how damaged joints are treated by orthopaedic surgeons, it will create economic value through the commercialization of IP, and most importantly it will improve patient experience and their long-term health and well-being.

149 945 €

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

What does the fossil record tell us about the evolution of colour in animals through deep time? Evidence of colour in fossils can inform on the visual signalling strategies used by ancient animals. Research to date often has a narrow focus, lacks a broad phylogenetic and temporal context, and rarely incorporates information on taphonomy. This proposal represents a bold new holistic approach to the study of fossil colour: it will couple powerful imaging- and chemical analytical techniques with a rigorous programme of fossilisation experiments simulating decay, burial, and transport, and analysis of fossils and their sedimentary context, to construct the first robust models for the evolution of colour in animals through deep time. The research will resolve the original integumentary colours of fossil higher vertebrates, and the original colours of fossil hair; the fossil record of non-melanin pigments in feathers and insects; the biological significance of monotonal patterning in fossil insects; and the evolutionary history of scales and 3D photonic crystals in insects. Critically, the research will test, for the first time, whether evidence of fossil colour can solve broader evolutionary questions, e.g. the true affinities of enigmatic Cambrian chordate-like metazoans, and feather-like integumentary filaments in dinosaurs. The proposal entails construction of a dedicated experimental maturation laboratory for simulating the impact of burial on tissues. This laboratory will form the core of the world’s first integrated ‘experimental fossilisation facility’, consolidating the PI’s team as the global hub for fossil colour research. The research team comprises the PI, three postdoctoral researchers, and three PhD students, and will form an extensive research network via collaborations with 13 researchers from Europe and beyond. The project will reach out to diverse scientists and will inspire a positive attitude to science among the general public and policymakers alike.

1 562 000 €

Start date: 2016-01-01, End date: 2020-12-31

Work conducted in my laboratory on the trypanosome killing factor of human serum led to the identification of the primate-specific Apolipoprotein L1 (APOL1) as a novel pore-forming protein with striking similarities with proteins of the apoptotic BCL2 family. APOL1 belongs to a family of proteins induced under inflammatory conditions in myeloid and endothelial cells. APOL1 is efficiently neutralized by the SRA protein of Trypanosoma rhodesiense, accounting for the ability of this trypanosome subspecies to infect humans and cause sleeping sickness. We found that natural APOL1 variants escaping SRA neutralization and therefore conferring human resistance to T. rhodesiense are associated with chronic kidney disease. Moreover, transgenic mice expressing these APOL1 variants exhibit an obese phenotype. Our unpublished results also indicate that APOLs control the lifespan of dendritic cells and podocytes activated by viral stimuli. Therefore, we propose that the pathology of APOL variants is due to their deregulated activity on the control of the cellular lifespan in myeloid/endothelial cells activated by pathogen detection. This project aims at characterizing (i) the molecular mechanism by which APOLs control the lifespan of activated dendritic cells and podocytes, which has direct impact on innate immunity and inflammation, and (ii) the mechanism by which APOL1 variants cause pathology. In addition, we plan to detail the physiological function of APOLs by studying the phenotype of transgenic mice either expressing human APOL1 (wild-type and variants) or devoid of APOL genes, which we have recently generated. Finally, we propose to exploit the extraordinary potential of trypanosomes for antigenic variation in order to produce SRA variants able to neutralize the pathogenic APOL1 variants. Preliminary experiments suggest that in podocytes SRA antagonizes APOL1 induction by viral stimulus and subsequent cell death, opening new perspectives to treat kidney disease.

2 250 000 €

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

In this project, innovative techniques to reconstruct ancient economies are developed and new insights in the trade and processing of mineral raw materials are gained based on interdisciplinary archaeological and archaeometrical research. An innovative methodology for and a practical provenance database of the primary origin of natron glass from the Hellenistic-Roman world will be established. The project investigates both production and consumer sites of glass raw materials using both typo-chronological and archaeometrical (isotope geochemical) study of finished glass artefacts at consumer sites as well as mineralogical and chemical characterisation of raw glass and mineral resources at primary production sites. Suitable sand resources in the locations described by ancient authors will be identified through geological prospecting on the basis of literature review and field work. Sand and flux (natron) deposits will be mineralogically and geochemically characterised and compared to the results of the archaeological and geochemical investigations of the glass. Through integrated typo-chronological and archaeometrical analysis, the possible occurrence of primary production centres of raw glass outside the known locations in Syro-Palestine and Egypt, particularly in North-Africa, Italy, Spain and Gaul will be critically studied. In this way, historical, archaeological and archaeometrical data are combined, developing new interdisciplinary techniques for innovative archaeological interpretation of glass trade in the Hellenistic-Roman world.

954 960 €

Start date: 2009-11-01, End date: 2014-10-31

Spontaneous protein crystallization is a rare event in biology. Eosinophilic inflammation such as seen in the airways in asthma, chronic rhinosinusitis and helminth infection is however accompanied by accumulation of large amounts of extracellular Charcot-Leyden crystals. These are made of Galectin-10, a protein of unknown function produced by eosinophils, hallmark cells of type 2 immunity. In mice, eosinophilic inflammation is also accompanied by protein crystal build up, composed of the chitinase-like proteins Ym1 and Ym2, produced by alternatively activated macrophages. Here we challenge the current view that these crystals are just markers of eosinophil demise or macrophages activation. We hypothesize that protein crystallization serves an active role in immunoregulation of type 2 immunity. On the one hand, crystallization might turn a harmless protein into a danger signal. On the other hand, crystallization might sequester and eliminate the physiological function of soluble Galectin-10 and Ym1, or prolong it via slow release elution. For full understanding, we therefore need to understand the function of the proteins in a soluble and crystalline state. Our program at the frontline of immunology, molecular structural biology and clinical science combines innovative tool creation and integrative research to investigate the structure, function, and physiology of galectin-10 and related protein crystals. We chose to study asthma as the crystallizing proteins are abundantly present in human and murine disease. There is still a large medical need for novel therapies that could benefit patients with chronic steroid-resistant disease, and are alternatives to eosinophil-depleting antibodies whose long term effects are unknown.

