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

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

149 062 €

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

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

1 493 679 €

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

Our field is cryptology. Our overarching objective is to advance significantly the frontiers in design and analysis of high-security cryptography for the future generation. Particularly, we wish to enhance the efficiency, functionality, and, last-but-not-least, fundamental understanding of cryptographic security against very powerful adversaries. Our approach here is to develop completely novel methods by deepening, strengthening and broadening the algebraic foundations of the field. Concretely, our lens builds on the arithmetic codex. This is a general, abstract cryptographic primitive whose basic theory we recently developed and whose asymptotic part, which relies on algebraic geometry, enjoys crucial applications in surprising foundational results on constant communication-rate two-party cryptography. A codex is a linear (error correcting) code that, when endowing its ambient vector space just with coordinate-wise multiplication, can be viewed as simulating, up to some degree, richer arithmetical structures such as finite fields (or products thereof), or generally, finite-dimensional algebras over finite fields. Besides this degree, coordinate-localities for which simulation holds and for which it does not at all are also captured. Our method is based on novel perspectives on codices which significantly widen their scope and strengthen their utility. Particularly, we bring symmetries, computational- and complexity theoretic aspects, and connections with algebraic number theory, -geometry, and -combinatorics into play in novel ways. Our applications range from public-key cryptography to secure multi-party computation. Our proposal is subdivided into 3 interconnected modules: (1) Algebraic- and Number Theoretical Cryptanalysis (2) Construction of Algebraic Crypto Primitives (3) Advanced Theory of Arithmetic Codices

2 447 439 €

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

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

1 952 374 €

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

Linear Parameter-Varying (LPV) systems are flexible mathematical models capable of representing Nonlinear (NL)/Time-Varying (TV) dynamical behaviors of complex physical systems (e.g., wafer scanners, car engines, chemical reactors), often encountered in engineering, via a linear structure. The LPV framework provides computationally efficient and robust approaches to synthesize digital controllers that can ensure desired operation of such systems - making it attractive to (i) high-tech mechatronic, (ii) automotive and (iii) chemical-process applications. Such a framework is important to meet with the increasing operational demands of systems in these industrial sectors and to realize future technological targets. However, recent studies have shown that, to fully exploit the potential of the LPV framework, a number of limiting factors of the underlying theory ask a for serious innovation, as currently it is not understood how to (1) automate exact and low-complexity LPV modeling of real-world applications and how to refine uncertain aspects of these models efficiently by the help of measured data, (2) incorporate control objectives directly into modeling and to develop model reduction approaches for control, and (3) how to see modeling & control synthesis as a unified, closed-loop system synthesis approach directly oriented for the underlying NL/TV system. Furthermore, due to the increasingly cyber-physical nature of applications, (4) control synthesis is needed in a plug & play fashion, where if sub-systems are modified or exchanged, then the control design and the model of the whole system are only incrementally updated. This project aims to surmount Challenges (1)-(4) by establishing an innovative revolution of the LPV framework supported by a software suite and extensive empirical studies on real-world industrial applications; with a potential to ensure a leading role of technological innovation of the EU in the high-impact industrial sectors (i)-(iii).

1 493 561 €

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

Carbon Nanotubes (CNTs) are considered to be one of 21st century’s most promising materials and over the past decade, tremendous scientific advances have been achieved in the synthesis and processing of these materials. However, the uptake of CNTs by high-tech industry is hampered by a lack of high-throughput processes to structure CNTs into aligned and densely packed assemblies. This is key to fabricate next generation CNT devices, and to date, the CNT community is still struggling to achieve this, especially over large areas. As part of the ERC Starting Grant HiENA, we are pioneering a potentially disruptive strategy to control the packing of CNTs and to fabricate large area films of aligned CNT. In this process, we start from newly developed ultra-high density dispersion of CNTs which can form liquid crystal domains. These domains are aligned by controlling shear in a custom designed coating head which then continuously dispenses the CNTs on a roll-to-roll coater which was recently purchased by the host group. To quantify the performance of the proposed technology, the parameter space of the coating process will be mapped out in terms of throughput, film thickness, uniformity, and conductivity. Finally, we devised a two-step commercialisation plan which targets less to more demanding markets including thin film heaters, ultra-lightweight electro-magnetic shields, as well as interconnects and sensors for flexible electronics. We believe this project is timely on the one hand because of the technology push of improved CNT processing and on the other hand by the pull from several new markets including flexible electronics and the rise of the Internet of Things which will require a drastic increase in low cost electronic manufacturing technologies. The ERC Proof of Concept grant ARENA aspires to contribute to this need by taking a leap forward in the large scale processing of next generation CNT devices.

