ERC FUNDED PROJECTS

I propose to pursue two emerging Force Microscopy techniques that allow measuring structural properties below the surface of the specimen. Whereas Force Microscopy (most commonly known under the name AFM) is usually limited to measuring the surface topography and surface properties of a specimen, I will demonstrate that Force Microscopy can achieve true 3D images of the structure of the cell nucleus. In Ultrasound Force Microscopy, an ultrasound wave is launched from below towards the surface of the specimen. After the sound waves interact with structures beneath the surface of the specimen, the local variations in the amplitude and phase shift of the ultrasonic surface motion is collected by the Force Microscopy tip. Previously, measured 2D maps of the surface response have shown that the surface response is sensitive to structures below the surface. In this project I will employ miniature AFM cantilevers and nanotube tips that I have already developed in my lab. This will allow me to quickly acquire many such 2D maps at a much wider range of ultrasound frequencies and from these 2D maps calculate the full 3D structure below the surface. I expect this technique to have a resolving power better than 10 nm in three dimensions as far as 2 microns below the surface. In parallel I will introduce a major improvement to a technique based on Nuclear Magnetic Resonance (NMR). Magnetic Resonance Force Microscopy measures the interaction of a rotating nuclear spin in the field gradient of a magnetic Force Microscopy tip. However, these forces are so small that they pose an enormous challenge. Miniature cantilevers and nanotube tips, in combination with additional innovations in the detection of the cantilever motion, can overcome this problem. I expect to be able to measure the combined signal of 100 proton spins or fewer, which will allow me to measure proton densities with a resolution of 5 nm, but possibly even with atomic resolution.

1 794 960 €

Start date: 2008-08-01, End date: 2013-07-31

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

1 225 000 €

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

Multidrug resistance of pathogenic bacteria has become a serious threat to public health. The need to develop novel technologies to combat the evolution of bacterial drug resistance is clearly a matter of public concern and urgency. The consequences of AMR include (i) reducing our ability to treat common infectious, resulting in prolonged illness and a greater risk of complications; (ii) patients remaining infectious for longer due to ineffective treatments, making them more likely to pass infections on to others; (iii) compromising advances in modern medicine (such as organ transplantation or chemotherapy) due to risk of infection; and (iv) increasing economic burden on health care systems, families, and societies. This project aims to assess the commercial viability of an alternative approach to this problem.

150 000 €

Start date: 2019-08-01, End date: 2021-01-31

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

1 499 195 €

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

The proposal refers to a patented adapter that can transform a commercial grade digital camera or the camera in a smart phone into a depth resolved imaging instrument. Several adapters will be assembled, making use of optical coherence tomography (OCT) technology protected by some other of PI’s patents. The activity takes advantage of recent progress in commercial grade cameras in terms of their modes of operation as well as in terms of parameters of their devices, such as sensitivity and speed of their photodetector arrays. Three versions of low cost functional OCT systems will be assembled as proof of concepts responding to needs of three possible markets that can be addressed by such an adapter: 1. En-face depth resolved, high transversal resolution microscope; 2. Fast cross sectioning imager. 3. Swept source volumetric analyser. Industrial input comes from a company involved in professional eye imaging systems, a company already selling adapters for smart phones to perform medical imaging, a company specialised in digital photographic equipment and a company efficient in prototyping photonics equipment and handling medical images. Clinical input is provided by two specialists in the two highest potential medical imaging markets of the adapter serving ophthalmology and ear, nose and throat speciality.

149 300 €

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

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

The project has a goal of starting up a small business producing highly special customizable microscope systems for biomedical research. Microscopic imaging is one of the major drivers of the progress in biomedical and life sciences. The development of novel concepts, addressing the challenges of advanced optical microscopy, represents the front line of scientific research. Modern microscopes are not purely optical devices anymore. They have developed into complex integrated systems, combining optics, mechanics, electronics, feedback control systems, and image processing Many novel concepts of modern microscopy, while very interesting for research, still have to prove the commercial profitability. Such developments can be effectively addressed by start-up companies with a goal of either custom development, production and service of these advanced systems, or development and selling the IP to a larger player. The major goal of this proposal is the creation of the first commercial optical microscope, the performance of which depends completely on the adaptive optics feedback controls. To prove the feasibility of this approach, we select a highly attractive technical concept of adaptive light sheet microscope, developed in our group in the framework of the ERC project. In this aspect, our development relates to ordinary microscope system in the same way as “fly by wire” airplane relates to an old-fashioned one. Our contribution in the development of instrumentation for biomedical research will bring a positive impact on our knowledge about the nature and ourselves, the quality of life and life expectation of the population. Our proposal addresses the largest societal challenge of Europe: the healthcare. Our instrument will contribute to the understanding of complex diseases and support the greying population to stay healthy and self-supportive for extended period of time.

149 998 €

Start date: 2017-05-01, End date: 2018-10-31

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

2 430 140 €

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

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

550 000 €

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

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

One’s ability to remember visual material such as objects, faces, and spatial locations over a short period of time declines with age. The proposed research will examine whether these deficits are explained by a reduction in visual working memory (VWM) capacity, or an impairment in one’s ability to maintain, or ‘bind’ appropriate associations among pieces of related information. In this project successful binding is operationally defined as the proper recall or recognition of objects that are defined by the conjunction of multiple visual features. While tests of long-term memory have demonstrated that, despite preserved memory for isolated features, older adults have more difficulty remembering conjunctions of features, no research has yet investigated analogous age related binding deficits in VWM. This is a critical oversight because, given the current state of the science, it is unknown whether these deficits are specific to the long-term memory system, or if they originate in VWM. The project interweaves three strands of research that each investigate whether older adults have more difficulty creating, maintaining, and updating bound multi-feature object representations than younger adults. This theoretical program of enquiry will provide insight into the cognitive architecture of VWM and how this system changes with age, and its outcomes will have wide ranging multi-disciplinary applications in applied theory and intervention techniques that may reduce the adverse consequences of aging on memory.

500 000 €

Start date: 2008-09-01, End date: 2011-08-31

The Arctic has risen to global attention in recent years, as it has been reconfigured through debates about global environmental change, resource extraction and disputes over sovereign rights. Within these discourses, little attention has been paid to the cultures of the Arctic. Indeed, it often seems as if the Circumpolar Arctic in global public understanding remains framed as a 'natural region' - that is, a place where the environment dominates the creation of culture. This framing has consequences for the region, because through this the Arctic becomes constructed as a space where people are absent. This proposal aims to discover how and why this might be so. The proposal argues that this construction of the Arctic emerged from the exploration of the region by Europeans and North Americans and their contacts with indigenous people from the middle of the eighteenth century. Particular texts, cartographic representations and objects were collected and returned to sites like London, Copenhagen, Berlin and Philadelphia. The construction of the Arctic thereby became entwined within the growth of colonial museum cultures and, indeed, western modernity. This project aims to delineate the networks and collecting cultures involved in this creation of Arctic Cultures. It will bring repositories in colonial metropoles into dialogue with sites of collection in the Arctic by tracing the contexts of discovery and memorialisation. In doing so, it aspires to a new understanding of the consequences of certain forms of colonial representation for debates about the Circumpolar Arctic today. The project involves research by the Principal Investigator and four Post Doctoral Researchers at museums, archives, libraries and repositories across Europe and North America, as well as in Greenland and the Canadian Arctic. A Project Assistant based in Oxford will help facilitate the completion of the research.

