ERC FUNDED PROJECTS

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

In an era of rapid climate change there is a pressing need to understand whether and how organisms are able to adapt to novel environments. Such understanding is hampered by a major divide in the life sciences. Disciplines like systems biology or neurobiology make rapid progress in unravelling the mechanisms underlying the responses of organisms to their environment, but this knowledge is insufficiently integrated in eco-evolutionary theory. Current eco-evolutionary models focus on the response patterns themselves, largely neglecting the structures and mechanisms producing these patterns. Here I propose a new, mechanism-oriented framework that views the architecture of adaptation, rather than the resulting responses, as the primary target of natural selection. I am convinced that this change in perspective will yield fundamentally new insights, necessitating the re-evaluation of many seemingly well-established eco-evolutionary principles. My aim is to develop a comprehensive theory of the eco-evolutionary causes and consequences of the architecture underlying adaptive responses. In three parallel lines of investigation, I will study how architecture is shaped by selection, how evolved response strategies reflect the underlying architecture, and how these responses affect the eco-evolutionary dynamics and the capacity to adapt to novel conditions. All three lines have the potential of making ground-breaking contributions to eco-evolutionary theory, including: the specification of evolutionary tipping points; resolving the puzzle that real organisms evolve much faster than predicted by current theory; a new and general explanation for the evolutionary emergence of individual variation; and a framework for studying the evolution of learning and other general-purpose mechanisms. By making use of concepts from information theory and artificial intelligence, the project will also introduce various methodological innovations.

2 500 000 €

Start date: 2018-12-01, End date: 2023-11-30

Systemic Sclerosis (SSc, scleroderma) is a complex autoimmune disorder of unclear aetiology, culminating in excessive extracellular matrix deposition (fibrosis/tissue scarring) in skin and internal organs (e.g. joints, heart, lung, gastrointestinal tract and kidneys). More than half of the patients will ultimately die as a result of organ complications. The medical need is exacerbated by the lack of curative treatments and the lack of specific and sensitive molecular markers to facilitate reliable diagnosis and prognosis. My team has recently demonstrated, through research funded by the ERC Starting Grant CIRCUMVENT, that the chemokine CXCL4 is a central player in the pathogenesis of SSc. Our results suggest that CXCL4 has great potential as 1) a biomarker to assist early diagnosis, 2) a biomarker to predict SSc disease course, and 3) a therapeutic target for the treatment or prevention of fibrosis in patients with SSc. Currently, a robust, accessible, reliable, cheap and fast assay to determine CXCL4 levels for clinical use is lacking. This prohibits the use of CXCL4 to predict clinical and treatment outcome and complicates the large-scale replication experiments across multiple labs and cohorts that are necessary to validate the diagnostic value of CXCL4. Therefore, we argue that a reliable in vitro assay measuring circulating CXCL4 levels is highly needed and can be deployed as a research support tool to accelerate the implementation of clinical strategies based on CXCL4 and a clinical decision support tool in SSc to complement current diagnostic protocols. ASSYSt will focus on 1) the development of a reliable assay to adequately determine circulating CXCL4 levels irrespective of sample collection and storage conditions, 2) assessing the market potential of each of the applications listed above, and 3) defining a strong business strategy to guide route to market.

150 000 €

Start date: 2018-08-01, End date: 2020-01-31

Cosmic Rays (ionized atomic nuclei) are the only matter from beyond our solar system or even from extragalactic space, that we can directly investigate. Up to energies of 10^17 eV they most likely originate in our Galaxy. The highest-energy cosmic rays (>10^18 eV) cannot be magnetically bound any more to the Galaxy and are most likely of extragalactic origin. The pure existence of these particles raises the question about their origin – how and where are they accelerated? How do they propagate through the universe and interact? How can we directly probe extragalactic matter and how can we locate its origin? A key to understand the origin of cosmic rays is to measure the particle species (atomic mass). A precise mass measurement will allow discriminating astrophysical models and will clarify the reason for the observed suppression of the cosmic-ray flux at the highest energies, namely the maximum energy of the accelerators or the energy losses during propagation. I address these questions by employing a new technique to precisely measure the cosmic-ray mass composition, which my group pioneered, the radio detection of air showers (induced by high-energy cosmic rays in the atmosphere) on very large scales, detecting horizontal air showers with zenith angles from 60° to 90°. The new set-up will be the world-largest radio array, operated together with the well-established Auger surface and fluorescence detectors, forming a unique set-up to measure the properties of cosmic rays with unprecedented precision for energies above 10^17.5 eV. The radio technique is a cost-effective and robust method to measure the cosmic-ray energy and mass, complementary to established techniques. The energy scale of the radio measurements is established from first principles. The proposed detectors will also enhance the detection capabilities for high-energy neutrinos and the search for new physics through precision measurements of the electromagnetic and muonic shower components.

3 499 249 €

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

This project has the potential to radically change current understanding of cultic and social transformation in the post-exilic temple community of Jerusalem (c. 6th-4th centuries BCE), an important formative phase of ancient Judaism. “BABYLON” draws on recent, ground-breaking advances in the study of cuneiform texts to illuminate the Babylonian environment of the Judean exile, the socio-historical context which gave rise to the transformative era in Second Temple Judaism. In particular, these new data show that the parallels between Babylonian and post-exilic forms of cultic and social organization were substantially more far-reaching than presently recognized in Biblical scholarship. “BABYLON” will study the extent of these similarities and explore the question how Babylonian models could have influenced the restoration effort in Jerusalem. This goal will be achieved through four sub-projects. P1 will study the social dynamics and intellectual universe of the Babylonian priesthood. P2 will finalize the publication of cuneiform archives of Babylonian priests living in the time of the exile. P3 will identify the exact areas of change in the post-exilic temple community of Jerusalem. P4, the synthesis, will draw from each of these sub-projects to present a comparative study of the Second Temple and contemporary Babylonian models of cultic and social organization, and to propose a strategy of research into the possible routes of transmission between Babylonia and Jerusalem. The research will be carried out by three team members: the PI (P1 and P4), a PhD in Assyriology (P2) and a post-doctoral researcher in Biblical Studies specialized in the Second Temple period (P3 and P4). The participation of the wider academic community will be invited at two moments in the course of the project, in the form of a workshop and an international conference. “BABYLON” will adopt an interdisciplinary approach by bringing together Assyriologists and Biblical scholars for a much-needed dialogue, thereby exploding the artificial boundaries that currently exist in the academic landscape between these two fields.

1 200 000 €

Start date: 2009-09-01, End date: 2015-08-31

In this BioMechMeniscus project we will develop a workflow for optimal placement of a novel meniscus implant. The medial meniscus implant (named ‘Trammpolin’) has been developed using methods developed during the BioMechTools project such as 1) principle component analyses based on MRI-segmented image to assess the anatomical shape of the meniscus, 2) assessing sensitivity of cartilage stresses and implant strains on size and design-parameters using finite element techniques and 3) utilizing load-predictions from our award-winning musculoskeletal models. All data shows that the biomechanical behaviour of Trammpolin in the knee will be sensitive to appropriate sizing and positioning within the knee. Therefore, this BioMechMeniscus project focuses on developing a surgeon-friendly platform to pre-plan the size and position and to execute the surgery as accurately as possible. The software will automatically perform MRI-segmentation of the tibia, femur and meniscus insertion sites. Subsequently, the best meniscus implant size and position (leading to the lowest cartilage stress and acceptable implant strains) is proposed by the program. The surgeon can adapt the proposal and gets feedback about the expected changes in biomechanical performance. After the pre-plan is accepted a patient-specific arthroscopic surgical guide is 3-D printed which will be used as an aiming device for an external (standard) surgical guide for fixation of the horns. The project is subdivided in four Tasks and will last for 18 months. An experienced team will supervise a post-doc during the various activities. A project scheme is made and a risk and contingency plan is defined. A detailed competitor and commercial analysis has been made and we are convinced that with the BioMechMeniscus project we have a unique opportunity to bring a novel implant to the market and support it with a distinct pre-planning and surgical assistance tool to optimize clinical performance.