149 963 €

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

Since 2012, over 4 million people have fled Syria in ‘the most dramatic humanitarian crisis that we have ever faced’ (UNHCR). By November 2015 there were 1,078,338 refugees from Syria in Lebanon, 630,776 in Jordan and 2,181,293 in Turkey. Humanitarian agencies and donor states from both the global North and the global South have funded and implemented aid programmes, and yet commentators have argued that civil society groups from the global South are the most significant actors supporting refugees in Lebanon, Jordan and Turkey. Whilst they are highly significant responses, however, major gaps in knowledge remain regarding the motivations, nature and implications of Southern-led responses to conflict-induced displacement. This project draws on multi-sited ethnographic and participatory research with refugees from Syria and their aid providers in Lebanon, Jordan and Turkey to critically examine why, how and with what effect actors from the South have responded to the displacement of refugees from Syria. The main research aims are: 1. identifying diverse models of Southern-led responses to conflict-induced displacement, 2. examining the (un)official motivations, nature and implications of Southern-led responses, 3. examining refugees’ experiences and perceptions of Southern-led responses, 4. exploring diverse Southern and Northern actors’ perceptions of Southern-led responses, 5. tracing the implications of Southern-led initiatives for humanitarian theory and practice. Based on a critical theoretical framework inspired by post-colonial and feminist approaches, the project contributes to theories of humanitarianism and debates regarding donor-recipient relations and refugees’ agency in displacement situations. It will also inform the development of policies to most appropriately address refugees’ needs and rights. This highly topical and innovative project thus has far-reaching implications for refugees and local communities, academics, policy-makers and practitioners.

1 498 069 €

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

In many prevalent autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) autoantibodies are used as diagnostic and prognostic tools. Several of these autoantibodies target proteins that have been post-translationally modified (PTM). Examples of such modifications are citrullination and carbamylation. The success of B cell-targeted therapies in many auto-antibody positive diseases suggests that B cell mediated auto-immunity is playing a direct pathogenic role. Despite the wealth of information on the clinical associations of these anti-PTM protein antibodies as biomarkers we have currently no insight into why these antibodies are formed. Immunization studies reveal that PTM proteins can induce antibody responses even in the absence of exogenous adjuvant. The reason why these PTM proteins have ‘autoadjuvant’ properties that lead to a breach of tolerance is currently unknown. In this proposal, I hypothesise that the breach of tolerance towards PTM proteins is mediated by complement factors that bind directly to these PTM. Our preliminary data indeed reveal that several complement factors bind specifically to PTM proteins. Complement could be involved in the autoadjuvant property of PTM proteins as next to killing pathogens complement can also boost adaptive immune responses. I plan to unravel the importance of the complement–PTM protein interaction by answering these questions: 1) What is the physiological function of complement binding to PTM proteins? 2) Is the breach of tolerance towards PTM proteins influenced by complement? 3) Can the adjuvant function of PTM be used to increase vaccine efficacy and/or decrease autoreactivity? With AUTOCOMPLEMENT I will elucidate how PTM-reactive B cells receive ‘autoadjuvant’ signals. This insight will impact on patient care as we can now design strategies to either block unwanted ‘autoadjuvant’ signals to inhibit autoimmunity or to utilize ‘autoadjuvant’ signals to potentiate vaccination.