1 996 250 €

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

Knowledge is an anthropological constant that is indissociable from the birth and interactions of human societies, but is at best a secondary concern for scholars of international relations and globalization. Contemporary global studies are thus unable to account for the co-constitution of knowledge and politics at a macro-scale, and remain especially blind to the historical patterns of epistemic development that operate at the level of the species as a whole and have shaped its global political history in specific, path-dependent ways up to now. ARTEFACT is the first project to pursue a knowledge-centered investigation of global politics. It is uniquely grounded in an anthropological approach that treats globalization and human knowledges beyond their modern manifestations, from the longue-durée perspective of our species’ social history. 'The global as artefact' is more than a metaphor. It reflects the premise that human collectives 'make' the political world not merely through ideas, language, or norms, but primordially through the material infrastructures, solutions, objects, practices, and skills they develop in response to evolving structural challenges. ARTEFACT takes agriculture as an exemplary and especially timely case-study to illuminate the entangled global histories of knowledge and politics, analyzing and comparing four increasingly inclusive 'global political systems' of the Ancient, Medieval, Modern, and Contemporary eras and their associated agrarian socio-epistemic revolutions. ARTEFACT ultimately aims to 1) develop an original theory of the global, 2) launch Global Knowledge Studies as a new cross-disciplinary domain of systematic empirical and theoretical study, and 3) push the respective boundaries of the anthropology of knowledge, global history, and international theory beyond the state-of-the-art and toward a holistic understanding that can illuminate how past trends of socio-epistemic evolution might shape future paths of global life.

1 428 165 €

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

Atomic scale defects play a key role in determining the behaviour of all crystalline materials, profoundly modifying mechanical, thermal and electrical properties. Many current technological applications make do with phenomenological descriptions of these effects; yet myriad intriguing questions about the fundamental link between defect structure and material function remain. Transmission electron microscopy revolutionised the study of atomic scale defects by enabling their direct imaging. The novel coherent X-ray diffraction techniques developed in this project promise a similar advancement, making it possible to probe the strain fields that govern defect interactions in 3D with high spatial resolution (<10 nm). They will allow us to clarify the effect of impurities and retained gas on dislocation strain fields, shedding light on opportunities to engineer dislocation properties. The exceptional strain sensitivity of coherent diffraction will enable us to explore the fundamental mechanisms governing the behaviour of ion-implantation-induced point defects that are invisible to TEM. While we concentrate on dislocations and point defects, the new techniques will apply to all crystalline materials where defects are important. Our characterisation of defect structure will be combined with laser transient grating measurements of thermal transport changes due to specific defect populations. This unique multifaceted perspective of defect behaviour will transform our ability to devise modelling approaches linking defect structure to material function. Our proof-of-concept results highlight the feasibility of this ambitious research project. It opens up a vast range of exciting possibilities to gain a deep, fundamental understanding of atomic scale defects and their effect on material function. This is an essential prerequisite for exploiting and engineering defects to enhance material properties.

1 610 231 €

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

This project focuses on the historical analysis of institutions and their impact on economic development through the investigation of a legal instrument – general average (GA) – which underpins maritime trade by redistributing damages’ costs across all interested parties. This will be pursued through the comparative investigation of GA in those European countries where substantial data exists: Italy, Spain, England, France and the Low Countries (1500-1800). Average and insurance were both created in the Middle Ages to facilitate trade through the redistribution of risk. Insurance has been widely studied, average – the expenses which can befall ships and cargoes from the time of their loading aboard until their unloading (due to accidents, jettison, and unexpected costs) – has been neglected. GA still plays an essential role in the redistribution of transaction costs, and being a form of strictly mutual self-protection, never evolved into a speculative financial instrument as insurance did; it therefore represents an excellent case of long-term effectiveness of a non-market economic phenomenon. Although the principle behind GA was very similar across Europe, in practice there were substantial differences in declaring and adjudicating claims. GA reports provide unparalleled evidence on maritime trade which, analysed quantitatively and quantitatively through a novel interdisciplinary approach, will contribute to the reassessment of the role played by the maritime sector in fostering economic growth during the early modern first globalization, when GA was the object of fierce debates on state jurisdiction and standardization of practice. Today they are regulated by the York-Antwerp Rules (YAR), currently under revision. This timely conjuncture provides plenty of opportunities for active engagement with practitioners, thereby fostering a creative dialogue on GA historical study and its future development to better face the challenges of mature globalization.

1 854 256 €

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

The role of intestinal bacteria in human health and disease has been intensively studied; however the viral composition of the microbiome, the virome, remains largely unknown. As many of the viruses are bacteriophages, they are expected to be a major factor shaping the human microbiome. The dynamics of the virome during early life, its interaction with host and environmental factors, is likely to have profound effects on human physiology. Therefore it is extremely timely to study the virome in depth and on a wide scale. This ERC project aims at understanding how the gut virome develops during the first year of life and how that relates to the composition of the bacterial microbiome. In particular, we will determine which intrinsic and environmental factors, including genetics and the mother’s microbiome and diet, interact with the virome in shaping the early gut microbiome ecosystem. In a longitudinal study of 1,000 newborns followed at 7 time points from birth till age 12 months, I will investigate: (1) the composition and evolution of the virome and bacterial microbiome in the first year of life; (2) the role of factors coming from the mother and from the host genome on virome and bacterial microbiome development and their co-evolution; and (3) the role of environmental factors, like infectious diseases, vaccinations and diet habits, on establishing the virome and overall microbiome composition during the first year of life. This project will provide crucial knowledge about composition and maturation of the virome during the first year of life, and its symbiotic relation with the bacterial microbiome. This longitudinal dataset will be instrumental for identification of microbiome markers of diseases and for the follow up analysis of the long-term effect of microbiota maturation later in life. Knowledge of the role of viruses in shaping the microbiota may promote future directions for manipulating the human gut microbiota in health and disease.

1 499 881 €

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

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

Social interactions are multifaceted and subtle, yet we can almost instantaneously discern if two people are cooperating or competing, flirting or fighting, or helping or hindering each other. Surprisingly, the development and brain basis of this remarkable ability has remained largely unexplored. At the same time, understanding how we develop the ability to process and use social information from other people is widely recognized as a core challenge facing developmental cognitive neuroscience. The Becoming Social project meets this challenge by proposing the most complete investigation to date of the development of the behavioural and neurobiological systems that support complex social perception. To achieve this, we first systematically map how the social interactions we observe are coded in the brain by testing typical adults. Next, we investigate developmental change both behaviourally and neurally during a key stage in social development in typically developing children. Finally, we explore whether social interaction perception is clinically relevant by investigating it developmentally in autism spectrum disorder. The Becoming Social project is expected to lead to a novel conception of the neurocognitive architecture supporting the perception of social interactions. In addition, neuroimaging and behavioural tasks measured longitudinally during development will allow us to determine how individual differences in brain and behaviour are causally related to real-world social ability and social learning. The planned studies as well as those generated during the project will enable the Becoming Social team to become a world-leading group bridging social cognition, neuroscience and developmental psychology.