150 000 €

Start date: 2017-11-01, End date: 2019-04-30

Recent advances in cryptography yielded the blockchain technology, which enables a radically new and decentralized method to maintain authoritative records, without the need of trusted intermediaries. Bitcoin, a cryptocurrency blockchain application has already demonstrated that it is possible to operate a purely cryptography-based, global, distributed, decentralized, anonymous financial network, independent from central and commercial banks, regulators and the state. The same technology is now being applied to other social domains (e.g. public registries of ownership and deeds, voting systems, the internet domain name registry). But research on the societal impact of blockchain innovation is scant, and we cannot properly assess its risks and promises. In addition, crucial knowledge is missing on how blockchain technologies can and should be regulated by law. The BlockchainSociety project focuses on three research questions. (1) What internal factors contribute to the success of a blockchain application? (2) How does society adopt blockchain? (3) How to regulate blockchain? It breaks new ground as it (1) maps the most important blockchain projects, their governance, and assesses their disruptive potential; (2) documents and analyses the social diffusion of the technology, and builds scenarios about the potential impact of blockchain diffusion; and (3) it creates an inventory of emerging policy responses, compares and assesses policy tools in terms of efficiency and impact. The project will (1) build the conceptual and methodological bridges between information law, the study of the self-governance of technological systems via Science and Technology Studies, and the study of collective control efforts of complex socio-technological assemblages via Internet Governance studies; (2) address the most pressing blockchain-specific regulatory challenges via the analysis of emerging policies, and the development of new proposals.

1 499 631 €

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

Worldwide, wireless communication traffic is growing at a staggering pace. Driven by digitalization of nearly every aspect of our lives and by the ‘Fourth Industrial Revolution’, the numbers of mobile broadband devices as well as the proliferation of small sensing and actuating devices (the ‘Internet of Things’) are exploding. The vast majority of wireless traffic is generated indoors, and radio-based wireless networks such as Wi-Fi are getting into severe states of traffic congestion. By means of Optical Wireless Communication (OWC), vast new spectrum bands can be opened without licensing needs, which provides relief to the use of congested unlicensed radio-spectrums. We have developed OWC by means of ultra-high capacity 2D-steered narrow infrared optical beams. Our research group recently made a breakthrough by improving the download speed of indoor Wi-Fi by a factor beyond 300x compared to conventional Wi-Fi via radio waves. In our approach, we can devote and guarantee the full capacity to each separate device in the room. This is an extensive improvement to the current technologies, which are allocating the available capacity among all the users in a shared fashion. The technical and pre-commercialisation work in this PoC project will equip us with the sufficient IP protection strategy, patent portfolio, business plan, industry and application piloting networks, initial contacts with funding bodies and make our technology more mature, ready-to-be-taken out from the laboratory to real-life experiments. By commercialising our novel innovation, we aim for strong global impact by developing dramatic improvement in wireless connectivity. This will concretely lead to an orders-of-magnitude higher wireless capacity per user, reduced energy consumption, improved privacy, improved resources utilization by novel networking dynamics and avoiding radio spectrum licensing issues.

150 000 €

Start date: 2018-06-01, End date: 2019-11-30

In the pursuit for engineering CELL HYBRIDGE regenerative medicine implants able to regenerate skeletal tissues by controlling adult stem cell activity, we have developed an innovative method to successfully improve cell migration into electrospun scaffolds. Whereas this has a direct impact in CELL HYBRIDGE as part of the planned activities, we unexpectedly discovered that the same scaffolds display wavy patterns that have a direct influence on cell differentiation by enhancing their intrinsic capacity to produce growth factors. Driven by these observations, we have optimized the methodology and are able today to control the formation of such wavy patterns at a single fiber as well as multiple fiber scales by controlling the degree of buckling that the fibers are exposed to during processing. In doing so, we can reproduce the same waviness that is observed in several native tissues, among which tendons and ligaments. The aim of BUCKLING BRIDGES is to further investigate these instructive scaffolds as potentially smart implants for the regeneration of anterior cruciate ligaments. This will be done by further confirming our in vitro data and proof our concept by showing successful ligament regeneration in a preclinical animal model. While doing so, we will also explore the market potential of such products and develop a business plan for the creation of a spin-off company: TISSUE BRICKS.

150 000 €

Start date: 2018-01-01, End date: 2019-12-31

Mammalian complement recognizes a variety of cell-surface danger and damage signals to clear invading microbes and injured host cells, while protecting healthy host cells. Improper complement responses contribute to diverse pathologies, ranging from bacterial infections up to paralyzing Guillain-Barré syndrome and schizophrenia. What determines the balance between complement attack reactions and host-cell defense measures and, thus, what drives cell fate is unclear. My lab has a long-standing track record in elucidating molecular mechanisms underlying key complement reactions. We have revealed, for example, how the interplay between assembly and proteolysis of these large multi-domain protein complexes achieves elementary regulatory functions, such as localization, amplification and inhibition, in the central (so-called alternative) pathway of complement. Results from my lab underpin research programs for the development of novel therapeutic approaches in academia and industry. Here the goal is to understand how the molecular mechanisms of complement attack and defense on cell membranes determine clearance of a cell. Enabled by new mechanistic insights and preliminary data we can now address both long-standing and novel questions. In particular, we will address the role of membrane organization and dynamics in complement attack and defense. Facilitated by recent technological developments, we will combine crystallography, cryo-EM, cryo-ET and high-resolution microscopy to resolve complement complex formations and reactions on membranes. Thus, this project aims to provide an integrative understanding of the molecular complement mechanisms that determine cell fate. Results will likely be of immediate importance for novel therapeutic approaches for a range of complement-related diseases. Furthermore, it will provide clarity into the general, and possibly fundamental, role of complement in tissue maintenance in mammals.

2 332 500 €

Start date: 2018-07-01, End date: 2023-06-30

We have witnessed significant work-life policy advancements designed to help men and women more equally combine employment with other spheres of life in recent decades, yet gender inequality persists. Improving gender equality in work-life balance is therefore high on policy agendas throughout Europe. Decades of research in this area have produced key insights but work-family theories fail to sufficiently explain the tenacity of this inequality. Earlier applications of a capabilities approach to work-life balance offer promising inroads, yet the importance of community remains absent. The CAPABLE project will generate fundamentally new knowledge on how work-life balance policies impact an individual’s capability to achieve this balance in Europe by incorporating the understudied dimension of community. Capabilities reflect what individuals are effectively able to achieve. CAPABLE asks: To what extent do work-life balance policies enhance men and women’s capabilities to achieve work-life balance? To answer this question, we will develop and apply complex models derived from Sen’s capability approach to analyse: 1. the availability, accessibility and design of work-family policies; 2. what these policies mean for men and women’s capabilities to achieve work-life balance based on their embeddedness in individual, community and social contexts; 3. whether work-life policies enhance individual wellbeing; and 4. what policy tools are needed for developing sustainable work-life balance policies that enhance gender equal work-life capabilities. CAPABLE will progress scientific and policy frontiers using innovative, mixed-methods approaches at multiple policy levels. The conceptual clarity and empirical advancements provided will significantly expand our understanding of work-life policies in relation to individual capabilities. Furthermore, it will produce key insights into how sustainable work-life policies addressing gender inequality in work-life can be developed.

1 999 748 €

Start date: 2018-12-01, End date: 2023-11-30

With this proposal the PI capitalises on his recent breakthroughs in transition metal catalysed carbene (migratory) insertion reactions to build up a new research line for controlled catalytic preparation of a variety of new functionalised (co)polymers with expected special material properties. Metallo-carbenes are well-known intermediates in olefin cyclopropanation and olefin metathesis, but the PI recently discovered that their chemistry is far richer. He demonstrated for the first time that metallo-carbenoids can be used in transition metal catalysed insertion polymerisation to arrive at completely new types of stereoregular carbon-chain polymers functionalised at each carbon of the polymer backbone. Rhodium mediated polymerisation of carbenes provides the means to prepare new materials with yet unknown properties. It also provides a valuable alternative to prepare practically identical polymers as in the desirable (but still unachievable) highly stereo-selective (co)polymerisation of functionalised olefins, representing the ‘holey-grail’ in world-wide TM polymerisation catalysis research. The mechanism and scope of this remarkable new discovery will be investigated and new, improved catalysts will be developed for the preparation of novel materials based on homo- and copolymerisation of a variety of carbene precursors. Copolymerisation of carbenes and other reactive monomers will also be investigated and the properties of all new materials will be investigated. In addition the team will try to uncover new reactions in which carbene insertion reactions play a central role. DFT calculations suggest that the transition state (TS) of the new carbene polymerisation reaction is very similar to the TS’s of a variety of carbonyl insertion reactions. Based on this analogy, the team will investigate several new carbene insertion reactions, potentially leading to new, useful polymeric materials and new synthetic routes to prepare small functional organic molecules.