1 999 803 €

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

Long-term studies of free-living vertebrate populations have proved a rich resource for understanding evolutionary and ecological processes, because individuals’ life histories can be measured by tracking them from birth/hatching through to death. In recent years the ‘animal model’ has been applied to pedigreed long-term study populations with great success, dramatically advancing our understanding of quantitative genetic parameters such as heritabilities, genetic correlations and plasticities of traits that are relevant to microevolutionary responses to environmental change. Unfortunately, quantitative genetic approaches have one major drawback – they cannot identify the actual genes responsible for genetic variation. Therefore, it is impossible to link evolutionary responses to a changing environment to molecular genetic variation, making our picture of the process incomplete. Many of the best long-term studies have been conducted in passerine birds. Unfortunately genomics resources are only available for two model avian species, and are absent for bird species that are studied in the wild. I will fill this gap by exploiting recent advances in genomics technology to sequence the entire transcriptome of the longest running study of wild birds – the great tit population in Wytham Woods, Oxford. Having identified most of the sequence variation in the great tit transcriptome, I will then genotype all birds for whom phenotype records and blood samples are available This will be, by far, the largest phenotype-genotype dataset of any free-living vertebrate population. I will then use gene mapping techniques to identify genes and genomic regions responsible for variation in a number of key traits such as lifetime recruitment, clutch size and breeding/laying date. This will result in a greater understanding, at the molecular level, how microevolutionary change can arise (or be constrained).

1 560 770 €

Start date: 2008-10-01, End date: 2014-06-30

In the last forty years, researchers in the Field of Migration and Ethnic Studies looked at the integration of migrants and their descendants. Concepts, methodological tools and theoretical frameworks have been developed to measure and predict integration outcomes both across different ethnic groups and in comparison with people of native descent. But are we also looking into the actual integration of the receiving group of native ‘white’ descent in city contexts where they have become a numerical minority themselves? In cities like Amsterdam, now only one in three youngsters under age fifteen is of native descent. This situation, referred to as a majority-minority context, is a new phenomenon in Western Europe and it presents itself as one of the most important societal and psychological transformations of our time. I argue that the field of migration and ethnic studies is stagnating because of the one-sided focus on migrants and their children. This is even more urgent given the increased ant-immigrant vote. These pressing scientific and societal reasons pushed me to develop the project BAM (Becoming A Minority). The project will be executed in three harbor cities, Rotterdam, Antwerp and Malmö, and three service sector cities, Amsterdam, Frankfurt and Vienna. BAM consists of 5 subprojects: (1) A meta-analysis of secondary data on people of native ‘white’ descent in the six research sites; (2) A newly developed survey for the target group; (3) An analysis of critical circumstances of encounter that trigger either positive or rather negative responses to increased ethnic diversity (4) Experimental diversity labs to test under which circumstances people will change their attitudes or their actions towards increased ethnic diversity; (5) The formulation of a new theory of integration that includes the changed position of the group of native ‘white’ descent as an important actor.

2 499 714 €

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

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 "hot" 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 "buffer gas cooling" 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

Pericytes, located at intervals along capillaries, have recently been revealed as major controllers of brain blood flow. Normally, they dilate capillaries in response to neuronal activity, increasing local blood flow and energy supply. But in pathology they have a more sinister role. After artery block causes a stroke, the brain suffers from the so-called “no-reflow” phenomenon - a failure to fully reperfuse capillaries, even after the upstream occluded artery has been reperfused successfully. The resulting long-lasting decrease of energy supply damages neurons. I have shown that a major cause of no-reflow lies in pericytes: during ischaemia they constrict and then die in rigor. This reduces capillary diameter and blood flow, and probably degrades blood-brain barrier function. However, despite their crucial role in regulating blood flow physiologically and in pathology, little is known about the mechanisms by which pericytes function. By using blood vessel imaging, patch-clamping, two-photon imaging, optogenetics, immunohistochemistry, mathematical modelling, and live human tissue obtained from neurosurgery, this programme of research will: (i) define the signalling mechanisms controlling capillary constriction and dilation in health and disease; (ii) identify the relative contributions of neurons, astrocytes and microglia to regulating pericyte tone; (iii) develop approaches to preventing brain pericyte constriction and death during ischaemia; (iv) define how pericyte constriction of capillaries and pericyte death contribute to Alzheimer’s disease; (v) extend these results from rodent brain to human brain pericytes as a prelude to developing therapies. The diseases to which pericytes contribute include stroke, spinal cord injury, diabetes and Alzheimer’s disease. These all have an enormous economic impact, as well as causing great suffering for patients and their carers. This work will provide novel therapeutic approaches for treating these diseases.