1 500 000 €

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

The Endoplasmic Reticulum (ER) membrane in all eukaryotic cells has an intricate protein network that facilitates protein biogene-sis and homeostasis. The molecular complexity and sophisticated regulation of this machinery favours study-ing it in its native microenvironment by novel approaches. Cryo-electron tomography (CET) allows 3D im-aging of membrane-associated complexes in their native surrounding. Computational analysis of many sub-tomograms depicting the same type of macromolecule, a technology I pioneered, provides subnanometer resolution insights into different conformations of native complexes. I propose to leverage CET of cellular and cell-free systems to reveal the molecular details of ER protein bio-genesis and homeostasis. In detail, I will study: (a) The structure of the ER translocon, the dynamic gateway for import of nascent proteins into the ER and their maturation. The largest component is the oligosaccharyl transferase complex. (b) Cotranslational ER import, N-glycosylation, chaperone-mediated stabilization and folding as well as oligomerization of established model substrate such a major histocompatibility complex (MHC) class I and II complexes. (c) The degradation of misfolded ER-residing proteins by the cytosolic 26S proteasome using cytomegalovirus-induced depletion of MHC class I as a model system. (d) The structural changes of the ER-bound translation machinery upon ER stress through IRE1-mediated degradation of mRNA that is specific for ER-targeted proteins. (e) The improved ‘in silico purification’ of different states of native macromolecules by maximum likelihood subtomogram classification and its application to a-d. This project will be the blueprint for a new approach to structural biology of membrane-associated processes. It will contribute to our mechanistic understanding of viral immune evasion and glycosylation disorders as well as numerous diseases involving chronic ER stress including diabetes and neurodegenerative diseases.

2 496 611 €

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

Massive stars play many key roles in Astrophysics. As COSMIC ENGINES they transformed the pristine Universe left after the Big Bang into our modern Universe. We use massive stars, their explosions and products as COSMIC PROBES to study the conditions in the distant Universe and the extreme physics inaccessible at earth. Models of massive stars are thus widely applied. A central common assumption is that massive stars are non-rotating single objects, in stark contrast with new data. Recent studies show that majority (70% according to our data) will experience severe interaction with a companion (Sana, de Mink et al. Science 2012). I propose to conduct the most ambitious and extensive exploration to date of the effects of binarity and rotation on the lives and fates of massive stars to (I) transform our understanding of the complex physical processes and how they operate in the vast parameter space and (II) explore the cosmological implications after calibrating and verifying the models. To achieve this ambitious objective I will use an innovative computational approach that combines the strength of two highly complementary codes and seek direct confrontation with observations to overcome the computational challenges that inhibited previous work. This timely project will provide the urgent theory framework needed for interpretation and guiding of observing programs with the new facilities (JWST, LSST, aLIGO/VIRGO). Public release of the model grids and code will ensure wide impact of this project. I am in the unique position to successfully lead this project because of my (i) extensive experience modeling the complex physical processes, (ii) leading role in introducing large statistical simulations in the massive star community and (iii) direct involvement in surveys that will be used in this project.

1 926 634 €

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

Imagine a heart that could no longer suffer from life-threatening rhythm disturbances, and not because of pills or traumatizing electroshocks from an Implantable Cardioverter Defibrillator (ICD) device. Instead, this heart has become able to rapidly detect & terminate these malignant arrhythmias fully on its own, after gene transfer. In order to explore this novel concept of biological auto-detection & termination of arrhythmias, I will investigate how forced expression of particular engineered proteins could i) allow cardiac tissue to become a detector of arrhythmias through rapid sensing of acute physiological changes upon their initiation. And how after detection, ii) this cardiac tissue (now as effector), could terminate the arrhythmia by generating a painless electroshock through these proteins. To this purpose, I will first explore the requirements for such detection & termination by studying arrhythmia initiation and termination in rat models of atrial & ventricular arrhythmias using optical probes and light-gated ion channels. These insights will guide computer-based screening of proteins to identify those properties allowing effective arrhythmia detection & termination. These data will be used for rational engineering of the proteins with the desired properties, followed by their forced expression in cardiac cells and slices to assess anti-arrhythmic potential & safety. Promising proteins will be expressed in whole hearts to study their anti-arrhythmic effects and mechanisms, after which the most effective ones will be studied in awake rats. This unexplored concept of self-resetting an acutely disturbed physiological state by establishing a biological detector-effector system may yield unique insight into arrhythmia management. Hence, this could provide distinctively innovative therapeutic rationales in which a diseased organ begets its own remedy, e.g. a Biologically-Integrated Cardiac Defibrillator (Bio-ICD).

1 485 028 €

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

Recent intensive research on the laser spectroscopy of neutral gas-phase biomolecules has yielded a detailed picture of their structures and conformational preferences away from the complications of the bulk environment. In contrast, work on ionic systems has been sparse despite the fact that many important molecular groups are charged under physiological conditions. To address this probelm, we have developed a custom-built laser spectrometer, which incorporates a distincitive electrospray ionisation (ESI) cluster ion source, dedicated to producing biological anions (ATP,oligonucleotides) and their microsolvated clusters for structural characterization. Many previous laser spectrometers with ESI sources have suffered from producing &quot;hot&quot; congested spectra as the ions were produced at ambient temperatures. This is a particularly serious limitation for spectroscopic studies of biomolecules, since these systems can possess high internal energies due tothe presence of numerous low frequency modes. Our spectrometer overcomes this problem by exploiting the newly developed physics technique of &quot;buffer gas cooling&quot; to produce cold ESI molecular ions. In this proposal, we now seek to exploit the new laser-spectrometer to perform detailed spectroscopic interrogations of ESI generated biomolecular anions and clusters. In addition to traditional ion-dissociation spectroscopies, we propose to develop two new laser spectroscopy techniques (Two-color tuneable IR spectroscopy and Dipole-bound excited state spectroscopy) to give the broadest possible structural characterizations of the systems of interest. Studies will focus on ATP/GTP-anions, olignonucleotides, and sulphated and carboxylated sugars. These methodologies will provide a general approach for performing temperature-controlled spectroscopic characterizations of isolated biological ions, with measurements on the corresponding micro-solvated clusters providing details of how the molecules are perturbed by solvent.

1 250 000 €

Start date: 2008-10-01, End date: 2015-06-30

Plant NLR-type immune receptors tend to have a narrow spectrum of pathogen recognition, which is currently limiting their value in agriculture. NLRs can recognize pathogen effectors through unconventional domains that have evolved by duplication of an effector target followed by fusion into the NLR. One NLR with an integrated domain is the rice resistance protein Pik-1, which binds an effector of the blast fungus Magnaporthe oryzae via its Heavy-Metal Associated (HMA) domain. We solved the crystal structure of the HMA domain of Pik-1 in complex with a blast fungus effector and gained an unprecedented level of detail of the molecular interactions that define pathogen recognition. This led to the overall aim of this proposal to generate a complete picture of the biophysical interactions between blast fungus effectors and HMA-containing cereal proteins to guide the retooling of the plant immune system towards resistance to blast diseases. M. oryzae is a general cereal killer that infects wheat, barley and rice, which are staple food for a majority of the world population. The central hypothesis of the proposed research is that mutations in cereal HMA-containing proteins will result in broad-spectrum resistance to blast fungi. To achieve our goal, we will pursue the following objectives: 1. BIOPHYSICS. Define the biophysical properties that underpin binding of M. oryzae effectors to HMA-containing proteins of cereal crops. 2. RECEPTOR ENGINEERING. Develop Pik-1 receptors that respond to a wide-spectrum of M. oryzae effectors. 3. GENOME EDITING. Mutate HMA domain-containing genes in cereal genomes to confer broad-spectrum blast resistance. At the completion of this project, we will generate a thorough understanding of the biophysical properties of pathogen effector binding to cereal HMA proteins, and deliver traits and non-transgenic cultivars for breeding blast disease resistance in cereal crops.