1 250 000 €

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

Familial forms of neurodegenerative diseases are caused by mutations in a single gene. It is unknown whether distinct mutations in the same gene or in functionally related genes cause disease through similar or disparate mechanisms. Furthermore, the precise molecular mechanisms underlying virtually all neurodegenerative disorders are poorly understood, and effective treatments are typically lacking. This is also the case for Charcot-Marie-Tooth (CMT) peripheral neuropathy caused by mutations in five distinct tRNA synthetase (aaRS) genes. We previously generated Drosophila CMT-aaRS models and used a novel method for cell-type-specific labeling of newly synthesized proteins in vivo to show that impaired protein translation may represent a common pathogenic mechanism. In this proposal, I aim to determine whether translation is also inhibited in CMT-aaRS mouse models, and whether all mutations cause disease through gain-of-toxic-function, or alternatively, whether some mutations act through a dominant-negative mechanism. In addition, I will evaluate whether all CMT-aaRS mutant proteins inhibit translation, and I will test the hypothesis, raised by our unpublished preliminary data shown here, that a defect in the transfer of the (aminoacylated) tRNA from the mutant synthetase to elongation factor eEF1A is the molecular mechanism underlying CMT-aaRS. Finally, I will validate the identified molecular mechanism in CMT-aaRS mouse models, as the most disease-relevant mammalian model. I expect to elucidate whether all CMT-aaRS mutations cause disease through a common molecular mechanism that involves inhibition of translation. This is of key importance from a therapeutic perspective, as a common pathogenic mechanism allows for a unified therapeutic approach. Furthermore, this proposal has the potential to unravel the detailed molecular mechanism underlying CMT-aaRS, what would constitute a breakthrough and a requirement for rational drug design for this incurable disease.

2 000 000 €

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

The 3D organization of chromosomes within the nucleus is of great importance to control gene expression. The cohesin complex plays a key role in such higher-order chromosome organization by looping together regulatory elements in cis. How these often megabase-sized looped structures are formed is one of the main open questions in chromosome biology. Cohesin is a ring-shaped complex that can entrap DNA inside its lumen. However, cohesin’s default behaviour is that it only transiently entraps and then releases DNA. Our recent findings indicate that chromosomes are structured through the processive enlargement of chromatin loops, and that the duration with which cohesin embraces DNA determines the degree to which loops are enlarged. The goal of this proposal is two-fold. First, we plan to investigate the mechanism by which chromatin loops are formed, and secondly we wish to dissect how looped structures are maintained. We will use a multi-disciplinary approach that includes refined genetic screens in haploid human cells, chromosome conformation capture techniques, the tracing in vivo of cohesin on individual DNA molecules, and visualization of chromosome organization by super-resolution imaging. With unbiased genetic screens, we have identified chromatin regulators involved in the formation of chromosomal loops. We will investigate how they drive loop formation, and also whether cohesin’s own enzymatic activity plays a role in the enlargement of loops. We will study whether and how these factors control the movement of cohesin along individual DNA molecules, and whether chromatin loops pass through cohesin rings during their formation. Ultimately, we plan to couple cohesin’s linear trajectory along chromatin to the 3D consequences for chromosomal architecture. Together our experiments will provide vital insight into how cohesin structures chromosomes.

1 998 375 €

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

In dementia at the end of life, cognitive and physical decline imply that control is typically lost. CONT-END will examine control in the context of three emerging interventions which contain a controversial element of striving for control in the process of dying with dementia: advance care planning of the end of life, use of new technology to monitor symptoms when unable to self-report, and euthanasia. To perform outstanding research, the proposed research examines control at the level of clinical practice, but also at the level of end-of-life research practice. The latter provides ample opportunities for researchers to control the research process. That is, research designs are often flexible and we will study if and how this impacts research in an emotionally charged area. I will take an empirical mixed-methods approach to study the two practices in parallel. The work is organised in three related Work Packages around three research questions. (1) In a 6-country study, I will examine if and when people with dementia, family caregivers and physicians (900 respondents) find the interventions, shown on video, acceptable. (2) A cluster-randomised 3-armed controlled trial in 279 patients and their family caregivers assesses effects of two types of advance care planning differing in level of control (detailed advance treatment orders versus goal setting and coping based) on outcomes ranging from favourable to less favourable, and whether effects differ in subgroups. Cases in which the technology is preferred or applied are observed. (3) Ethnographic fieldwork in two different end-of-life research practices and a Delphi study to synthesize CONT-END’s findings assess how researchers shape findings. This greatly improves the quality of CONT-END and provides the input to develop new methodology for improving research quality and integrity.

1 988 972 €

Start date: 2018-12-01, End date: 2023-11-30

Networks are the backbone of our society, but configuring them is error-prone and tedious: misconfigured networks result in headline grabbing network outages that affect many users and hurt company revenues while security breaches that endanger millions of customers. There are currently no guarantees that deployed networks correctly implement their operator’s policy. Existing research has focused on two directions: a) low level analysis and instrumentation of real networking code prevents memory bugs in individual network elements, but does not capture network-wide properties desired by operators such as reachability or loop freedom; b) high-level analysis of network-wide properties to verify operator policies on abstract network models; unfortunately, there are no guarantees that the models are an accurate representation of the real network code, and often low-level errors invalidate the conclusions of the high-level analysis. We propose to achieve provably correct networks by simultaneously targeting both low-level security concerns and network-wide policy compliance checking. Our key proposal is to rely on exhaustive network symbolic execution for verification and to automatically generate provably correct implementations from network models. Generating efficient code that is equivalent to the model poses great challenges that we will address with three key contributions: a) We will develop a novel theoretical equivalence framework based on symbolic execution semantics, as well as equivalence-preserving model transformations to automatically optimize network models for runtime efficiency. b) We will develop compilers that take network models and generate functionally equivalent and efficient executable code for different targets (e.g. P4 and C). c) We will design algorithms that generate and insert runtime guards that ensure correctness of the network with respect to the desired policy even when legacy boxes are deployed in the network.

1 325 000 €

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

Why are some people more likely to commit crime than others? Answers to this question, which is at the heart of criminology, can be grouped into two broad views. On the one hand, dispositional perspectives argue that stable factors within the individual, such as lack of self-control, lie at the roots of criminal conduct. Sociogenic perspectives, on the other hand, put the locus of study outside the individual and point towards factors such as rough neighborhoods, parental unemployment, and deviant peers, as the main causes of crime. In spite of ample empirical support for both views, there has been relatively little constructive engagement with each other. Capitalizing on my multidisciplinary background and drawing on social psychology and evolutionary theory, I outline a new perspective on criminal behavior –Time Frame Theory (TFT)– that integrates both views. TFT is premised on the idea that short-term mindsets encourage crime and specifies how both individual dispositions and sociogenic variables can encourage such mindsets. I test this theory using a combination of longitudinal research and behavioral field experiments. Besides aiming to mend the current theoretical disconnect in criminology and providing the foundation for a common paradigm, the proposed research program goes a step further by using TFT as the basis for a behavioral intervention to reduce crime. Building on recent pilot research, I use virtual reality technology in combination with a smartphone application to instill a future-oriented mindset in offenders. I am convinced that this combination of novel theory and innovative methodology may lead not only to a breakthrough in our understanding of delinquency but can also provide a blueprint for a scalable and evidence-based intervention to reduce it.

1 763 690 €

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

The increasing adoption of digital technologies worldwide creates data flows from places and populations that were previously digitally invisible. The resulting ‘data revolution’ is hailed as a transformative tool for human and economic development. Yet the revolution is primarily a technical one: the power to monitor, sort and intervene is not yet connected to a social justice agenda, nor have the organisations involved addressed the discriminatory potential of data technologies. Instead, the assumption is that the power to visualise and monitor will inevitably benefit the poor and marginalised. This research proposes that a conceptualisation of data justice is necessary to determine ethical paths through a datafying world. Its two main aims are: first, to provide the first critical assessment of the case for, and the obstacles to, data justice as an overall framework for data technologies’ design and governance. Second, to present a conceptual framework for data justice, refining it through public debate. The project will develop an interdisciplinary approach integrating critical data studies with development studies and legal philosophy. Using Sen's Capabilities Approach, it will conceptualise data justice along three dimensions of freedoms: (in)visibility, digital (dis)engagement, and nondiscrimination. Multi-sited ethnography in combination with digital methods will be used to build a conceptual framework, which will then be tested and shaped by debates held in nine locations worldwide. The research is groundbreaking in terms of 1) its use of the Capabilities Approach to address the social impacts of data technologies; 2) its integrative approach to problems previously addressed by the fields of law, informatics and development studies, and 3) its aim to reconcile negative with positive technologically-enabled freedoms, integrating data privacy, nondiscrimination and non-use of data technologies into the same framework as representation and access to data.