2 499 846 €

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

Brain consists of two basic cell types – neurons and glia. However, the study of glia in brain function has traditionally been neglected in favor of their more “illustrious” counter-parts – neurons that are classed as the computational units of the brain. Glia have usually been classed as “brain glue” - a supportive matrix on which neurons grow and function. However, recent evidence suggests that glia are more than passive “glue” and actually modulate neuronal function. This has lead to the proposal of a “tripartite synapse”, which recognizes pre- and postsynaptic neuronal elements and glia as a unit. However, what is still lacking is rudimentary information on how these cells actually function in situ. Here we propose taking a “bottom-up” approach, by identifying the molecules (and interactions) that control glial function in situ. This is complicated by the fact that glia show profound changes when placed into culture. To circumvent this, we will use recently developed cell sorting techniques, to rapidly isolate genetically marked glial cells from brain – which can then be analyzed using advanced biochemical and physiological techniques. The long-term aim is to identify proteins that can be “tagged” using transgenic technologies to allow protein function to be studied in real-time in vivo, using sophisticated imaging techniques. Given the number of proteins that may be identified we envisage developing new methods of generating transgenic animals that provide an attractive alternative to current “state-of-the art” technology. The importance of studying glial function is given by the fact that every major brain pathology shows reactive gliosis. In the time it takes to read this abstract, 5 people in the EU will have suffered a stroke – not to mention those who suffer other forms of neurotrauma. Thus, understanding glial function is not only critical to understanding normal brain function, but also for relieving the burden of severe neurological injury and disease

1 490 168 €

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

The Bantu Expansion is not only the main linguistic, cultural and demographic process in Late Holocene Africa. It is also one of the most controversial issues in African History that still has political repercussions today. It has sparked debate across the disciplines and far beyond Africanist circles in an attempt to understand how the young Bantu language family (ca. 5000 years) could spread over large parts of Central, Eastern and Southern Africa. This massive dispersal is commonly seen as the result of a single migratory macro-event driven by agriculture, but many questions about the movement and subsistence of ancestral Bantu speakers are still open. They can only be answered through real interdisciplinary collaboration. This project will unite researchers with outstanding expertise in African archaeology, archaeobotany and historical linguistics to form a unique cross-disciplinary team that will shed new light on the first Bantu-speaking village communities south of the rainforest. Fieldwork is planned in parts of the Democratic Republic of Congo, the Republic of Congo and Angola that are terra incognita for archaeologists to determine the timing, location and archaeological signature of the earliest villagers and to establish how they interacted with autochthonous hunter-gatherers. Special attention will be paid to archaeobotanical and palaeoenvironmental data to get an idea of their subsistence, diet and habitat. Historical linguistics will be pushed beyond the boundaries of vocabulary-based phylogenetics and open new pathways in lexical reconstruction, especially regarding subsistence and land use of early Bantu speakers. Through interuniversity collaboration archaeozoological, palaeoenvironmental and genetic data and phylogenetic modelling will be brought into the cross-disciplinary approach to acquire a new holistic view on the interconnections between human migration, language spread, climate change and early farming in Late Holocene Central Africa.

1 997 500 €

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

Curli are functional amyloid fibers that constitute the major protein component of the extracellular matrix in pellicle biofilms formed by Bacteroidetes and Proteobacteria. Unlike the protein misfolding and aggregation events seen in pathological amyloid diseases such as Alzheimer’s and Parkinson’s disease, curli are the product of a dedicated protein secretion machinery. Curli formation requires a specialised and mechanistically unique transporter in the bacterial outer membrane, as well as two soluble accessory proteins thought to facilitate the safe guidance of the curli subunits across the periplasm and to coordinate their self-assembly at cell surface. In this interdisciplinary research program we will study the structural and molecular biology of E. coli curli biosynthesis and address the fundamental questions concerning the molecular processes that allow the spatially and temporally controlled transport and deposition of these pro-amyloidogenic polypeptides. We will structurally unravel the secretion machinery, trap and analyse critical secretion intermediates and through in vitro reconstitution, assemble a minimal, self-sufficient peptide transport and fiber assembly system. The new insights gained will set the stage for targeted interventions in curli -mediated biofilm formation and this research project will develop a new framework to harness the unique properties found in curli structure and biosynthesis for biotechnological applications as in patterned functionalized nanowires and directed, selective peptide carriers.

1 989 489 €

Start date: 2015-06-01, End date: 2020-05-31

OPPSEXRIGHTS will be the first large-scale, transnational study to consider the effects of recent Sexual and Gender Rights and Equalities (SGRE) on those who oppose them, by exploring opponents’ experiences of the transformation of everyday spaces. It will work beyond contemporary polarisations, creating new possibilities for social transformation. This cutting-edge research engages with the dramatically altered social and political landscapes in the late 20th and early 21st Century created through the development of lesbian, gay, bisexual, and trans, and women’s rights. Recent reactionary politics highlight the pressing need to understand the position of those who experience these new social orders as a loss. The backlash to SGRE has coalesced into various resistances that are tangibly different to the classic vilification of homosexuality, or those that are anti-woman. Some who oppose SGRE have found themselves the subject of public critique; in the workplace, their jobs threatened, while at home, engagements with schools can cause family conflicts. This is particularly visible in the case studies of Ireland, UK and Canada because of SGRE. A largescale transnational systematic database will be created using low risk (media and organisational discourses; participant observation at oppositional events) and higher risk (online data collection and interviews) methods. Experimenting with social transformation, OPPSEXRIGHTS will work to build bridges between ‘enemies’, including families and communities, through innovative discussion and arts-based workshops. This ambitious project has the potential to create tangible solutions that tackle contemporary societal issues, which are founded in polarisations that are seemingly insurmountable.