2 491 893 €

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

To successfully complete secondary education, persistent learning behavior is essential. Why are some adolescents more resilient to setbacks at school than others? In addition to actual ability, students’ implicit beliefs about the nature of their abilities have major impact on their motivation and achievements. Ability beliefs range from viewing abilities as “entities” that cannot be improved much by effort (entity beliefs), to believing that they are incremental with effort and time (incremental beliefs). Importantly, ability beliefs shape which goals a student pursues at school; proving themselves (performance goals) or improving themselves (learning goals). The central aims of the proposal are to unravel 1) the underlying processing mechanisms of how beliefs and goals shape resilience to setbacks at school and 2) how to influence these mechanisms to stimulate persistent learning behavior. Functional brain research, including my own, has revealed the profound top-down influence of goals on selective information processing. Goals may thus determine which learning-related information is attended. Project 1 jointly investigates the essential psychological and neurobiological processes to unravel the longitudinal effects of beliefs and goals on how the brain prioritizes information during learning, and how this relates to school outcomes. Project 2 reveals how to influence this interplay with the aim to long-lastingly stimulate persistent learning behavior. I will move beyond existing approaches by introducing a novel intervention in which students experience their own learning-related brain activity and its malleability. The results will demonstrate how ability beliefs and goals shape functional brain development and school outcomes during adolescence, and how we can optimally stimulate this interplay. The research has high scientific impact as it bridges multiple disciplines and thereby provides a strong impulse to the emerging field of educational neuroscience.

1 597 291 €

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

This project is an interdisciplinary study of the role of indigenous knowledge in the making of science. Situated at the intersection of history and anthropology, its main research objective is to understand the transformation of information and practices of South American indigenous peoples into a body of knowledge that became part of the Western scholarly canon. It aims to explore, by means of a distinctive case-study, how European science is constructed in intercultural settings. This project takes the book Historia Naturalis Brasiliae (HNB), published in 1648 by Piso and Marcgraf, as its central focus. The HNB is the first product of the encounter between early modern European scholarship and South American indigenous knowledge. In an encyclopedic format, it brings together information about the natural world, linguistics, and geography of South America as understood and experienced by indigenous peoples as well as enslaved Africans. Its method of construction embodies the intercultural connections that shaped practices of knowledge production in colonial settings across the globe, and is the earliest example of such in South America. With my research team, I will investigate how indigenous knowledge was appropriated and transformed into European science by focusing on ethnobotanics, ethnozoology, and indigenous material culture. Since the HNB and its associated materials are kept in European museums and archives, this project is timely and relevant in light of the growing concern for the democratization of heritage. The current debate about the societal role of publicly-funded cultural institutions across Europe argues for the importance of multi-vocality in cultural and political processes. This project proposes a more inclusive interpretation and use of the materials in these institutions and thereby sets an example of how European heritage institutions can use their historical collections to reconnect the past with present-day societal concerns.

1 475 565 €

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

As one of the largest carbon reservoirs in the Earth system, the ocean is central to understanding past, present and future fluctuations in atmospheric carbon dioxide. In this context, microscopic plants called phytoplankton are key as they consume carbon dioxide during photosynthesis and transfer part of this carbon to the ocean’s interior and ultimately the lithosphere. The overall abundance of phytoplankton also forms the foundation of ocean food webs and drives the richness of marine fisheries. It is key that we understand drivers of variations in phytoplankton growth, so we can explain changes in ocean productivity and the global carbon cycle, as well as project future trends with confidence. The numerical models we rely on for these tasks are prevented from doing so at present, however, due to a major theoretical gap concerning the role of trace metals in shaping phytoplankton growth in the ocean. This omission is particularly lacking at regional scales, where subtle interactions can lead to their co-limitation of biological activity. While we have long known that trace metals are fundamentally important to the photosynthesis and respiration of phytoplankton, it is only very recently that the necessary large-scale oceanic datasets required by numerical models have become available. I am leading such efforts with the trace metal iron, but we urgently need to expand our approach to other essential trace metals such as cobalt, copper, manganese and zinc. This project will combine knowledge of biological requirement for trace metals with these newly emerging datasets to move ‘beyond the iron curtain’ and develop the first ever complete numerical model of resource limitation of phytoplankton growth, accounting for co-limiting interactions. Via a progressive combination of data synthesis and state of the art modelling, I will deliver a step-change into how we think resource availability controls life in the ocean.

1 668 418 €

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

Homogeneous catalysis is of prime importance for the selective synthesis of high added value chemicals. Many of the currently available catalysts rely on noble metals (Ru, Os, Rh, Ir, Pd, Pt), which suffer from a high toxicity and environmental impact in addition to their high cost, calling for the development of new systems based on first-row transition metals (Mn, Fe, Co, Ni, Cu). The historical paradigm for catalyst design, i.e. one or more donor ligands giving electron density to stabilize a metal center and tune its reactivity, is currently being challenged by the development of acceptor ligands that mostly withdraw electron density from the metal center upon binding. In the last decade, such ligands – mostly based on boron and heavier main-group elements – have evolved from a structural curiosity to a powerful tool in designing new reactive units for homogeneous catalysis. I will develop a novel class of ligands that use C=E (E=O, S, NR) multiple bonds anchored in close proximity to the metal by phosphine tethers. The electrophilic C=E multiple bond is designed to act as an acceptor moiety that adapts its binding mode to the electronic structure of reactive intermediates with the unique additional possibility of involving the lone pairs on heteroelement E in cooperative reactivity. Building on preliminary results showing that a C=O bond can function as a hemilabile ligand in a catalytic cycle, I will undertake a systematic, experimental and theoretical investigation of the structure and reactivity of M–C–E three membered rings formed by side-on coordination of C=E bonds to a first-row metal. Their ability to facilitate multi-electron transformations (oxidative addition, atom/group transfer reactions) will be investigated. In particular, hemilability of the C=E bond is expected to facilitate challenging C–C bond forming reactions mediated by Fe and Ni. This approach will demonstrate a new conceptual tool for the design of efficient base-metal catalysts.

1 500 000 €

Start date: 2017-08-01, End date: 2022-07-31

Cancer screening and the diagnostics industry: a comparative analysis of the political economy of diagnostic innovation A decade after the Human Genome Project, major public and private investments continue to fuel expectations of a genomic revolution in biomedicine. The freight of expectations surrounding the new “age of diagnostics” is accompanied by much uncertainty about how public policy should steer diagnostic innovation, with much debate about inter alia the harms of creating diagnostic monopolies through gene patenting, and the risks of under- or over-regulation. However, due to the paucity of research on diagnostic innovation, policy deliberation is driven more by anecdote and expert opinion than empirical evidence. With a specific focus on screening/early detection of cancer, this project will map industry dynamics, technological trajectories and regulatory developments in Europe and the USA from 1996 to the present day. Combining quantitative and qualitative methods, the project’s innovative dimensions include a new conceptual model of socio-technical transition in the diagnostics sector, and the first integrative analysis linking scientometric data on the interactions between public and private actors in the diagnostic research domain with comparative transnational analysis of regulatory decision-making. Through a novel integration of conceptual insights from the literature on biomedicalisation and scholarship on socio-technical regime change, this project aims to advance both fields of research by applying a new multi-scale, multi-level model of socio-technical transition. The project will provide unprecedented insight into the factors shaping the development of a new generation of molecular diagnostic tests, and examine how these technologies are reconfiguring disease categories and redrawing the boundaries between health and sickness. We will establish a platform of theory and methods for a broader programme of work on diagnostic innovation.