1 495 986 €

Start date: 2018-03-01, End date: 2023-02-28

Digital identity management concerns the control of digitized information pertaining to a person. This type of information is usually referred to as `personal data’, or ‘personally identifiable information’. With digitisation and automation processes pervading virtually all aspects and domains of society, the routine registration of personal identifiable data is increasing exponentially. The implied risks and challenges to fundamental rights like privacy and non-discrimination are recognized on the highest policy levels, but as of today still poorly understood or analyzed. In view of the fact that ‘identity’ is also a key concept in contemporary social theory, and conceptualisations of the relation between technology and society, ethics and normativity, a field of enquiry emerges at the crossroads of contemporary theoretical, technological and societal developments representing opportunities for frontier research. The overall aims of the project are to increase understanding of the social and ethical aspects of digital identity management (IDM), to further theorising the concept of identity, and to contribute to the quality and social/ethical acceptability of technological developments. The project will achieve these goals by bringing recent insights gained from several disciplines (science and technology studies, surveillance studies, social and technology philosophy, computer ethics) to bear on actual developments in digital identity management, thus exploring novel ways to identify and articulate the issues concerned. With a series of interdisciplinary studies focussing on different application areas of IDM, we intend to produce more fine-grained knowledge of the ways IDM is implicated in contemporary transformations of identity. The programme will involve three complementary PhD projects, and one integrative postdoc project, thus achieving a strong concentration of groundbreaking knowledge on a set of fast emerging intellectual and societal problems.

1 833 000 €

Start date: 2008-10-01, End date: 2014-05-31

The DNA within our cells is constantly being damaged by both environmental and endogenous agents; of the many forms of DNA damage, the DNA double-strand break (DSB) is considered to be most dangerous. Correct processing of DSBs is not only essential for maintaining genomic integrity but is also required in specific biological processes, such as meiotic recombination and V(D)J recombination, in which DNA breaks are deliberately generated. In animals, defects in the proper response to DSBs can thus have different outcomes: cancer predisposition, embryonic lethality, or compromised immunity. Many genes that play a role in the processing of DSBs have been identified over the past decades, mainly by cloning genes that are responsible for specific human genomic instability or immune deficiency syndromes, and by genetic approaches using unicellular eukaryotes and rodent cell lines. It is, however, evident that many components required in higher eukaryotes are not yet known and the identification of those will be a major challenge for future research. Here, we will for the first time systematically test all genes encoded by an animals genome directly for their involvement in the cellular response to DSB in both somatic and germline tissues: we will use our recently developed transgenic animal models (C. elegans) that visualizes repair of a single localized genomic DNA break in genome wide RNAi screenings to identify (and then characterize) the complement of genes that are required to keep our genome stable, and when mutated can predispose humans to cancer. In parallel, we will study the cellular response to single DNA breaks that are artificially generated during different stages of gametogenesis, as well as address the developmental consequences of DSB induction during the earliest stages of embryonic development – an almost completely unexplored area in the field of genome instability and DNA damage responses.

1 060 000 €

Start date: 2008-05-01, End date: 2014-04-30

Tissue engineering aims at the creation of living implants to replace, repair, or regenerate damaged, diseased, or aged tissues, which holds tremendous possibilities to both extend our lives and improve our quality of life. During the last decades, our ability to create small tissues to heal small animals e.g. mice and rats has taken a breath taking leap. However, we have relentlessly struggled to create viable tissues of human-relevant sizes. Creating solid large tissues imposes lethal nutrient diffusion limitations, which causes the living implant to suffer from starvation, loss of function, and inevitable failure. I hypothesize that this key challenge can be tackled by recruiting and developing advanced enabling nano- and micro-technologies. The ENABLE project begins with the design and development of a widely applicable platform that will enable large solid engineered tissues to survive and function by actively sustaining the implants metabolic needs. This platform is based on a unique two pronged strategy that rely on distinct technologies: oxygen releasing micromaterials, fabricated using a next-generation droplet generator, to enable short term survival of the implant, while embedded bioprinting will endow implants with a complex 3D vascular network to enable their long term survival. As proof of principle, the effects of ENABLE’s platform will be investigated using a critical bone defect in which I analyse the survival and function of the created living implants. The anticipated outcomes of this proposal are three fold: first, I will develop a next-generation engineered tissue that will overcome the current size restrictions via the use of enabling technologies; second, I will reveal new knowledge on the role of the oxygen tension on vascularization and tissue formation by enabling control over the in vivo oxygen tension; and third, I will develop a novel strategy that enables the treatment of critical bone defects.

1 500 000 €

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

This project supports OAPEN to enlarge the quality controlled collection of open access books already hosted by the OAPEN Library, and to develop additional services for publishers, libraries and research funders in the areas of dissemination, quality assurance and digital preservation. The project specifically intends to enlarge the collection of OA books and chapters relating to research funded through ERC grants, by aggregating these publications and enabling publishers and authors to deposit these publications directly into the OAPEN Library. The project will develop new components to increase the visibility and usage of the ERC collection, to improve integration with OpenAIRE, and to increase the understanding of societal and scholarly impact of ERC publications through an Altmetrics service. New components include: - Collection view: a separate website providing a branded view of the ERC collection, thereby improving the overall visibility of the collection; - Research grant information: adding standard information from ERCEA and other sources to provide additional information about the research connected to the publication, improving discoverability and usage of the ERC collection; - Review linking: exploring whether it is possible to link to reviews of publications, to promote these publications and increase usage.

60 000 €

Start date: 2018-01-01, End date: 2019-12-31

My aim is to understand the exact genetic contribution in every patient with Amyotrophic Lateral Sclerosis (ALS), a lethal disease with a life time risk of 0.3% and an urgent unmet therapeutic need. I have recently shown a disproportionate large contribution from low-frequency genetic variants in ALS. ALS is not simply a collection of unique rare diseases with a monogenetic cause nor is it a diagnostic continuum with a complex contribution of thousands of small effect factors. ALS is in-between, which I call “simplex”, where in each patient a few, considerably strong genetic factors with or without environmental factors are at play. ALS mutations are characterized by reduced penetrance, variable clinical expressivity, have specific pleiotropic clinical features and interact with environmental factors. These phenomena are unexplained, but provide me with important and new opportunities in order to unravel the clinical, genetic and biological heterogeneity in ALS. I have created new research fields to go an important step beyond the state of the art: Splitting by lumping uses novel machine learning algorithms to reclassify patients using clinical pleiotropic features, environmental factors and blood epigenetic profiles to identify novel ALS mutations. Imaging genomics overlays patterns in ALS-associated brain morphology on MRI with brain gene-expression patterns to find ALS mutations. ALS risk in 3D integrates data on three-dimensional folding of DNA with genetic data to identify causal mutations and mutation-to-mutation interaction. ALS genomic modifiers in 3D identifies modifiers of C9orf72 mutations through the development of cellular reporter assays and CRISPR-Cas9 based screens. Genomic findings are translated using cellular models which can be used for targeted and unbiased drug screens. If successful, my approaches can be applied beyond the scope of this ERC and will have a clear impact on clinical trial design and genetic counselling in ALS in particular.

1 980 434 €

Start date: 2018-07-01, End date: 2023-06-30

How do organisms evolve? I propose to study how biochemical networks reorganize during evolution without compromising fitness. This is a complex problem: firstly, it is hard to know if a mutation increased fitness because this depends on the environment it arose in, which is typically unknown. Secondly, it is hard to find out how adaptive mutations improve fitness, because in cells, all biochemical networks are connected. I will reduce the complexity by two approaches, focused on symmetry-breaking in budding yeast, a functionally conserved process, which is the first step for polarity establishment and essential for proliferation. First, I will study how adaptive mutations improve fitness in yeast cells, which are evolved after the deletion of an important symmetry-breaking gene. I will use fluorescent live-cell microscopy of polarisation markers to measure fitness, defined as the rate of symmetry breaking. I will combine my data with a kinetic mathematical model to determine how specific network structures facilitate evolutionary network reorganisation. Second, to test predicted network structures, I will build minimal evolvable networks for symmetry breaking in vitro. In my definition of such a network, all of the components are essential for either fitness or evolvability. I will encapsulate the necessary proteins in emulsion droplets to form a functional evolvable network and use fluorescence microscopy to measure its fitness (the rate of a single protein-spot formation on a droplet membrane) and evolvability (the number of accessible neutral or adaptive mutations in the one-step mutational landscape of the network). Next, I will study how increasing the number of components affects the network’s evolvability and fitness. This research will explain how proteins essential in one species have been lost in closely related species. My expertise with in vitro systems, modelling, biophysics and evolution makes me uniquely qualified for this ambitious project.