1 988 652 €

Start date: 2019-10-01, End date: 2024-09-30

The dielectric properties of biological tissues are of fundamental importance to the understanding of the interaction of electromagnetic fields with the human body. These properties are used to determine the safety of electronic devices, and in the design, development and refinement of electromagnetic medical imaging and therapeutic devices. Many historical studies have aimed to establish the dielectric properties of a broad range of tissues. A growing number of recent studies have sought to more accurately estimate these dielectric properties by standardising measurement procedures, and in some cases, measuring the dielectric properties in-vivo. However, these studies have often produced results in direct conflict with historical studies, casting doubt on the accuracy of the currently utilised dielectric properties. At best, this uncertainty could significantly delay the development of electromagnetic imaging or therapeutic medical devices. At worst, the health dangers of electromagnetic radiation could be under-estimated. The applicant will embark upon frontier research to develop improved methods and standards for the measurement of the dielectric properties of biological tissue. The research programme will accelerate the design and development of electromagnetic imaging and therapeutic devices, at a time when the technology is gaining significant momentum. The primary objective of the research is to develop a deep understanding of the fundamental factors which contribute to errors in dielectric property measurement. These factors will include in-vivo/ex-vivo measurements and dielectric measurement method used, amongst many others. Secondly, a new open-access repository of dielectric measurements will be created based on a greatly enhanced understanding of the mechanisms underlying dielectric property measurement. Finally, new electromagnetic-based imaging and therapeutic medical devices will be investigated, based on the solid foundation of dielectric data.

1 499 329 €

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

"Summary: the quest for a general functional tensor framework for blind source separation Our overall objective is the development of a general functional framework for solving tensor based blind source separation (BSS) problems in biomedical data fusion, using tensor decompositions (TDs) as basic core. We claim that TDs will allow the extraction of fairly complicated sources of biomedical activity from fairly complicated sets of uni- and multimodal data. The power of the new techniques will be demonstrated for three well-chosen representative biomedical applications for which extensive expertise and fully validated datasets are available in the PI’s team, namely: • Metabolite quantification and brain tumour tissue typing using Magnetic Resonance Spectroscopic Imaging, • Functional monitoring including seizure detection and polysomnography, • Cognitive brain functioning and seizure zone localization using simultaneous Electroencephalography-functional MR Imaging integration. Solving these challenging problems requires that algorithmic progress is made in several directions: • Algorithms need to be based on multilinear extensions of numerical linear algebra. • New grounds for separation, such as representability in a given function class, need to be explored. • Prior knowledge needs to be exploited via appropriate health relevant constraints. • Biomedical data fusion requires the combination of TDs, coupled via relevant constraints. • Algorithms for TD updating are important for continuous long-term patient monitoring. The algorithms are eventually integrated in an easy-to-use open source software platform that is general enough for use in other BSS applications. Having been involved in biomedical signal processing over a period of 20 years, the PI has a good overview of the field and the opportunities. By working directly at the forefront in close collaboration with the clinical scientists who actually use our software, we can have a huge impact."

2 500 000 €

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

The BIRTH project will investigate the key biological and cultural mechanisms affecting fertility rates resulting the Neolithic Demogaphic Transition, the major demographic shift in human evolution. We integrate skeletal markers with micro-nutritional and macro-scaled cultural effects on fertility rates during the Early-Middle Holocene (10000-5000 BC) in the Central Balkans. Human, animal and plant remains, will be analysed using methods from bioarchaeological, forensic, chemical sciences in order to: 1) Investigate variability in the pattern of birth rates (number of pregnancies, interval(s) between them and the duration of the reproductive period) through histological analysis of irregularities in tooth cementum of women; 2) Determine paleoobstetric and neonatal body characteristics, health status and nutrition through analysis of skeletal remains; 3) Determine micronutritional changes during the Early-Middle Holocene through trace element (Zn, Ca and Fe) analysis; 4) Investigate the micro and macronutritional value of prehistoric foodstuffs, through an analysis of animal and plant remains and to compare the nutritional intake in relation to health and fertility; 5) Establish a chronology of the NDT in the Balkans by summed radiocarbon probability distributions; 6) Explore the possible role of culture in driving fertility increases, through analysis of community attitudes to birthing trough investigation of neonate graves and artifact connected to the birthing process. Given that the issues of health and fertility are of utmost importance in the present as they were in the past, the BIRTH project offers new understanding of biocultural mechanisms which led to fertility increase and novel approaches to ancient skeletal heritage, and emphasizes their great potential for modern humanity.

1 714 880 €

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

While previous studies have investigated cell-signalling pathways that facilitate mechanotransduction and have provided a wealth of data, to date, in vivo mechanobiology is not fully understood. In the research study proposed the applicant will embark upon frontier research to delineate these specific aspects of bone mechanotransduction during normal physiology, disease and for tissue regeneration purposes. If these quantities were better understood the proposed research program will deliver significant advances in the understanding of the mechanical regulation of bone remodelling during normal physiology and osteoporosis, and will enhance approaches for regeneration of bone tissue for treatment of bone pathologies. The primary objective is to delineate the normal mechanosensory and signalling mechanisms of bone cells. The secondary objective is to determine whether the regulatory role of bone cells is inhibited or impaired during bone diseases such as osteoporosis. The final objective of this project is to develop an in vitro mechanical loading device that can enhance bone tissue regeneration and thereby advance current treatment approaches for bone pathologies. To address these objectives, five hypotheses have been defined, each of which will underpin the research of five work packages. A combination of experimental studies, using animal models and in vitro cell culture, and computational modelling will be taken to test each of these hypotheses. Answering these hypotheses will bring us closer to an understanding of the origins of bone mechanobiology and diseases such as osteoporosis. Furthermore, the results of these studies will facilitate development of novel approaches to enhance bone regeneration in vitro.

1 499 911 €

Start date: 2011-02-01, End date: 2016-01-31

Humans and other primates possess an exquisite capacity to grasp and manipulate objects. The seemingly effortless interaction with objects in everyday life is subserved by a number of cortical areas of the visual and the motor system. Recent research has highlighted that dorsal stream areas in the posterior parietal cortex are involved in object processing. Because parietal lesions do not impair object recognition, the encoding of object shape in posterior parietal cortex is considered to be important for the planning of actions towards objects. In order to succesfully grasp an object, the complex pattern of visual information impinging on the retina has to be transformed into a motor plan that can control the muscle contractions. The neural basis of visuomotor transformations necessary for directing actions towards objects, however, has remained largely unknown. This proposal aims to unravel the pathways and mechanisms involved in programming actions towards objects - an essential capacity for our very survival. We envision an integrated approach to study the transformation of visual information into motor commands in the macaque brain, combining functional imaging, single-cell recording, microstimulation and reversible inactivation. Our research efforts will be focussed on parietal area AIP and premotor area F5, two key brain areas for visually-guided grasping. Above all, this proposal will move beyond purely descriptive measurements of neural activity by implementing manipulations of brain activity to reveal behavioral effects and interdependencies of cortical areas. Finally the data obtained in this project will pave the way to use the neural activity recorded in visuomotor areas to act upon the environment by grasping objects by means of a robot hand.