1 347 992 €

Start date: 2017-04-01, End date: 2021-09-30

Solar energy conversion will play an essential role in the future supply of clean energy. Secure access to energy sources will require energy conversion technologies that are low impact, distributed and accessible both technically and financially. Molecular electronic materials embody these possibilities, offering facile synthesis, low energy production and the versatility to allow performance to be maximized for specific applications. Moreover, they bring appealing similarities with nature’s intrinsically low impact energy conversion materials. Whilst molecular semiconductors have been studied in detail for solar-to-electric energy conversion they have seldom been studied for solar-to-chemical conversion or for charge storage. However, they bring exciting potential advantages in terms of their light harvesting properties, the range of microstructures possible and the ability to tune their electrical properties. Polymer materials applied to solar chemical generation could open up an innovative route to artificial fuels, with the option to control light harvesting and charge separation through structural control. Polymer materials applied to mixed (electronic / ionic) conduction provide a route to lower cost electrochemical storage, as well as to biocompatible devices and sensors. Stimulated by recent experimental breakthroughs in the application of polymers as photocatalysts and ion transport media I will exploit my expertise in multi-scale modelling and functional characterization of molecular electronic materials and devices to develop a design framework for energy conversion and storage in conjugated polymer materials. This proposal aims to disentangle the parameters that govern the performance of conjugated polymer based photocatalysts and ion transport media to discover the underlying functional mechanisms. The tools generated will serve to enable the design and development of high performance materials for energy conversion devices.

2 351 550 €

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

Carbon and water in its various states of matter make up a substantial proportion of our Universe. The two materials are highly dissimilar with respect to their chemical and physical properties. Elemental carbon is even often referred to as a hydrophobic, ‘water-hating’ material. Yet, the two materials often coexist and critical processes take place at the interface between these unlike chemical species. This includes the hydration shells of hydrophobic moieties in biomolecules, clathrate hydrate materials where water molecules crystallise around hydrophobic guest species as well as icy comets which are often black due to the presence of carbon at their surfaces. The aim of the CARBONICE project is to investigate the interface and interplay between water and carbon in detail. Using new and innovative experimental strategies, the water molecule will be placed in a variety of different yet highly relevant carbon environments. This will give us unprecedented insights into how water hydrates hydrophobic species which is highly important in the context of hydrophobic interactions. Investigations into how carbon species influence phase transitions of ice will give new insights into crystallisation phenomena but will also reveal the factors that lead to the formation of either ferro- or antiferroelectric ices. Creating carbon – ice composites in the lab as they exist on comets will enable us to understand the complex weather cycles on comets and may help explaining the unusual surface features recently identified by the Rosetta space probe. In summary, this truly multidisciplinary project opens up a new spyhole to critically important processes at the water – carbon interface. The results will have an impact on the space, atmospheric and general materials sciences but will also be highly relevant with respect to further optimising the computer models of water as well as understanding the properties of water in nano-confinements and how it drives biological processes.

1 999 806 €

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

"This proposal aims to create a new generation of security assurance. It investigates whether one can certify an inter-connected dynamically changing system in such a way that one can prove its security properties without disclosing sensitive information about the system's blueprint. This has several compelling advantages. First, the security of large-scale dynamically changing systems will be significantly improved. Second, we can prove properties of topologies, hosts and users who participate in transactions in one go, while keeping sensitive information confidential. Third, we can prove the integrity of graph data structures to others, while maintaining their their confidentiality. This will benefit EU governments and citizens through the increased security of critical systems. The proposal pursues the main research hypothesis that usable confidentiality-preserving security assurance will trigger a paradigm shift in security and dependability. It will pursue this objective by the creation of new cryptographic techniques to certify and prove properties of graph data structures. A preliminary investigation in 2015 showed that graph signature schemes are indeed feasible. The essence of this solution can be traced back to my earlier research on highly efficient attribute encodings for anonymous credential schemes in 2008. However, the invention of graph signature schemes only clears one obstacle in a long journey to create a new generation of security assurance systems. There are still many complex obstacles, first and foremost, assuring ""soundness"" in the sense that integrity proofs a verifier accepts translate to the state of the system at that time. The work program involves six WPs: 1) to develop graph signatures and new cryptographic primitives; 2) to establish cross-system soundness; 3) to handle scale and change; 4) to establish human trust and usability; 5) to create new architectures; and 6) to test prototypes in practice."

1 485 643 €

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

Whereas the human heart cannot regenerate cardiac muscle after myocardial infarction, certain fish efficiently repair their hearts. Astyanax mexicanus, a close relative of the zebrafish, is a single fish species comprising cave-dwelling and surface river populations. Remarkably, while surface fish regenerate their heart after injury, cavefish cannot and form a permanent fibrotic scar, similar to the human heart. Using transcriptomics analysis and immunohistochemistry, we have identified key differences in the scarring and inflammatory response between the surface and cavefish heart after injury. These differences include extracellular matrix (ECM) proteins, growth factors and macrophage populations present in one, but not the other population, suggesting properties unique to the surface fish scar that promote heart regeneration. The objective of the proposed project is to characterise and utilise these findings to identify therapeutic targets to heal the human heart after myocardial infarction. First, we will analyse the identified differences in scarring and immune response between the fish in detail, before testing the role of the most interesting proteins and macrophage populations during regeneration using CRISPR mutagenesis and clodronate liposomes. Next, we will link the key scarring and inflammatory differences directly to both the genome and the ability for heart regeneration using new and prior Quantitative Trait Loci analyses. This will allow to find the most fundamental molecular mechanisms directing the wound healing process towards regeneration versus scarring. Together with an in vitro and in vivo small molecule screen directed specifically at influencing scarring towards a more ‘fish-like’ regenerative phenotype in the cavefish and mouse heart after injury, this will provide targets for therapeutic strategies to maximise the endogenous regenerative potential of the mammalian heart, with the aim to find a cure for myocardial infarction.

1 499 429 €

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

Despite decades of research, developing ways to overcome drug resistance in cancer is the most challenging bottleneck for curative therapies. This is because, in some forms of cancer, the cancer stem cells from which the diseases arise are constantly evolving, particularly under the selective pressures of drug therapies, in order to survive. The events leading to drug resistance can occur within one or more individual cancer stem cell(s) – and the features of each of these cells need to be studied in detail in order to develop drugs or drug combinations that can eradicate all of them. The BCR-ABL+ and BCR-ABL- myeloproliferative neoplasms (MPN) are a group of proliferative blood diseases that can be considered both exemplars of precision medicine and of the drug resistance bottleneck. While significant advances in the management of MPN have been made using life-long and expensive tyrosine kinase inhibitors (TKI), patients are rarely cured of their disease. This is because TKI fail to eradicate the leukaemia stem cells (LSC) from which MPN arise and which persist in patients on treatment, often leading to pervasive drug resistance, loss of response to therapy and progression to fatal forms of acute leukaemia. My goal is to change the way we study the LSC that persist in MPN patients as a means of delivering more effective precision medicine in MPN that is a “game-changer” leading to therapy-free remission (TFR) and cure. Here, I will apply an innovative strategy, ChAMPioN, to study the response of the MPN LSC to TKI in innovative pre-clinical laboratory models and directly in patients with MPN - up to the resolution of individual LSC. This work will reveal, for the first time, the molecular and clonal evolution of LSC during TKI therapies, thus enabling the development of more accurate predictions of TKI efficacy and resistance and rational approaches for curative drug therapies.