1 500 000 €

Start date: 2018-02-01, End date: 2023-01-31

In Europe, understanding and respect for those who hold different opinions are needed more than ever. In this context, exposure to dissimilar content in the media is crucial because encountering views that challenge one’s beliefs is hoped to foster tolerance. More and more scholars are interested in media diversity and more and more policymakers encourage citizens to see dissimilar views in the media. However, exposure to difference can also do harm, increasing conflict among citizens with different opinions (backfire effects). Despite these dangers, we lack a comprehensive model that explains when and why exposure to dissimilar views amplifies or attenuates hostilities. What encourages people to see dissimilar political content, on which issues, and in which media? Under what conditions, for whom, and why does exposure to dissimilar views backfire? What can be done to minimize the harms and maximize the benefits of encountering difference? This project addresses these questions. It will advance an evidence-based theoretical model that identifies the individual, social, and system factors that together drive dissimilar exposure and its effects on understanding and respect between citizens with different views. This model accounts for old and new media, various political issues, and intended and incidental exposure.The model will be tested in four projects, each offering methodological breakthroughs. I will use latest techniques in ‘big data’ research, automated content analyses, panel surveys, qualitative work, and experiments; the first project to use this necessary variety of cutting-edge techniques conjointly and comparatively. This project will advance academic knowledge. Its findings are crucial for scholars across disciplines, policymakers who optimize media diversity policies, and media and campaign designers. Only if we know when, how, and why citizens are affected by dissimilar media will we be able to enhance respect and understanding in diverse societies.

1 499 384 €

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

Very recently, a new class of sub-luminous accreting neutron stars and black holes has been identified. I propose to use these objects to probe the extreme physical processes which are associated with such compact stars. Just as with their better known brighter cousins, studying them when they are actively accreting and when they are in their quiescent states will give us clues about the behavior of ultra-dense matter in neutron stars and the way neutron-star magnetic fields decay due to the accretion of matter. However, given that these new systems behave differently, I expect to derive from their study a novel perspective which will gain in value even further when contrasted with our current knowledge. I further believe their study will allow me to significantly strengthen the observational proof for the presence of event horizons in black holes. The uncommon nature of these systems suggests that they are very unusual outcomes of binary evolution, and I expect this will also provide us with a different set of clues than we have had until now about the formation of binaries which harbor compact stars. These objects have only recently been discovered, both because we did not have the sensitivity to see them, and because we did not know how to optimize our searches to find them. Current instruments finally have reached the necessary sensitivity. I propose new approaches to find and study these sub-luminous systems using these X-ray and radio instruments in combination with multi-wavelength studies. I expect to find these systems in greater numbers than before, allowing systematic studies of their properties which in turn will provide the ingredients needed to investigate the fundamental physics associated with neutron stars and black holes and serve as input for my proposed theoretical study into binary evolution.

500 000 €

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

"The recent developments of the Tomographic Particle Image Velocimetry technique and of the non-intrusive pressure field characterization method, by the applicant at TU Delft Aerospace Engineering, now opens unforeseen perspectives in the area of unsteady flow diagnostics and experimental aero-acoustics. As a result of this work it is now possible not only to quantify complex flows in their three-dimensional structure, but also to extract quantities such as pressure. The current research proposal aims at the development of an innovative approach to experimental aero-acoustics and flow control making use of the recently developed Tomographic-PIV technique. The objective is to fully describe and quantify the flow pattern and the related acoustic source term at its origin, which is of paramount importance to understand and control the processes like acoustic noise production and flow separation dominating aerodynamic drag. This is relevant for the improvement of aircrafts design as far as drag reduction and noise emission is related and should enable the development of ""greener"" aircrafts for a sustainable growth of aviation in populated areas, in harmony with the technology innovation policy in Europe (7th Framework Programme) and TU Delft sustainable development focus (CleanEra, Cost-Effective Low emission And Noise Efficient regional Aircraft) at Aerospace Engineering. To achieve this step it is required that such new-generation diagnostic approach by the Tomo-PIV technique is further developed into a quadri-dimensional measurement tool (4D-PIV), enabling to extract the relevant acoustic information from the experimental observation invoking the aeroacoustic analogies. A wide industrial and academic network (DLR, AIRBUS, DNW, NLR, LaVision, EWA, JMBC Burgerscentrum) developed in recent years is available to exploit the results of the proposed activity."

1 498 000 €

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

My project is to write a history of the formation of Islam using the vastly important but largely neglected papyri from Egypt. Until the introduction of paper in the 10th C., papyrus was the Mediterranean world’s primary writing material. Thousands of papyrus documents survive, preserving a minutely detailed transcription of daily life, as well as the only contemporary records of Islam’s rise and first wave of conquests. As an historian and papyrologist, my career has been dedicated to developing the potential of this extraordinary resource. The prevailing model of Islam’s formation is based on sources composed by a literary élite some 150 years after the events they describe. The distortions this entails are especially problematic since it was in these first two centuries that Islam’s institutional, social and religious framework developed and stabilised. To form a meaningful understanding of this development requires tackling the contemporary documentary record, as preserved in the papyri. Yet the technical difficulties presented by these mostly unpublished and uncatalogued documents have largely barred their use by historians. This project is a systematic attempt to address this critical problem. The project has three stages: 1) a stocktaking of unedited Arabic, Coptic and Greek papyri; 2) the editing of a corpus of the most significant papyri; 3) the presentation of a synthetic historical analysis through scholarly publications and a dedicated website. By examining the impact of Islam on the daily life of those living under its rule, the goal of this project is to understand the striking newness of Islamic society and its debt to the diverse cultures it superseded. Questions will be the extent, character and ambition of Muslim state competency at the time of the Islamic conquest; the steps – military, administrative and religious – by which it extended its reach and what this tells us about the origins and evolution of Muslim ideas of rulership, religion and pow

1 000 000 €

Start date: 2009-03-01, End date: 2015-02-28

"Aim: To radically change the field of gossip research, this project builds theory that connects divergent perspectives on the effects of gossip on work group outcomes. Background: Gossip, informal evaluative talk about absent third parties, is omnipresent in organizational groups. However, for scientists and practitioners alike, it is still an ""unknown force"" in organizations, because research findings about its effects on group functioning and performance are inconsistent. Whereas some studies point to the disruptive aspects of gossip, others claim it enhances group cooperation. Innovation: I present the Gossip Origins, Subsequent Social Information Processing, and Performance (GOSSIPP)-framework, a new paradigm that views gossip in groups as a multi-level phenomenon: It, for the first time, systematically connects individual gossipers' intentions to group-level outcomes via social information processing by gossip recipients. Propositions: Group members may gossip to benefit themselves or their group (proself vs. prosocial intentions, or motives). Receivers' reactions to gossip are affected by how they perceive senders' motives. These reactions in turn affect group-level processes. How these processes affect group performance depends on the type of group task. Methodology: Four subprojects test the framework, applying a cross-disciplinary multi-method approach. Subprojects 1 and 2 employ laboratory experiments to assess causal effects of gossipers' motives and recipients' reactions on group processes and performance. Subproject 3 examines effects of different group compositions and feedback loops between performance and gossip, employing self-organizing computer modelling. Finally, to assess external validity, Subproject 4 examines work teams. Results will lead to long-sought understanding of when and why gossip is a functional or dysfunctional force and will enable evidence-based advice to organizations about the meaning and functionality of gossip for groups."

1 999 693 €

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

Fiber-top sensors (D. Iannuzzi et al., patent application number PCT/NL2005/000816) are a new generation of miniaturized devices obtained by carving tiny movable structures directly on the cleaved edge of an optical fiber. The light coupled into the fiber allows measurements of the position of the micromechanical parts with sub-nanometer accuracy. The monolithic structure of the device, the absence of electronic contacts on the sensing head, and the simplicity of the working principle offer unprecedented opportunities for the development of scientific instruments for applications in and outside research laboratories. For example, a fiber-top scanning probe microscope (also in the form of a PenFM, where a fiber-top atomic force microscope would be incorporated in a pen-like stylus) could be routinely used in harsh environments and could be easily handled by untrained personnel or through remote control systems – a fascinating perspective for utilization, among others, in surgery rooms and space missions. Similarly, the development of fiber-top biochemical sensors could be exploited for the implementation of portable equipment for in vivo and Point of Care medical testing. Fiber-top sensors could be used for the measurement of parameters of medical relevance in interstitial fluid or in blood – an interesting opportunity for intensive care monitoring and early detection of life-threatening diseases. This scenario calls for a coordinated research program dedicated to this novel generation of devices. It is my intention to forge a laboratory gravitating around fiber-top technology. My group will have the opportunity to pioneer this research area and to become the reference point in the field, on the forefront of an emerging subject that might represent a major breakthrough in the future development of micromachined sensors.