1 499 200 €

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

Feeding the growing world population under changing climate conditions poses an unprecedented challenge on global agriculture and our current pace to breed new high yielding crop varieties is too low to face the imminent threats on food security. This ERC project proposes a novel crossing scheme that allows for an expeditious evaluation of combinations of potential yield contributing alleles by unifying ‘classical’ breeding with gene-centric molecular biology. The acronym BREEDIT, a word fusion of breeding and editing, reflects the basic concept of combining breeding with multiplex genome editing of yield related genes. By introducing plants with distinct combinations of genome edited mutations in more than 80 known yield related genes into a crossing scheme, the combinatorial effect of these mutations on plant growth and yield will be evaluated. Subsequent rounds of crossings will increase the number of stacked gene-edits per plant, thus increasing the combinatorial complexity. Phenotypic evaluations throughout plant development will be done on our in-house automated image-analysis based phenotyping platform. The nature and frequency of Cas9-mediated mutations in the entire plant collection will be characterised by multiplex amplicon sequencing to follow the efficiency of CRISPR-cas9 genome editing and to identify the underlying combinations of genes that cause beneficial phenotypes (genetic gain). The obtained knowledge on yield regulatory networks can be directly implemented into current molecular breeding programs and the project will provide the basis to develop targeted breeding schemes implementing the optimal combinations of beneficial alleles into elite material. BREEDIT will be a major step forward in integrating basic knowledge on genes with plant breeding and has the potential to provoke a paradigm shift in improving crop yield.

2 474 790 €

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

Sexual reproduction depends on the programmed induction of DNA double-strand breaks (DSBs) and their ensuing repair by homologous recombination. This complex process is essential for sexual reproduction because it ultimately allows the pairing and separation of homologous chromosomes during formation of haploid gametes. Although meiotic recombination has been investigated for decades, many of the underlying molecular processes remain unclear, largely due to the lack of biochemical studies. I have recently made important progress by, for the first time, successfully purifying proteins involved in two aspects of meiotic recombination: DSB formation and the final stage of formation of the crossovers that are a central raison-d’être of meiotic recombination. This has opened new avenues for future research that I intend to pursue in my own laboratory. Here, I propose a set of biochemical approaches, complemented by molecular genetics methods, to gain insights into four central problems: (i) How meiotic proteins collaborate to induce DSBs; (ii) How DSB proteins interact with components that form the axes of meiotic chromosomes; (iii) How proteins involved at later stages of recombination form crossovers; and (iv) How crossover proteins interact with components of synapsed chromosomes. For each problem, I will set up in vitro systems to probe the activities of the players involved, their interactions with DNA, and their assembly into macromolecular complexes. In addition, I propose to develop new methodology for identifying proteins that are associated with DNA that has undergone recombination-related DNA synthesis. My goal is to gain insights into the mechanisms that govern meiotic recombination. Importantly, these mechanisms are intimately linked not only to gamete formation, but also to the general recombination pathways that all cells use to maintain genome stability. In both contexts, our findings will be relevant to the development and avoidance of disease states.

1 499 075 €

Start date: 2019-07-01, End date: 2024-06-30

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

1 400 885 €

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

Cancer is the result of a multi-step process requiring the accumulation of mutations in several genes. For most cancers, the target cells of oncogenic mutations are unknown. Adult stem cells (SCs) might be the initial target cells as they self-renew for extended periods of time, providing increased opportunity to accumulate the mutations required for cancer formation. Certain cancers contain cells characteristics of SC with high self-renewal capacities and the ability to reform the parental tumor upon transplantation. However, whether the initial oncogenic mutations arise in normal stem cells or in more differentiated cells that re-acquire stem cell-like properties remains to be determined. The demonstration that SCs are the target cells of the initial transforming events and that cancers contain cells with SC characteristics await the development of tools allowing for the isolation and characterization of normal adult SCs. In most epithelia from which cancers naturally arise, such tools are not yet available. We have recently developed novel methods to specifically mark and isolate multipotent epidermal slow-cycling SCs, making it now possible to determine the role of SC during epithelial cancer formation. In this project, we will use mice epidermis as a model to define the role of SC in epithelial cancer initiation and growth. Specifically, we will determine whether epithelial SCs are the initial target cells of oncogenic mutations during skin cancer formation, whether oncogenic mutations lead preferentially to skin cancer when they arise in SC rather than in more committed cells and whether cancer stem cells contribute to epithelial tumor growth and relapse after therapy.

1 600 000 €

Start date: 2008-07-01, End date: 2013-12-31

"Capnocytophaga canimorsus are Gram-negative bacteria from the normal oral flora of dogs, which cause rare but severe infections in humans that have been bitten or simply licked. The most common syndrome is fulminant septicemia with peripheral gangrene. Mortality reaches 40 % in spite of antibiotherapy and amputations. My laboratory pioneered recently the study of this new pathogen. We engineered genetic tools, sequenced and annotated the genome and determined the surface proteome of a strain isolated from a fatal infection. This showed that C. canimorsus have abundant surface-exposed lipoproteins forming a new kind of feeding complexes, some of them specialized in deglycosylating glycoproteins from the host. This property allows C. canimorsus to feed by grazing oligosaccharides at the surface of human cells. The present research program aims at characterizing these deglycosylating complexes, unravelling their role in neutralizing the innate immunity and promoting growth within the host and finally characterizing their assembly at the bacterial surface. Genomic comparisons will help defining which of these many complexes play a critical role in human pathogenesis. Besides this, the lipopolysaccharide structure will be determined and genetically manipulated to understand its low endotoxicity and small anti-inflammatory effectors present in the culture supernatant of C. canimorsus will be identified. Growth in human blood of wild type and mutant strains will be monitored by isothermal microcalorimetry in the hope of developing a surrogate of animal model. Such a ""virulence"" model would allow to address the question whether all dog's strains are equally dangerous for humans. It would also open an avenue for testing differences in individual human susceptibility. All this knowledge will give new insights in this emerging pathogen and might lead to prevention of the disease caused by C. canimorsus"