3 005 818 €

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

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

There has been vast improvement in workplace gender equality, but there remain marked differences in the roles in which women and men work. Explanations for this inequality have focused on the barriers women face. However, as women begin to enter male-dominated roles, a new explanation has arisen: that remaining gender inequality must reflect fundamental differences between women and men, including differences in (a) ambition and desire for power, (b) needs for work-life balance, and (c) willingness to take career risks. Central to this analysis is the assumption that the glass ceiling is broken and thus inequality must be due to women’s active choices. This explanation downplays the fact that social context continues to be a barrier to women’s success and places responsibility for gender inequality on women themselves. Indeed, there has arisen the suggestion that gender equality necessitates women overcoming ‘internal obstacles’, ‘leaning-in’ and altering their choices (Sandberg, 2013), rather than challenging the status quo. I argue that diametrically contrasting structural barriers with women’s choices is unhelpful. Instead, I suggest that women’s choices are shaped and constrained by the gendered nature of organisational and social contexts and how women see themselves within these contexts. I propose a programme of research, across 3 integrated streams, that investigates how social and organisational structures define identities and constrain women’s choices in relation to ambition, work-life balance, and career risk-taking. I have four key objectives: (1) to clarify how organisational and social contexts define identity and constrain women’s choices, (2) to use an interdisciplinary, multi-methodological approach, to produce innovative theory and data, (3) to work collaboratively with stakeholders, and (4) to inform practical interventions designed to facilitate the increase of women’s participation in hitherto male-dominated roles.

1 998 722 €

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

A highly significant division in present-day Europe is between two types of legal system: the Continental with foundations in Civil Law (law with an ultimately Roman law basis), and English Common Law. Both trace their continuous history back to the twelfth century. The present project re-evaluates this vital period in legal history, by comparing not just English Common Law and Continental Civil Law (or “Ius commune”), but also the customary laws crucially important in Continental Europe even beyond the twelfth century. Such laws shared many features with English law, and the comparison thus disrupts the simplistic English:Continental distinction. The project first analyses the form, functioning and development of local, national, and supra-national laws. Similarities, differences, and influences will then be examined from perspectives of longer-term European legal development. Proper historical re-examination of the subject is very timely because of current invocation of supposed legal histories, be it Eurosceptic celebration of English Common Law or rhetorical use of Ius commune as precedent for a common European Law. F. W. Maitland wrote that ‘there is not much “comparative jurisprudence” for those who do not know thoroughly well the things to be compared’. A comparative project requires collaboration – PI, senior researcher, post-doctoral and doctoral researchers, and Advisory Board. It also needs an integrated approach, through carefully selected areas, themes, and sources. The purpose is not just to provide geographical and thematic coverage but to assemble scholars who overcome divisions of approach in legal historiography: between lawyers and historians, between national traditions, between Common Law and Civil Law. The project is thus very significant in developing methods for writing comparative legal history - and legal history and comparative law more widely - in terms of uncovering patterns, constructing narratives, and testing theories of causation.

2 161 502 €

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

Coherence of law is created in the writings of legal scholars who systematize rules and principles of law. Their pursuit of coherence is vital for the effectiveness of legal systems. However, coherence of law has almost not been analysed in a systematic, empirical way. The project will therefore develop a methodology that will address coherence across forms (‘sources’) of law (legislation, legal scholarship, case law, customs), across themes (e.g. criminal law and contracts) and across authors, and which will additionally encompass interaction with societal demand and contextual factors. The methodology will be ground-breaking because it will disentangle the concept of coherence into measurable modes of interconnectedness, weighing them together so as to assess (in)coherence at the level of the legal system. This methodology will constitute a stepping stone for a new field of dynamic coherence of law created through legal scholarship that will ultimately improve the quality of law. It will be founded on academic writings on law from the early modern period (ca. 1500 - ca. 1800) that concern the theme of collateral rights, that is, those rights facilitating expropriation of the assets of debtors in case of their default. Indications are that the impact of rules on collateral rights hinged on coherence as established in legal writings, and that in the period mentioned legal coherence for this theme was increasing. Coherence in development will be traced in the interpretations of legal scholars following on from interactions between scholarly writings, local law (bylaws, judgments) and commercial practice (contracts). Connections of rules and principles found will be presented in frames of analysis that cluster them along variables of context, time and source of law. The combination of legal analysis with a broad scope of coherence (cross-source, context-driven) will build bridges across gaps now existing between the different disciplines that study law.

1 495 625 €

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

Do even the smallest clouds simply drift with the wind? Vast areas of our oceans and land are covered with shallow cumulus clouds. These low-level clouds are receiving increased attention as uncertainties in their representation in global climate models lead to a spread in predictions of future climate. This attention emphasizes radiative and thermodynamic impacts of clouds, which are thought to energize the large-scale Hadley circulation. But broadly overlooked is the impact of shallow cumuli on the trade-winds that drive this circulation. Reasons for this negligence are a lack of observations of vertical wind structure and the wide range of scales involved. My project will test the hypothesis that shallow cumuli can also slow down the Hadley circulation by vertical transport of momentum. First, observations of clouds and winds will be explicitly connected and the causality of their relationship will be exposed using ground-based and airborne measurements and high-resolution modeling. Second, new lidar techniques aboard aircraft are exploited to validate low-level winds measured by the space-borne Aeolus wind lidar and collect high-resolution wind and turbulence data. Third, different models of momentum transport by shallow convection will be developed to represent its impact on winds. Last, evidence of global relationships between winds and shallow cumulus are traced in Aeolus and additional satellite data and the impact of momentum transport on circulations in a control and warmer climate is tested in a general circulation model. This project exploits my expertise in observing and modeling clouds and convection focused on a hypothesis which, if true, will strongly influence our understanding of the sensitivity of circulations and the sensitivity of climate. It will increase the predictability of low-level winds and convergence patterns, which are important to many disciplines, including climate studies, numerical weather prediction and wind-energy research.

1 867 120 €

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

The vast majority of our knowledge about how the brain encodes information has been obtained from recordings of one or few neurons at a time or from global mapping methods such as fMRI. These approaches have left unexplored how neuronal activity is distributed in space and time within a cortical column and how hundreds of neurons interact to process sensory information. By taking advantage of the most recent advances in two-photon microscopy, the proposed project addresses two broad aims, with a particular focus on the function and development of primary visual cortex: 1) to understand how cortical neuronal networks encode visual information, and 2) to understand how they become specialised for sensory processing during postnatal development. For the first aim, we will use in vivo two-photon calcium imaging to record activity simultaneously from hundreds of neurons in visual cortex while showing different visual stimuli to anaesthetised mice. This approach enables us for the first time to characterise in detail how individual neurons and neuronal subsets interact within a large cortical network in response to artificial and natural stimuli. Genetically-encoded fluorescent proteins expressed in distinct cell-types will inform us how excitatory and inhibitory neurons interact to shape population responses during vision. For the second aim, the same approach will be used to describe the maturation of cortical network function after the onset of vision and to assess the role of visual experience in this process. We will additionally use Channelrhodopsin-2, a genetic tool for remote control of action potential firing, to examine the role of correlated neuronal activity on establishment of functional cortical circuits. Together, this work will bring us closer to unravelling how sensory coding emerges on the level of neuronal networks.