1 799 915 €

Start date: 2008-06-01, End date: 2013-05-31

While significant progress has been made in the diagnosis and treatment of cancer, several major issues remain unresolved. First, only a minority of patients respond to most forms of (chemo)therapy. It is generally believed that this poor responsiveness to drugs has its origin, at least in part, in the molecular heterogeneity of cancer. This heterogeneity requires the use of biomarkers to stratify patients having seemingly similar tumors according to their likely responses to specific cancer therapies. To identify such biomarkers, we will use large-scale genetic screens to identify genes that are causally involved in controlling responses to cancer drugs. Such genes are likely biomarkers of drug responsiveness in the clinic. Availability of such drug response biomarkers will facilitate a more personalized therapy choice for each individual patient. A second major deficit in effective cancer therapy is the lack of sufficient highly selective drug targets. The large-scale cancer genome re-sequencing efforts already indicate that there is a paucity of druggable genes that are consistently mutated in cancer and the same holds true for genes that are consistently over-expressed in cancer. Hence, there is an urgent need for innovative drug targets that have a similar cancer-selectivity as the genes that are specifically mutated or over-expressed in cancer. In this project, we will use large-scale loss of function genetic screens, exploiting the concept of synthetic lethality , to identify genes whose inactivation is selectively toxic to cells having a defined cancer-specific genetic alteration. Drugs against these targets will be highly cancer-selective, as their activity hinges on the presence of a specific genetic defect, which is only present in the cancer cell.

2 176 000 €

Start date: 2010-06-01, End date: 2015-05-31

Galactic Astronomy is entering a new era, driven by state-of-the-art instrumentation and large surveys, and by the dramatic leaps in our understanding of galaxy formation provided by the cosmological LCDM framework. These surveys have shown that the Galaxy is up for discoveries every single month, and have revealed the first footprints of past mergers. This Era will reach its summit when the Gaia mission, scheduled for launch in 2011, provides the much-awaited survey of Galactic phase-space for a billion stars. This motivates us to propose a program that will provide a comprehensive view of the dynamical imprints leftover from the Galaxy s evolutionary history. This program will address the following key questions: How much memory does a galaxy like the Milky Way retain of its past? What is the relative importance of internally driven (secular processes) and externally acquired (mergers) phase-space substructure? What was the merging history of the Galaxy? Is the Galaxy consistent with LCDM? This ambitious program will advance the field of Galactic archaeology beyond the state-of-the-art thanks to two developments: the Aquarius Project simulations and the RAVE spectroscopic survey. The Aquarius are the largest ever cosmological simulations of a Milky Way dark matter halo. When complemented with a recently built phenomenological galaxy formation model, these superb simulations will serve for comparisons to the latest observational datasets, and in particular to the RAVE survey that is providing a fantastic dynamical map of the Solar vicinity. This will enable us to be in prime position to exploit the first Gaia data release in 2013, and before the end of this Research Program, to harvest its key scientific goal, namely to unravel the assembly history of the Milky Way.

1 613 680 €

Start date: 2010-01-01, End date: 2015-12-31

The overall aim of this research project is to assess the feasibility and legitimacy of the current model of global tax governance and the role of the OECD and EU in international tax lawmaking. Unlike the former OECD projects that only provide for exchange of information between countries, in the BEPS Project, the EU Anti-Tax Avoidance Directive, the EU state aid investigations and the EU External Strategy, the OECD and the EU focus on substantive issues that when implemented will change the international tax architecture of developed and developing countries. These initiatives aim to ensure that governments engage in fair competition and that multinationals pay their fair share. Even though these objectives are legitimate, these developments raise the questions what is the role of the OECD and the EU in global tax governance? and under what conditions can the model of global tax governance be feasible and legitimate for both developed and developing countries? These initiatives have generated tensions between developed and developed countries and between EU and third (non-EU) countries. The tensions between countries call for the articulation of a new framework of global tax governance that is legitimate and based on considerations of fairness for all countries participating. Against this background, my project will first assess the feasibility of the legal transplant of the BEPS minimum standards into the tax systems of 12 countries of research by asking three sub-questions (i) why are these countries participating in the BEPS Project? (ii) how will the BEPS minimum standards be transplanted into the tax system of these countries? and (iii) how can the differences in tax systems and tax cultures of these countries influence the content of these minimum standards? Thereafter, the conditions for the legitimacy of the role of the OECD and the EU will be provided in light of the theories of legitimacy and governance.

1 384 750 €

Start date: 2018-02-01, End date: 2023-01-31

The success of humans depends on their ability to cooperate. Cooperation requires learning to avoid actions that harm others and select those that balance benefits for self and others. Reinforcement leaning captures how individuals learn to optimize benefits for themselves, by associating actions and outcomes for the self. The social context requires to incorporate outcomes for others into that equation by transforming them into the currency used to value our own outcomes. Research on empathy, by suggesting that we transform the emotions of others into neural representation of how we would feel in their stead, provides testable mechanistic hypotheses of how we do that. The painful facial expression of our friend after we kick him would be transformed into the pain we would feel when kicked, associating kicking with negative value, thereby motivating us to stop kicking. Testing this hypothesis would require altering brain activity in the anterior insula and cingulate involved in this process, and showing that these changes alter decision making. Because current tools in humans cannot selectively modulate activity in these deeper regions we however remain frustratingly powerless to do so. Here we will develop a brand new method using ultrasounds to modulate brain activity at any depth to brake down this barrier. Using fmri, we will measure vicarious activity and compare it with computational models. This will push our understanding of our social nature to a new computational level, and pave the way to a more causal understanding of prosociality that can inform successful interventions for so far untreatable antisocial disorders. More generally deep brain stimulation via US, and the understanding of how US modulate brain activity, will unleash affective neuroscience to noninvasively explore what had remained beyond our reach: the causal relationship between deeper (limbic) structures and behavior and cognition.

1 500 000 €

Start date: 2018-07-01, End date: 2023-06-30

Sensory cilia are organelles extending like antennas from many eukaryotic cells, with crucial functions in sensing and signalling. Cilia consist of an axoneme built of microtubules, enveloped by a specialized membrane. Ciliary development and maintenance depend critically on a specific, microtubule-based intracellular transport mechanism, intraflagellar transport (IFT). In my laboratory, we study the chemosensory cilia of C. elegans, which sense water-soluble molecules in the animal’s environment for chemotaxis. Over the past years, we have developed a unique set of quantitative, single-molecule fluorescence microscopy tools that allow us to visualize and quantify IFT dynamics with unprecedented detail in living animals. So far, our focus has been on the cooperation of the motor proteins driving IFT. The overall objective of my current proposal is to zoom out and shed light on the connection between ciliary structure, chemosensory function and IFT, from a systems perspective. Recent work has indicated that axoneme length is controlled by IFT. Preliminary results from my laboratory show that axoneme length changes dynamically in response to perturbations of IFT or cilia. Furthermore, we have shown that IFT is substantially affected upon exposure of animals to known repellent solutions. The four major aims in my proposal are to: • determine how directional changes in IFT are regulated and are affected by external disturbances, • understand the dynamics of the axonemal microtubules and how IFT affects these dynamics and vice versa, • study how sensory ciliary function affects IFT and ciliary structure, • further develop our (single-molecule) fluorescence microscopy toolbox by improving instrumentation and using better fluorescent probes and sensors. These experiments will place my lab in a unique position to push forward our understanding of the relationship between structure, function and dynamics of transport of this fascinating and fundamental organelle.

2 499 580 €

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

In this Proof-of-Concept project I will show the commercial potential of ruthenium-based photoactivated chemotherapy (PACT) compounds developed in my ERC Starting Grant by demonstrating their efficacy on hypoxic cancer models. Photoactivated chemotherapy is a new class of phototherapy to treat cancer. In principle, PACT looks similar to photodynamic therapy (PDT): light irradiation of the tumour in vivo leads to local activation of the anticancer prodrug, thereby limiting the toxicity of the treatment to the diseased tissue, and thus lowering side effects for the patient. However, the mechanisms of PACT and PDT are very different: in PDT the light-absorbing prodrug requires molecular oxygen to kill the cancer cells, whereas in PACT oxygen is not involved in prodrug activation. As a consequence, PACT agents should be able to treat hypoxic tumours, which are characterized by low oxygen concentrations and high resistance to PDT and other existing therapies. In this project the efficacy of a selection of Ru-based PACT compounds will be tested in hypoxic cancer models and compared to their efficacy in normoxic conditions. In parallel I will develop, in collaboration with my network of collaborators from the clinics, business analysts, and patent attorney, a plan for (pre) clinical development of PACT compounds.