1 473 338 €

Start date: 2012-07-01, End date: 2016-06-30

We have recently discovered a series of carbene iridium complexes that are highly active in water oxidation catalysis (Angew. Chem. Int. Ed. 2010, 49, 9765, see also picture). As the water oxidation half-cycle is the demanding (and thus far prohibitive) step when splitting water to oxygen and hydrogen, these iridium complexes hold great potential for the generation of hydrogen as fuel from renewable, non-fossil sources. A key component for the efficient water oxidation appears to be the mesoionic carbene ligand, which is non-innocent and capable of assisting in proton-coupled electron transfer processes. Within this proof-of-concept project we now aim at evaluating a range of factors that will be pivotal to move this fundamentally interesting reactivity pattern into a prototypical device for energy generation. The principal goal thus consists of establishing the viability and to address technical issues and overall directions for using carbene iridium complexes in energy conversion processes. Clarification of intellectual property rights and deciding on an appropriate patent/licensing strategy constitutes a primary subaim. A specific and critical point to be addressed pertains to the robustness and activity of the catalyst in order to warrant the costs for using a precious metal in energy conversion and storage processes. Optimized catalysts will thus be essential, and will be combined with a photo-absorbing semiconductor as water reduction catalyst to accomplish full water splitting in a single, eventually light-driven device. In parallel, industrial contacts will be sought to identify domains for application of the catalytic device, in which longevity will be among the key criteria.

136 076 €

Start date: 2012-10-01, End date: 2013-09-30

Summary: Comprehensive set of circuits and design methods to create next generation electronic circuits with strong built-in trust and security. Electronics are integrating/invading into the human environment at an amazing speed, called the Internet-of-Things and next the Internet-of-Everything. This creates huge security problems. Distributed (e.g. body) sensors, pick up often very private data, which is sent digitally into the cloud, over wireless and wired links. Protection of this data relies on high-quality cryptographic algorithms and protocols. The nodes need to be cheap and lightweight, making them very vulnerable to eavesdropping and abuse. Moreover, post-Snowden, society realizes that the attack capabilities of intelligence agencies, and probably following soon of organized crime and other hackers, are orders of magnitude stronger than imagined. Thus there is a strong demand to re-establish trust in ICT systems. In this proposal we focus on the root of trust: the digital hardware. The overall objective is to provide fundamental enabling technologies for secure trustworthy digital circuits which can be applied in a wide range of applications. To master complexity, digital hardware design is traditionally split into different abstraction layers. We revisit these abstraction layers from a security viewpoint: we look at process variations to the benefit of security, standard cell compatible digital design flow with security as design objective, hardware IP blocks for next generation cryptographic algorithms and protocols (e.g. authenticated encryption schemes, post-quantum public key schemes), integration into embedded HW/SW platforms, and methods to provide trust evidence to higher levels of abstraction. To strengthen the security we investigate the links between the layers. Finally an embedded application is selected as design driver, the security evaluation of which will be fed back to the individual layers.

2 369 250 €

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

"DNA methylation was originally described in the 1970s as an epigenetic mark involved in transcriptional silencing, but the existence of DNA demethylation and the enzymes involved in this process were only recently discovered. In particular, it was established that TET hydroxylases catalyze the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) through a reaction requiring oxygen (O2) and 2-oxoglutarate (2OG). DNA demethylation as mediated by TET hydroxylases has so far predominantly been studied in the context of stem cells, but its precise contribution to carcinogenesis remains largely enigmatic. Nevertheless, somatic mutations in TETs have been identified in numerous cancers. Tumor hypoxia is linked to increased malignancy, poor prognosis and resistance to cancer therapies. In this proposal, we aim to assess how hypoxia directly impacts on the cancer epigenome through the dependence of TET-mediated DNA demethylation on O2. First of all, we will study the effect of O2 and 2OG concentration on TET hydroxylase activity, as well as the overall and locus-specific changes of their product (5hmC). Secondly, because much of the hypoxic response is executed through HIFs, we will investigate how HIF binding is influenced by DNA methylation and if so, whether TET hydroxylases are targeted to HIF (or other) binding sites to maintain them transcriptionally active. Thirdly, we will assess to what extent 5hmC profiles differ between tumor types and construct a comprehensive panel of (tumor-specific) 5hmC sites to assess the global and locus-specific relevance of 5hmC in various cancers. Finally, since hypoxia is a key regulator of the cancer stem cell (CSC) niche and within the tumor microenvironment also promotes metastasis, we will establish the in vivo relevance of DNA demethylation, as imposed by tumor hypoxia, in the CSC niche and during metastasis. Overall, we thus aim to establish the interplay between tumor hypoxia and the DNA methylome."

1 920 000 €

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

Since early 2015, the media continuously confront us with images of refugee children drowning in the Mediterranean, surviving in appalling conditions in camps or walking across Europe. Within this group of fleeing children, a considerable number is travelling without parents, the unaccompanied refugee minors. While the media images testify to these flight experiences and their possible huge impact on unaccompanied minors’ wellbeing, there has been no systematic research to fully capture these experiences, nor their mental health impact. Equally, no evidence exists on whether the emotional impact of these flight experiences should be differentiated from the impact of the traumatic events these minors endured in their home country or from the daily stressors in the country of settlement. This project aims to fundamentally increase our knowledge of the impact of experiences during the flight in relation to past trauma and current stressors. To achieve this aim, it is essential to set up a longitudinal follow-up of a large group of unaccompanied refugee minors, whereby our study starts from different transit countries, crosses several European countries, and uses innovative methodological and mixed-methods approaches. I will hereby not only document the psychological impact these flight experiences may have, but also the way in which care and reception structures for unaccompanied minors in both transit and settlement countries can contribute to reducing this mental health impact. This proposal will fundamentally change the field of migration studies, by introducing a whole new area of study and novel methodological approaches to study these themes. Moreover, other fields, such as trauma studies, will be directly informed by the project, as also clinical, educational and social work interventions for victims of multiple trauma. Last, the findings on the impact of reception and care structures will be highly informative for policy makers and practitioners.