1 080 000 €

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

Processes on the Antarctic continental shelf and slope are crucially important for determining the rate of future sea level rise, setting the properties and volume of dense bottom water exported globally, and regulating the carbon cycle. Yet our ability to model and predict these processes over future decades remains rudimentary. This deficiency in understanding originates in a lack of observations in this inaccessible region. The COMPASS project seeks to rectify that by exploiting new technology - autonomous marine vehicles called gliders - to observe, quantify and elucidate processes on the continental shelf and slope of Antarctica that are important for climate. The COMPASS objective is to make a step-change in our quantitative understanding of: (i) the ocean front that marks the boundary between the Antarctic continental shelf and the open ocean, and its associated current system; (ii) the interaction between ocean, atmosphere and sea-ice on the Antarctic continental shelf; and (iii) the exchange of heat, salt and freshwater with the cavities beneath ice shelves. These goals will be met by a series of targeted ocean glider campaigns around Antarctica, spanning different flow regimes, including areas where warm water is able to access the continental shelf and influence ice shelves, areas where the continental shelf is cold and fresh, and areas where the continental shelf hosts cold, salty, dense water that eventually spills into the abyss. A unique circumpolar assessment of ocean properties and dynamics, including instabilities and mixing, will be undertaken. COMPASS will develop new technology to deploy a profiling glider into inaccessible environments such as Antarctic polynyas (regions of open water surrounded by sea-ice). As well as scientific breakthroughs that will feed into future climate assessments, improving projections of future sea level rise and global temperatures, COMPASS will deliver enhanced design for future ocean observing systems.

3 499 270 €

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

Over the next five years an unprecedented number of initiatives will coalesce, contributing to an extension of the reach of the Internet to the world’s most remote regions. While previous efforts to expand Internet access have focused on urban areas, current initiatives are leveraging new technologies from drones to satellites to provide affordable access to the worlds poorest, many of whom are in Africa and live in regions where the state is weak and there is protracted violent conflict. Current debates have largely focused on technical issues of improving access, or assumed ways that technology will help ‘liberate’ populations or improve governance. This project focuses on a key puzzle that is often overlooked: How does increased access to social media affect the balance between peace-building efforts and attempts perpetuate violence in conflict-affected communities? With a focus on Africa (and particularly on religious and political violence in Eastern Africa), this project will investigate the relationship between social media and conflict through three research questions at the macro, meso and micro level: how are social media altering the transnational dimensions of conflict and peacebuilding? How are public authorities reacting to, and appropriating, social media to either encourage violence or promote peace? And in what ways are social media changing the way people experience, participate in, or respond to violent conflict? It will examine these questions in the context of dangerous speech online; the exit and entry of individuals away from, and into, conflict; the tactics and strategies actors adopt to shape the Internet; and how governance actors are leveraging social media in conflict-affected communities.

1 499 450 €

Start date: 2017-08-01, End date: 2022-07-31

Via our connections we learn about new ideas, quality of products, new investment opportunities and job opportunities. We influence and are influenced by our circle of friends. Firms are interconnected in complex processes of production and distribution. A firm’s decisions in a supply chain depends on other firms’ choices in the same supply chain, as well as on firms' behaviour in competing chains. Research on networks in the last 20 years has provided a series of tolls to study a system of interconnected economic agents. This project will advance the state of the art by further developing new applications of networks to better understand modern oligopoly markets. The project is organised into two sub-projects. In sub-project 1 networks will be used to model diffusion and adoption of network goods. Different consumers' network locations will summarise different consumers' level of influence. The objectives are to understand how firms incorporate information about consumers' influence in their marketing strategies—pricing strategy and product design. It will provide a rigorous framework to evaluate how the increasing ability of firms to gather information on consumers’ influence affects outcomes of markets with network effects. In sub-project 2 networks will be used to model how inputs—e.g., intermediary goods and patents—are combined to deliver final goods. Possible applications are supply chains, communication networks and networks of patents. The objectives are to study firms' strategic behaviour, like pricing and R&D investments, in a complex process of production and distribution, and to understand the basic network metrics that are useful to describe market power. This is particularly important to provide a guide to competition authorities and alike when they evaluate mergers in complex interconnected markets.

829 000 €

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

Vertebrates contain hundreds of different cell types which maintain phenotypic identity by a combination of epigenetic programming and genomic regulation. Systems biology approaches are now used in a number of laboratories to determine how transcription factors and chromatin marks pattern the human genome. Despite high conservation of the cellular and molecular function of many mammalian transcription factors, our recent experiments in matched mouse and human tissues indicates that most transcription factor binding events to DNA are very poorly conserved. A hypothesis that could account for this apparent divergence is that the larger regional pattern of transcription factor binding may be conserved. To test this, (1) we are characterizing the global transcriptional profile, chromatin state, and complete genomic occupancy of a set of tissue-specific transcription factors in hepatocytes of strategically chosen mammals; (2) to further identify the precise mechanistic contribution of cis and trans effects, we are comparing transcription factor binding at homologous regions of human and mouse DNA in a mouse line that carries human chromosome 21. Together, these projects will provide insight into the general principles of how transcriptional networks are evolutionarily conserved to regulate cell fate specification and function using a clinically important cell type as a model.

960 000 €

Start date: 2008-10-01, End date: 2013-09-30

Expansion of a hexanucleotide repeat G4C2 in the non-coding region of chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is a fatal condition characterized by progressive motor deficits, degeneration of upper and lower motor neurons (MNs) and death from neuromuscular respiratory failure in the majority of afflicted individuals within 3-5 years. Currently, the economic burden of care and treatment for patients with ALS/FTD is expensive and continues to significantly rise in Europe and worldwide. While significant genetic discoveries have been made in the field, they have not yet translated to treatment options for patients with ALS and FTD. Thus, research efforts aimed at identifying therapeutic targets are of the utmost importance to enable therapeutic development for these devastating disorders. In this ERC Proof of Concept project, we will design, optimise and test gene therapy vectors containing CRISPR/Cas9 system to selectively remove the pathogenic ALS/FTD-related C9orf72 hexanucleotide repeat expansion in mouse models of C9orf72-related ALS, with the ultimate aim of designing a therapy for patients with C9orf72-related ALS/FTD. The ultimate benefit of this approach goes far beyond just ALS/FTD however. A successful CNS gene therapy for C9orf72 related disease potentiates the prospect of developing similar approaches to treat multiple disease scenarios amenable to gene modification. Indeed, growing evidence suggests that C9orf72 repeat expansions also contribute to a wide spectrum of neurodegenerative diseases such as Alzheimer’s, Huntington’s, multiple sclerosis, Parkinson’s disease and cerebellar ataxias. We therefore anticipate that our strategy could be beneficial for other neurological conditions.