150 000 €

Start date: 2017-10-01, End date: 2019-03-31

Power beyond the state is most prevalent in economic infrastructure hubs with high technology and multiple global actors. Here, investors from emerging powers challenge traditional theory and practice. Chinese and Brazilian companies are now the most important bilateral investors in Africa. They apply existing rules and practices, and introduce new practices of governance and business-society relations that compete with Western norms. But their impact is not properly understood in theories of transnational governance. This project will rethink transnational governance by focusing on the margins of international relations to explain how models and experiences of actors from the Global South redefine the governance of economic hubs. Seemingly in the margins of international political economy, and neglected in International Relations, in Africa new forms of power and governance are invented and tested. Here states are weaker and experiments with multiple non-state actors and modes of governance tolerated. The fringes of theory-building in the discipline, the hubs of transnational economic infrastructure, and everyday practices of cross-border management can be theorized as arenas of the production, contestation and change of transnational governance. INFRAGLOB combines analysing the ideas driving Chinese and Brazilian management of large-scale port and mining projects with multi-sited ethnographic research of exemplary cases in Mozambique and Tanzania, establishing how these concepts are enacted, negotiated and disregarded in practice. It rethinks publics by mapping controversies that connect Africa, Brazil and China, and establishes how interactions and frictions between diverse practitioners and standards change broader transnational governance of business-community relations and security. ‘Infrastructure globalities’ will provide a unique understanding of how the Global South changes practices of governance and business-society relations in a multipolar world.

1 495 909 €

Start date: 2018-03-01, End date: 2023-02-28

Water is essential for life on our planet and is the solvent of choice for Nature to carry out her syntheses. In contrast, our methods of making complex organic molecules have taken us far away from the watery milieu of biosynthesis. Indeed, it is fair to say that most organic reactions commonly used both in academic laboratories and in industry fail in the presence of water or oxygen. At the same time of course, chemical reactors are very different from the cellular environment where Nature s synthesis is carried out. This research proposal aims to incorporate some of the key characteristic of cellular reactors, i.e. confinement, compartmentalization and interfaces, into model droplet-based reactors. The envisioned reactors will comprise of monodisperse aqueous droplets in oil carrier phases with volumes ranging from pL to nL, produced in microfluidics devices or in tubing, in very large numbers. These droplets will have precisely determined interfacial areas, which can be used for the study of so-called on water reactions, a new area of synthetic chemistry rapidly gaining in interest. Furthermore, the interfaces can be functionalized with catalytically active surfactants and by confining the droplets into ever decreasing volumes, the effect of nanoconfinement on enzymatic and other reactions can be studied. Finally, individual droplets provide a completely compartmentalized environment, suitable for the study of single enzymes in a crowded environment, but also for systematic studies into communication between compartmentalized, mutually incompatible, reaction systems. This proposal presents a radically new approach to increasing our understanding of chemical reactions in confined spaces and at interfaces and provides a technological platform for the creation of chemically linked networks with emerging complexity.

2 147 726 €

Start date: 2010-05-01, End date: 2015-04-30

The main research question of the study is: How and why do some European citizens generate a populist and Islamophobist discourse to express their discontent with the current social, economic and political state of their national and European contexts, while some members of migrant-origin communities with Muslim background generate an essentialist and radical form of Islamist discourse within the same societies? The main premise of this study is that various segments of the European public (radicalizing young members of both native populations and migrant-origin populations with Muslim background), who have been alienated and swept away by the flows of globalization such as deindustrialization, mobility, migration, tourism, social-economic inequalities, international trade, and robotic production, are more inclined to respectively adopt two mainstream political discourses: Islamophobism (for native populations) and Islamism (for Muslim-migrant-origin populations). Both discourses have become pivotal along with the rise of the civilizational rhetoric since the early 1990s. On the one hand, the neo-liberal age seems to be leading to the nativisation of radicalism among some groups of host populations while, on the other hand, it is leading to the islamization of radicalism among some segments of deprived migrant-origin populations. The common denominator of these groups is that they are both downwardly mobile and inclined towards radicalization. Hence, this project aims to scrutinize social, economic, political and psychological sources of the processes of radicalization among native European youth and Muslim-origin youth with migration background, who are both inclined to express their discontent through ethnicity, culture, religion, heritage, homogeneity, authenticity, past, gender and patriarchy. The field research will comprise four migrant receiving countries: Germany, France, Belgium, and the Netherlands, and two migrant sending countries: Turkey and Morocco.

2 276 125 €

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

Aromatic compounds are cheap and readily available, making them ideal starting materials for the synthesis of chiral alicyclic compounds, important synthetic building blocks for both natural product synthesis and drug discovery. However, general strategies for efficient, catalytic dearomatisation of aromatics are lacking. This proposal aims to fill this gap by developing general asymmetric methods for dearomatisation reactions of both electron-rich and electron-deficient aromatics. It relies on an innovative approach based on LA activation of the arenes, followed by copper catalyzed carbon-carbon bond forming reactions, with a special focus on environmentally benign and cost-effective processes. To achieve the overall aim of the proposed project, the research program is composed of four distinct but complementary research lines aiming at catalytic asymmetric dearomatisation/carbon-carbon bond forming reactions using: - Electron-deficient carbonyl substituted arenes - Pyridines and other N-containing heteroarenes - Phenols and anilines and fused analogues - Benzylic aromatic systems The remarkable and novel feature of this strategy is that it enables for the first time selective catalytic asymmetric dearomatisations of various classes of aromatic substrates following a general, unified concept. Furthermore, since sequential bond constructions take place in a single synthetic operation, a rapid increase of molecular complexity can be achieved at greatly reduced cost and increased atom-efficiency, thereby contributing to a more sustainable future. Consequently, there is huge potential for this strategy to become an invaluable instrument to access a wide variety of chiral carbocyclic compounds and I anticipate it will have a significant impact in the field of organic synthesis.

1 999 398 €

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

The development of games goes hand in hand with the development of human culture. Games offer a rich window of insight into our cultural past, but early examples were rarely documented and our understanding of them is incomplete. While there has been considerable historical research into games and their use as tools of cultural analysis, much is based on the interpretation of partial evidence with little mathematical analysis. This project will use modern computational techniques to help fill these gaps in our knowledge empirically. I will represent games as structured sets of ludemes (units of game-related information), which will allow the full range of traditional strategy games to be modelled in a single software system for the first time. This system will not only model and play games, but will evaluate reconstructions for quality and authenticity, and automatically improve them where possible. This will lay the foundations for a new field of study called digital archaeoludology, which will involve addressing technical challenges that could yield significant benefits in their own right, particularly in artificial intelligence. The ludemic model reveals innate mathematical relationships between games, allowing phylogenetic analysis. This provides a mechanism for creating a family tree/network of traditional games, which could reveal missing links and allow ancestral state reconstruction to shed light on the gaps in our partial knowledge. Locating ludemes culturally provides a mechanism for creating interactive maps that chart the transmission of mathematical ideas across cultures through play. This project seeks to bridge the gap between historical and computational studies of games, to provide greater insight into our understanding of them as cultural artefacts, and to pioneer new tools and techniques for their continued analysis. The aim is to restore and preserve our intangible cultural heritage (of game playing) through the tangible evidence available.

1 997 244 €

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

“Equipped with his five senses, man explores the universe around him and calls the adventure science” E.P. Hubble It is amazing how much we have learned about the working of our universe by using our five senses and how little we still know about the working of these senses themselves! Even though the molecular mechanism of sight, taste, and smell is known, we still don’t know how the mechanical sensations of touch and hearing function at the molecular level. Mechanosensitive (MS) ion channels, present in membranes, are the molecules that sense membrane tension in all species ranging from bacteria to man. They stay functional even in artificial membranes, indicating that mechanosensation occurs at the protein-lipid interface. In an effort to understand the mechanism of force sensation, the major limitation has been the inability to ‘observe’ the molecular changes occurring in MS channels from the onset of the force. The aim of this proposal is to understand how channel proteins sense mechanical force at the molecular level. A bacterial channel, MscL, will be used as a model for its natural function to couple tension in the membrane to protein conformational changes. Here, on the basis of my recent findings, I propose to build on synthetic biology approaches to develop unique tools to specifically address the MS channel, allowing controlling its activity extrinsically and reversibly. In combination with the spectroscopic techniques, I want to elucidate the mechanism of mechanosensation in MscL by measuring structural changes in the protein and its interaction with the surrounding lipids, starting from the onset of the force. The research will clarify not only the long-standing question of how MscL senses tension, but it will also shed light on the common property of mechanosensitivity among nature’s sensors in higher organisms; transient receptor-potential (TRP) channels, which are involved in hearing, touching and other sensory actions.