1 432 500 €

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

In the gastrointestinal tract, the balance between activation of the mucosal immune system and tolerance should be tightly regulated to maintain immune homeostasis to prevent chronic inflammation and tissue damage. Recently, the new concept was introduced that the vagus nerve plays an important role in modulating immune homeostasis as part of a so-called inflammatory reflex. We provided evidence for this concept in the gastrointestinal tract and showed that vagus nerve stimulation (VNS) reduced inflammation of the intestinal muscle layer. Moreover, we showed that this effect was mediated by activation of enteric cholinergic neurons (cholinergic tone) interacting with intestinal macrophages in the muscle layer. Of interest, we have collected exciting data that the vagus nerve (and thus the cholinergic tone) also significantly contributes to mucosal immune homeostasis. Mice that underwent vagotomy lost their ability to develop tolerance to oral feeding of an antigen, whereas VNS reduced mucosal inflammation in a model of food allergy. Based on these data, we hypothesize that the cholinergic tone is a major determinant of the tolerogenic microenvironment of the mucosal immune system, and want to further explore the immune-modulatory effect of the vagal innervation and enteric neurons on the macrophages residing in the lamina propria. In addition, we will further explore the therapeutic potential and the mechanisms involved of chronic VNS in colitis and food allergy. Finally, we will translate our preclinical findings to the human situation. The anti-inflammatory effect of VNS (applied during surgery) will be studied in human intestinal tissue whereas the therapeutic potential of chronic VNS in Crohn’s disease will be studied in a pilot trial. The outcome of this project will be ground-breaking and will have an immense impact on clinical management as it will provide new therapeutic opportunities for the treatment of immune-mediated gastrointestinal disorders.

2 495 200 €

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

Early Medieval Irish literature (7th–10th centuries) is vast in extent and rich in genres, but owing to its mostly anonymous transmission, for most texts the precise time and circumstances of composition are unknown. Unless where texts contain historical references, the only clues for a rough chronological positioning of the texts are to be found in their linguistic peculiarities. Phonology, morphology, syntax and the lexicon of the Irish language changed considerably from Early Old Irish (7th c.) into Middle Irish (c. 10th–12th centuries). However, only the relative sequence of changes is well understood; for most sound changes very few narrow dates have been proposed so far. It is the aim of Chronologicon Hibernicum to find a common solution for both problems: through the linguistic profiling of externally dated texts (esp. annalistic writing and sources with a clear historical anchorage) and through serialising the emerging linguistic and chronological data, progress will be made in assigning dates to the linguistic changes. Groundbreakingly, this will be done by using statistical methods for the seriation of the data, and for estimating dates using Bayesian inference. The resultant information will then be used to find new dates for hitherto undated texts. On this basis, a much tighter chronological framework for the developments of the Early Medieval Irish language will be created. In a further step it will be possible to arrive at a better chronological description of medieval Irish literature as a whole, which will have repercussions on the study of the history and cultural and intellectual environment of medieval Ireland and on its connections with the wider world. The data collected and analysed in this project will form the database Chronologicon Hibernicum which will serve as the authoritative guideline and reference point for the linguistic dating of Irish texts. In the future, the methodology will be transferable to other languages.

1 804 230 €

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

Cell-state switching in cancer allows cells to transition from a proliferative to an invasive and drug-resistant phenotype. This plasticity plays an important role in cancer progression and tumour heterogeneity. We have made a striking observation that cancer cells of different origin can switch to a common survival state. During this epigenomic reprogramming, cancer cells re-activate genomic enhancers from specific regulatory programs, such as wound repair and epithelial-to-mesenchymal transition. The goal of my project is to decipher the enhancer logic underlying this canalization effect towards a common survival state. We will then employ this new understanding of enhancer logic to engineer synthetic enhancers that are able to monitor and manipulate cell-state switching in real time. Furthermore, we will use enhancer models to identify cis-regulatory mutations that have an impact on cell-state switching and drug resistance. Such applications are currently hampered because there is a significant gap in our understanding of how enhancers work. To tackle this problem we will use a combination of in vivo massively parallel enhancer-reporter assays, single-cell genomics on microfluidic devices, computational modelling, and synthetic enhancer design. Using these approaches we will pursue the following aims: (1) to identify functional enhancers regulating cell-state switching by performing in vivo genetic screens in mice; (2) to elucidate the dynamic trajectories whereby cells of different cancer types switch to a common survival cell-state, at single-cell resolution; (3) to create synthetic enhancer circuits that specifically kill cancer cells undergoing cell-state switching. Our findings will have an impact on genome research, characterizing how cellular decision making is implemented by the cis-regulatory code; and on cancer research, employing enhancer logic in the context of cancer therapy.

1 999 660 €

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

CONTEXT - Nanoporous structures are used for application in catalysis, molecular separation, fuel cells, dye sensitized solar cells etc. Given the near molecular size of the porous network, it is extremely challenging to modify the interior surface of the pores after the nanoporous material has been synthesized. THIS PROPOSAL - Atomic Layer Deposition (ALD) is envisioned as a novel technique for creating catalytically active sites and for controlling the pore size distribution in nanoporous materials. ALD is a self-limited growth method that is characterized by alternating exposure of the growing film to precursor vapours, resulting in the sequential deposition of (sub)monolayers. It provides atomic level control of thickness and composition, and is currently used in micro-electronics to grow films into structures with aspect ratios of up to 100 / 1. We aim to make the fundamental breakthroughs necessary to enable atomic layer deposition to engineer the composition, size and shape of the interior surface of nanoporous materials with aspect ratios in excess of 10,000 / 1. POTENTIAL IMPACT Achieving these objectives will enable atomic level engineering of the interior surface of any porous material. We plan to focus on three specific applications where our results will have both medium and long term impacts: - Engineering the composition of pore walls using ALD, e.g. to create catalytic sites (e.g. Al for acid sites, Ti for redox sites, or Pt, Pd or Ni) - chemical functionalization of the pore walls with atomic level control can result in breakthrough applications in the fields of catalysis and sensors. - Atomic level control of the size of nanopores through ALD controlling the pore size distribution of molecular sieves can potentially lead to breakthrough applications in molecular separation and filtration. - Nanocasting replication of a mesoporous template by means of ALD can result in the mass-scale production of nanotubes.