2 499 954 €

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

Recent evidence demonstrates that cancer is overtaking cardiovascular disease as the number one cause of mortality in Europe. This is largely due to the lack of preventative measures for common (e.g. breast) or highly fatal (e.g. ovarian) human cancers. Most cancers are multifactorial in origin. The core hypothesis of this research programme is that the extremely high risk of BRCA1/2 germline mutation carriers to develop breast and ovarian cancer is a net consequence of cell-autonomous (direct effect of BRCA mutation in cells at risk) and cell non-autonomous (produced in distant organs and affecting organs at risk) factors which both trigger epigenetic, cancer-initiating effects. The project’s aims are centered around the principles of systems medicine and built on a large cohort of BRCA mutation carriers and controls who will be offered newly established cancer screening programmes. We will uncover how ‘cell non-autonomous’ factors work, provide detail on the epigenetic changes in at-risk tissues and investigate whether these changes are mechanistically linked to cancer, study whether we can neutralise this process and measure success in the organs at risk, and ideally in easy to access samples such as blood, buccal and cervical cells. In my Department for Women’s Cancer we have assembled a powerful interdisciplinary team including computational biologists, functionalists, immunologists and clinician scientists linked to leading patient advocacy groups which is extremely well placed to lead this pioneering project to develop the fundamental understanding of cancer development in women with BRCA mutations. To reset the epigenome, re-establishing normal cell identity and consequently reducing cancer risk without the need for surgery and being able to monitor the efficacy using multicellular epigenetic outcome predictors will be a major scientific and medical breakthrough and possibly applicable to other chronic diseases.

2 497 841 €

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

This project focuses on the appropriation of the Old Testament by early Christian interpreters of the Bible. A historical approach, not commonly adopted in the study of biblical interpretation, will enable us to study how this process contributed to the formation of distinctive Christian identities within the multicultural society of the late Roman principate and early Byzantine rule. The exegetes of this period were to a great extent responsible for the creation of a distinctive, sophisticated, and uncompromising discourse—a ‘totalising Christian discourse’, which determines Christian identities up to this day. In two projects, carried out by three researchers, we will make cross sections of the relevant material. It was allegorizing interpretation that enabled exegetes belonging to the so-called School of Alexandria to recognize Christ everywhere in the Old Testament, and thus to appropriate it and make it useful to the Church. Thus the Song of Songs was no longer considered an earthly love song, but was said to describe Christ’s love for the Church. Exegetes associated with the School of Antioch opposed to this kind of approach. They are often described as literalists. The traditional understanding of the distinctions between the two schools needs to be broadened and corrected by a picture of the actual practice of their hermeneutics. In my view the Antiochene opposition was brought about by the fact that pagan and ‘heretic’ critics did not accept the Alexandrian use of allegory. My innovative hypothesis is related to the central role played by the letters of the apostle Paul in the Antiochene reaction against Alexandria. For the Antiochenes, the use of Paul became an alternative means to bridge the gap between the two Testaments. Instead of a book in which every jot and tittle referred to Christ through allegory, the Antiochenes came to view the Old Testament as an amalgamation of moral lessons that agreed with Paul's teaching.

655 309 €

Start date: 2008-09-01, End date: 2013-12-31