1 449 236 €

Start date: 2008-09-01, End date: 2014-02-28

I seek to develop new ferroelectrics based on metal-organic frameworks with dipolar rotors. Ferroelectrics are targeted to be used as physically flexible memories and mechanical energy harvesters for biocompatible sensors and implantable monitoring devices. As ferroelectrics can store and switch their polarity, they can be used as memories. Via the piezoelectric effect, they can harvest mechanical vibrations. The materials most compatible with flexible substrates, are soft matter materials. However, these so far don’t meet the requirements. Especially lacking is a combination of i) polarisation stability, ii) a sufficiently low energy barrier for polarisation switching and iii) fast switching. As energy harvesters, soft matter materials are hampered by low piezoelectric coefficients. The main objective of this proposal is rational design of ferroelectrics by obtaining a fundamental understanding of the relation between structure and properties. I will achieve this by uniquely synthesizing polar rotors into 3D crystalline scaffolds that allow to alter the rotors’ nano-environement. I will achieve this via polar ligands in metal-organic frameworks (MOFs). The variability of MOFs allows to tune the nature of the hindrance towards rotation of the polar rotors. The tuneable flexibility allows to regulate the energy harvesting efficiency. Moreover, MOFs have already shown potential as biocompatible materials that can be integrated on physically flexible substrates. The research consists of i) synthesis of polar rotor MOFs with targeted variations, ii) reliable characterisation and computational modelling of the electronic properties, iii) nanoscopic insight in the switching dynamics. The approach allows to understand how ferro- and piezoelectricity are related to the materials’ structure, and hence to develop materials with exceptional performance. My recent observation of the ferroelectric behaviour of a nitrofunctionalised MOF is the basis for this proposal.

1 500 000 €

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

Our intestinal tract is colonized by a myriad of microbes that exceed our body cells in number and coding capacity and have important metabolic and signaling functions. Analysis of the diversity of these microbes inside revealed more than 1000 species, some of which have developed intimate interactions that are operating at the mucus interface separating the intestinal and microbial cells. Notably, we sustain and stimulate these interactions by feeding our microbes inside by the production of large amounts of mucus that equal the undigested components of our diet in caloric value. The understanding of the mucosal interactions is of great importance as they affect our immune system, signal to the brain-gut axis and provide a protective barrier against pathogens. Hence, this project aims to obtain fundamental understanding in the diversity and function of our microbes inside with a focus on mucus-binding bacteria that are either indigenous in the human intestine or ingested as part of our diet. The project will capitalize on (i) the recently developed high-throughput functional (meta)genomics approaches for human subjects, (ii) the genomic characterization of the mucus-degrading species Akkermansia muciniphila, an emerging biomarker for a healthy intestine, and (iii) the genome-driven discovery that the paradigm probiotic, Lactobacillus rhamnosus GG (LGG), contains cell-wall extended pili that strongly bind mucus and signal to human cells. A novel screening system will allow isolation of LGG derivatives with altered mucus-binding that will be instrumental in cause effect and other mechanistic studies. Moreover, the results will contribute to detailed insight in how our microbes inside develop mutualistic interactions, allowing for the design of new food-based approaches.

2 499 000 €

Start date: 2010-06-01, End date: 2015-05-31

microRNAs (miRNAs) are master regulators of gene expression capable of defining and altering cell identity. Because of their potency, small size, simple mode of action (target recognition through a Watson-Crick type of base pairing) and the possibility to inhibit them in vivo, miRNAs are valuable therapeutic targets. Recently, we have used novel functional-genetic screening approaches and identified the miR-372, 373 and 520, as well as the miR-221&222 family as cancerous miRNAs. These miRNAs are oncogenes, as they are deregulated in specific types of cancers, target tumor suppressors and their inhibition reverts cancerous phenotypes. However, at present almost nothing is known about the mechanisms governing the expression and function of these, as well as many other, oncogenic miRNAs. Here, I propose experiments to identify and characterize factors affecting the activity of oncogenic miRNAs using an array of molecular and genetic tools. Our preliminary results indicate the existence of novel regulators and mechanisms of miRNA activity. We therefore believe that the information collected here not only will lead to a better understanding of miRNA functions, but will also identify novel modes of manipulating miRNA activity in human disease.

1 349 760 €

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

Protein folding, the process by which a protein assumes its three-dimensional shape, is one of the basic unsolved problems of biophysical and biochemical research. Many of the structural changes taking place during protein folding, especially during the early stages, are as yet poorly understood. This is because high-resolution structural techniques generally lack the time resolution necessary for observation of folding dynamics, whereas methods that have the required time resolution generally lack structural specificity. We propose an experimental approach that combines the structure-sensitivity of multi-dimensional NMR with the ultrafast time resolution of optical techniques. To do this, we use two-dimensional optical spectroscopy (in particular, two-dimensional optical spectroscopy and time-resolved vibrational circular dichroism) in combination with site-specific labeling of proteins. This will make it possible to obtain a structurally and temporally resolved picture of protein folding, which can be regarded as a 'molecular movie' of the folding process. With the proposed method, we will investigate structural changes during protein folding at increasing levels of complexity: from the dynamics of alpha-helix nucleation, to the formation and structural characteristics of intermediate states in small globular proteins and complex beta-sheet topologies, to the nature of biologically functional, short-lived unfolded states in signalling proteins. At each of these levels of complexity, the proposed method will be used to unravel the mechanisms behind the respective folding events.

1 716 321 €

Start date: 2008-09-01, End date: 2014-08-31

The sophistication reached by organic chemistry has enabled the design and synthesis of a wide range of dynamic molecules that display controlled shape changes with an ever-increasing refinement. However, amplifying these molecular-scale dynamics to support shape-transformation in a broad range of macroscopic functions remains a key challenge. To address this challenge, I draw inspiration from living materials where molecular machines maintain out of equilibrium states by ingenious coupling with their anisotropic supramolecular environment, and ultimately promote the appearance of emergent properties on higher levels of organization. The aim of Morpheus is to develop shape-shifting materials and shape-generating photochemical systems by amplifying the motion of molecular machines over increasing length scales, towards the emergence of cohesive shape transformation in artificial tissue-like materials. We will (i) develop motorized materials by coupling light-driven molecular motors to liquid crystals and pre-program photoreaction-diffusion processes to achieve continuous motion; (ii) combine microfluidics with the anisotropic response of liquid crystal elastomers to create a library of shape-shifting bubbles and shells that undergo pre-programmed shape modification under irradiation with light; (iii) promote adhesion between units of mechanized matter, while preserving their original shape-shifting and shape-generating properties; and (iv) assemble tissue-like morphing materials from large cohesive networks of shape-shifting micro-spheres. This project will lay the scientific foundation for a new and multidisciplinary approach towards shape-generating molecular materials. It will yield unprecedented examples of emergent dynamics, provide simple models to untangle the underpinnings of mechanical transduction in nature, and contribute to developing new paradigms for the design of active matter.

2 000 000 €

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

An EEG calibration toolkit for monitoring rehabilitation of stroke patients EEG records electric potential differences from electrodes attached to the human skin. Since it is a brain imaging technique that provides a direct measure of neural activity, it is an ideal device to monitor stroke rehabilitation. For instance, the amplitude of an EEG response to a fixed external stimulus on the wrist could act as a biomarker quantifying the number of active cells in the primary somatosensory cortex. In this way, an EEG system could work as a simple monitoring device rendering direct feedback to healthcare workers on the success of the applied therapeutic strategy. This would greatly help to select the most optimal therapy for the individual patient. However, with the current state of the art a direct comparison between EEG amplitudes of different subjects is not possible because these amplitudes are strongly affected by inter individual skull variations. In this PoC project a calibration step is proposed to reduce these influences on the EEG biomarker. We will develop a software toolkit, allowing to execute the required calibration step with a minimum of patient burden. We foresee that the prototype delivered by the end of the project can be developed into a commercial accessory EEG software device that can be provided to end users for relatively small add-on price. Best practices of EEG calibration will be disseminated by publications, presentations at conferences, a special workshop and business development activities.

150 000 €

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

Dense gas-solid flows have been the subject of intense research over the past decades, owing to its wealth of scientifically interesting phenomena, as well as to its direct relevance for innumerable industrial applications. Dense gas solid flows are notoriously complex and its phenomena difficult to predict. This finds its origin in the large separation of relevant scales: particle-particle and particle-gas interactions at the microscale (< 1 mm) dictate the phenomena that occur at the macroscale (> 1 meter), the fundamental understanding of which poses a huge challenge for both the scientific and technological community. This proposal is aimed at providing a comprehensive understanding of large-scale dense gas-solid flow based on first principles, that is, based on the exchange of mass, momentum and heat at the surface of the individual solid particles, below the millimeter scale. To this end, we employ a multi-scale approach, where the gas-solid flow is described by three different models. Such an approach is by now widely recognized as the most rigorous and viable pathway to obtain a full understanding of dense-gas solid flow, and has become very topical in chemical engineering science. The unique aspect of this proposal is the scale and the comprehensiveness of the research: we want to consider, for the first time, the exchange of heat, momentum and energy, and the effects of polydispersity, heterogeneity, and domain geometries, at all three levels of modeling, and validated by one-to-one experiments. These generated insight and models will be extremely relevant for the design and scale-up of industrial equipment involving dispersed particulate flow, which is currently a fully empirical process, involving expensive and time-consuming experimentation.

2 500 000 €

Start date: 2010-03-01, End date: 2015-02-28