1 432 800 €

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

Through animal domestication humans profoundly altered their relationship with nature, controlling the breeding of their major food sources for material, social or symbolic profit. Understanding this complex process is a compelling research aim. There is a need to develop new high-resolution genetic tools to put flesh on the bones of this two-millenium long transition. These will take advantage of very recent advances: targeted next generation DNA sequencing, high throughput screening of expertly provenanced archaeological samples, and emerging knowledge of modern cattle, sheep and goat genome science plus their genetic geographies. Combining these, this proposal will develop an ancient DNA data matrix that will be unparalleled in archaeological science. These data will unlock the key genetic changes that accompany the domestic state and the breeding structures that are a consequence of human management. It will also identify the wild and proto-domestic populations that later herds emerge from. A more precise geography and timing of the key changes will enable richer contextualising inform our assessement of why these changes take place. The 10,000 year matrix for each species will function as a standard spatiotemporal reference grid on which any subsequent bone or animal artefact may be placed i.e. via genetic postcoding. Exceptional discontinuities in the matrix will highlight points of strong historical interest such as the emergence of new trade networks, migrations and periods of economic turbulence - perhaps driven by climate fluctuations or plagues. The final work objectives will focus on diachronic sample assemblages selected to have particular import for both historical events and transitions in material culture. For example, manuscript vellum samples will give a uniquely dated series that will enable correlation of genetic change with historical studies of the timing and impact of past animal plagues (e.g. in C 14th and C 18th Europe).

2 499 693 €

Start date: 2012-07-01, End date: 2018-06-30

"COGnitive NETwork (COGNET) is a new technology platform for materials, sensor and device design that exploits unique and hitherto unrecognised properties of random nanowire (NW) networks. These networks—comprised of metallic or semiconducting NWs connected to each other via junctions with controllably random property distributions—lead to new and unexpected levels of connectivity that are inherently scale dependent, creating opportunities for entirely new kinds of self-organised materials and devices. We propose to establish the ground rules for manipulating connectivity in NW networks. By choosing appropriate NWs and incorporating junctions with the approprate properties COGNET will enable the fabrication of (i) intelligent materials, (ii) neural networks and (iii) memory devices. Sequenced voltage pulse and back-gating techniques will in turn address and manipulate specific junctions or sets of junctions to demonstrate even higher density memory and in the case of neural networks, the possibility synaptic plasticity and self-learning."

2 497 125 €

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

This project will investigate how the prominence of counting and computation transforms many of the assumptions, operations and outcomes of the law. It targets two types of computational law: artificial legal intelligence or data-driven law (based on machine learning), and cryptographic or code-driven law (based on blockchain technologies). Both disrupt, erode and challenge conventional legal scholarship and legal practice. The core thesis of the research is that the upcoming integration of computational law into mainstream legal practice, could transform the mode of existence of law and notably of the Rule of Law. Such a transformation will affect the nature of legal protection, potentially reducing the capability of individual human beings to invoke legal remedies, restricting or ruling out effective redress. To understand and address this transformation, modern positive law will be analysed as text-driven law, enabling a comparative analysis of text-driven, data-driven and code-driven normativity. The overarching goal is to develop a new hermeneutics for computational law, based on (1) research into the assumptions and (2) the implications of computational law, and on (3) the development of conceptual tools to rethink and reconstruct the Rule of Law in the era of computational law. The intermediate goals are an in-depth assessment of the nature of legal protection in text-driven law, and of the potential for legal protection in data-driven and code-driven law. The new hermeneutics will enable a new practice of interpretation on the cusp of law and computer science. The research methodology is based on legal theory and philosophy of law in close interaction with computer science, integrating key insights into the affordances of computational architectures into legal methodology, thus achieving a pivotal innovation of legal method.

2 492 433 €

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

Low-rank matrix approximation (LRA) techniques such as principal component analysis (PCA) are powerful tools for the representation and analysis of high dimensional data, and are used in a wide variety of areas such as machine learning, signal and image processing, data mining, and optimization. Without any constraints and using the least squares error, LRA can be solved via the singular value decomposition. However, in practice, this model is often not suitable mainly because (i) the data might be contaminated with outliers, missing data and non-Gaussian noise, and (ii) the low-rank factors of the decomposition might have to satisfy some specific constraints. Hence, in recent years, many variants of LRA have been introduced, using different constraints on the factors and using different objective functions to assess the quality of the approximation; e.g., sparse PCA, PCA with missing data, independent component analysis and nonnegative matrix factorization. Although these new constrained LRA models have become very popular and standard in some fields, there is still a significant gap between theory and practice. In this project, our goal is to reduce this gap by attacking the problem in an integrated way making connections between LRA variants, and by using four very different but complementary perspectives: (1) computational complexity issues, (2) provably correct algorithms, (3) heuristics for difficult instances, and (4) application-oriented aspects. This unified and multi-disciplinary approach will enable us to understand these problems better, to develop and analyze new and existing algorithms and to then use them for applications. Our ultimate goal is to provide practitioners with new tools and to allow them to decide which method to use in which situation and to know what to expect from it.

1 291 750 €

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

Owing to their visual essence and status as a popular, modern medium, comics – newspaper strips, comics magazines and graphic novels – provide valuable insight into the transformation of collective consciousness. This project advances the hypothesis that children in comics are distinctive embodiments of the complex experience of modernity, channeling and tempering modern anxieties and incarnating the freedom denied to adults. In testing this hypothesis, the project constructs the first intercultural history of children in European comics, tracing the changing conceptualizations of child protagonists in popular comics for both children and adults from the mid-19th century to the present. In doing so, it takes key points in European history as well as the history of comics into account. Assembling a team of six multilingual researchers, the project uses an interdisciplinary methodology combining comics studies and childhood studies while also incorporating specific insights from cultural studies (history of family life, history of public life, history of the body, affect theory and scholarship on the carnivalesque). This enables the project to analyze the transposition of modern anxieties, conceptualizations of childishness, child-adult power relations, notions of liberty, visualizations of the body, family life, school and public life as well as the presence of affects such as nostalgia and happiness in comics starring children. The project thus opens up a new field of research lying at the intersection of comics studies and childhood studies and illustrates its potential. In studying popular but often overlooked comics, the project provides crucial historical and analytical material that will shape future comics criticism and the fields associated with childhood studies. Furthermore, the project’s outreach activities will increase collective knowledge about comic strips, which form an important, increasingly visible part of cultural heritage.