149 995 €

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

At the heart of the multi-faceted enterprise of formal semantics lies a simple yet powerful conception of meaning based on truth-conditions: one understands a sentence if one knows under which circumstances the sentence is true. This notion has been extremely fruitful resulting in a wealth of practical applications. But to what extent can it also account for the human linguistic behavior? The past decade has seen the increasing interaction between cognitive science and formal semantics, and the emergence of the new field of experimental semantics. One of its main challenges is the traditional normative take on meaning, which makes semantic theories hard to compare with experimental data. The aim of this project is to advance experimental semantics by building cognitive semantics, that is semantics founded on cognitive representations instead of normative logical abstractions. Numerical information plays a central role in communication. We talk about the number of students in a class, or the proportion of votes for a particular political party. In this project, I will focus on the linguistic expressions of quantities, known as quantifiers. Recent progress in the study of computational constraints on quantifier processing in natural language laid the groundwork for extending semantic theory with cognitive aspects. In parallel, cognitive science has furthered the study of non-linguistic quantity representations. This project will integrate formal models of quantifier semantics with cognitive quantity representations in order to obtain cognitive semantics of quantifiers, which is both logically precise and psychologically plausible. The theory will have significant repercussions, not only in the immediately related disciplines as semantics and psycholinguistics, but also beyond, e.g., in philosophy and in language technology.

1 457 063 €

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

"The management of mesoscale dynamics is the missing link in gaining complete control over chemical processes like heterogeneous catalysis. The ability to accurately position nanoscale active elements in cellular mesoscale (nm to µm-range) structures with high symmetrical order is instrumental in streamlining vital molecular or energetic paths. 3D periodicity in the structure that supports active or adsorption sites minimizes spatial variations in mass transport, whereas mesoscale control of the location of these sites gives a route to tuning activity and functionality. The introduction of mesoscale metamaterials expands the on-going trend in chemistry, of more and more dimensionally refined structured elements, a so to speak ""Moore's law in Process Intensification"". The roadmap to higher process efficiency dictates a next, disruptive step in mastering manufacturing control at smaller dimensions. The proposed disruptive technology to realize the required mesoscale features is Additive Manufacturing, which is the only method offering the desired freedom in shape, symmetry and composition. More specifically, this project explores electrospinning methods with precise intra-wire control of the position of active sites and accurately tuneable 3D inter-wire distances. This is seen as the ideal technique to reach the mesoscale material target, as the method is scalable to practical device volumes. The main ingredients of the novel technology are microfluidic networks to line up nanoparticles, before electrospinning them with integrated micromachined nozzles, and depositing them accurately in the form of 3D nanowire networks, using integrated circuit collector electrodes. Flow-through, cellular materials which are highly homogeneous in size and composition, or with intentionally embedded gradients, having features designed at the mesoscale, will be investigated for applications in the fields of heterogeneous catalysis and solar energy capture and conversion."

2 500 000 €

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

The profound trauma associated with rape and sexual violence in conflict has been extensively explored within existing scholarship. The fact that many survivors exhibit remarkable post-trauma resilience, however, remains critically under-investigated. CSRS will address this fundamental gap by undertaking a paradigm-shifting empirical study of the underlying conditions for resilience. It will then use this data to pioneer a new, survivor-centred model of transitional justice – the process of redressing the legacy of massive human rights abuses. Using the three comparative case studies of Bosnia-Hercegovina (BiH), the Democratic Republic of Congo (DRC) and Colombia, and adopting a social-ecological approach that emphasizes the interactions between individuals and their environments, CSRS consists of two inter-linked parts. The first part will involve extensive fieldwork, using a combination of quantitative and qualitative research methods, to generate a rich cross-cultural dataset that identifies and explains the key micro, meso and macro factors that foster resilience in survivors of war rape and sexual violence. The second part of CSRS will use this dataset to build an innovative, bottom-up model of transitional justice that prioritizes the long-term needs of survivors, reflecting the project’s hypothesis that a positive correlation exists between fulfilment of needs and resilience. This model will be developed with the input of survivors in BiH, the DRC and Colombia and in consultation with transitional justice scholars and practitioners. CSRS aims to transform transitional justice theory and practice. The project outputs will therefore include both academic publications and policy reports to communicate the model to the governments of the case study countries, the United Nations and a wider international audience with the overall aim of making empowerment and resilience part of a new transitional justice agenda.

1 790 580 €

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

Cells use an intricate network of intracellular signalling molecules to translate environmental changes, sensed via surface receptors, into cellular responses. Despite their prominent role in regulating every aspect of life, we lack a comprehensive understanding of how signalling networks convey extracellular information into specific bioactivities and fate decisions. To rationally manipulate cell fate, which could fundamentally change the way that we treat human diseases, first we need a systematic understanding of how signalling is initiated and propagated inside the cell. I discovered that specificity of cytokine receptor signalling not only depends on cellular determinants such as receptor density and endocytic trafficking, but can be systematically altered by modulating ligand binding parameters and receptor binding geometries. A fundamentally novel approach combining high-throughput flow cytometry and QMS with engineered cytokine surrogate ligands able to fine-tune signalling responses will generate detailed maps of the signalling networks engaged by cytokines in time and space to unveil the mechanistic basis that allow a receptor to trigger different signal activation programs and bioactivities in response to different ligands. By quantitatively characterizing the signalling programs activated by ligands, using state-of-the-art biochemical, biophysical, structural, genetic and fluorescence imaging techniques, I plan to identify events critical for cellular decisions. By fully characterizing the intracellular signalling network hard-wired inside a cell and understanding its dynamic in response to environmental changes will we be able to comprehend and manipulate the enormous functional plasticity exhibited by cells. TInsights generated will open new fields of investigation where engineered ligands prove indispensable to understand complex biological responses and greatly advance our understanding of cytokine biology and human immunology in health and disease.

1 687 500 €

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

Insects bristle with sensors, but how do they exploit this rich sensory information to achieve their extraordinary stability and manoeuvrability? Bird and insect wings deform in flight, and have passively deployable structures such as feathers and flaps, but how do they exploit these features when aircraft designers shy away from aeroelasticity? Birds fly without a vertical tailfin, but how do they maintain yaw stability when most aircraft require one to fly safely? Questions such as these drive my research on bird and insect flight dynamics. My research is unique in using the engineering tools of flight dynamics and control theory to analyse physiological and biomechanical data from real animals. One research track will use measurements of the forces and torques generated by insects flying tethered in a virtual-reality flight simulator to parameterise their equations of motion, in order to model the input-output relationships of their sensorimotor control systems. A second research track will measure the detailed wing kinematics and deformations of free-flying insects in order to analyse the effects of aeroelasticity on flight manoeuvres. A third research track will measure the wing and tail kinematics of free-flying birds using onboard wireless video cameras, and use system identification techniques to model how these affect the body dynamics measured using onboard instrumentation. Applying these novel experimental techniques will allow me to make and test quantitative predictions about flight stability and control. This highly interdisciplinary research bridges the fields of physiology and biomechanics, with significant feeds to and from engineering. My research will break new ground, developing novel experimental techniques and theoretical models in order to test and generate new hypotheses of adaptive function. Its broader impacts include the public interest in all things flying, and potential military and civilian applications in flapping micro-air vehicles.

1 954 565 €

Start date: 2008-06-01, End date: 2014-05-31