1 452 500 €

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

Connexin hemichannels and pannexin channels mediate the exchange of biochemical messengers between the cytosol of a cell and its extracellular environment. This type of cellular communication underlies cell death and inflammation, both which are associated with a plethora of diseases. Closing connexin hemichannels and pannexin channels therefore seems an interesting therapeutic strategy. In this respect, the ERC Starting Grant project CONNECT has demonstrated that peptide-based inhibition of Cx32 and Cx43 hemichannels as well as of Panx1 channels counteracts the manifestation of acute and chronic liver disease. However, these peptides cope with stability issues thus impeding clinical application. No other types of connexin hemichannel and pannexin channel inhibitors are available today despite their promising therapeutic potential. The present CONNECT-2-CLINIC project will meet this urgent need by generating specific and in vivo-applicable connexin hemichannel and pannexin channel inhibitors. These new inhibitors will be tested in vitro for their capacity to inhibit their target channels and to reduce inflammation. They will be subsequently tested in human-relevant mouse models of acute liver failure and non-alcoholic steatohepatitis. This dual technology track will be aligned by a 3-phase business track in order to analyze and create market value. By doing so, the CONNECT-2-CLINIC project will provide solid proof-of-concept for further pharmaceutical development and clinical application.

150 000 €

Start date: 2019-10-01, End date: 2021-03-31

In survival analysis investigators are interested in modeling and analysing the time until an event happens. It often happens that the available data are right censored, which means that only a lower bound of the time of interest is observed. This feature complicates substantially the statistical analysis of this kind of data. The aim of this project is to solve a number of open problems related to time-to-event data, that would represent a major step forward in the area of survival analysis. The project has three objectives: [1] Cure models take into account that a certain fraction of the subjects under study will never experience the event of interest. Because of the complex nature of these models, many problems are still open and rigorous theory is rather scarce in this area. Our goal is to fill this gap, which will be a challenging but important task. [2] Copulas are nowadays widespread in many areas in statistics. However, they can contribute more substantially to resolving a number of the outstanding issues in survival analysis, such as in quantile regression and dependent censoring. Finding answers to these open questions, would open up new horizons for a wide variety of problems. [3] We wish to develop new methods for doing correct inference in some of the common models in survival analysis in the presence of endogeneity or measurement errors. The present methodology has serious shortcomings, and we would like to propose, develop and validate new methods, that would be a major breakthrough if successful. The above objectives will be achieved by using mostly semiparametric models. The development of mathematical properties under these models is often a challenging task, as complex tools from the theory on empirical processes and semiparametric efficiency are required. The project will therefore require an innovative combination of highly complex mathematical skills and cutting edge results from modern theory for semiparametric models.

2 318 750 €

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

The evolution in drug regulation of the last 50 years has left pregnant women and their fetuses orphaned. This is particularly problematic for cancer during pregnancy, which raises a difficult and conflicting medical ethical decision process and which has recently become increasingly frequent. In 2012 we published the first prospective study indicating that antenatal exposure to cancer treatment can overall be considered safe. Building on this proof of concept, the current proposal wants to take a groundbreaking step towards developing a standard of care for cancer during pregnancy by addressing –in an integrated fashion- the challenges at the level of the fetus, the mother and the fetomaternal barrier. At the core of this proposal lies an international registry of pregnant women with cancer, along with a registry of their children, and biobanks of maternal, placental, cord blood and tumoral tissues. Research track ‘child’ aims to deliver robust evidence of fetal safety. Research track ‘mother’ aims to address the emerging concerns in the oncological management of the mother, and specifically, the possible distinct biology of pregnancy-associated breast cancer, the most frequent cancer type in pregnancy. The research approach includes large-scale clinical follow-up studies along with laboratory studies on patient biomaterials, including pharmacological investigations and RNA-sequencing studies. Complementary to these studies is research track ‘placenta’ in which cutting-edge models of human placental research are used to address the poorly understood physiological basis of the placental barrier function in this specific situation. This ambitious program will rely on a multidisciplinary team of experts. Not only may the scientific deliverables of this proposal constitute a major step forward to the well-being of both mother and fetus in a pregnancy complicated by cancer, the methodological approach may also provide critical impetus to further research in this field.

2 000 000 €

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

Side-channel attacks are an important threat against cryptographic implementations in which an adversary takes advantage of physical leakages, such as the power consumption of a smart card, in order to recover secret information. By circumventing the models in which standard security proofs are obtained, they can lead to powerful attacks against a large class of devices. As a consequence, formalizing implementation security and efficiently preventing side-channel attacks is one of the most challenging open problems in modern cryptography. Physical attacks imply new optimization criteria, with potential impact on the way we conceive algorithms and the way we design circuits. By putting together mathematical and electrical engineering problems, just as they are raised in reality, the CRASH project is expected to develop concrete basements for the next generation of cryptographic algorithms and their implementation. For this purpose, three main directions will be considered. First, we will investigate sound evaluation tools for side-channel attacks and validate them on different prototype chips. Second, we will consider the impact of physical attacks on the mathematical aspects of cryptography, both destructively (i.e. by developing new attacks and advanced cryptanalysis tools) and constructively (i.e. by investigating new cipher designs and security proof techniques). Third, we will evaluate the possibility to integrate physical security analysis into the design tools of integrated circuits (e.g. in order to obtain “physical security aware” compilers). Summarizing, this project aims to break the barrier between the abstractions of mathematical cryptography and the concrete peculiarities of physical security in present microelectronic devices. By considering the system and algorithmic issues in a unified way, it is expected to get rid of the incompatibilities between the separate formalisms that are usually considered in order to explain these concurrent realities.

1 498 874 €

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