ERC FUNDED PROJECTS

"Many of today's and tomorrow's computer systems are built on top of large-scale networks such as, e.g., the Internet, the world wide web, wireless ad hoc and sensor networks, or peer-to-peer networks. Driven by technological advances, new kinds of networks and applications have become possible and we can safely assume that this trend is going to continue. Often modern systems are envisioned to consist of a potentially large number of individual components that are organized in a completely decentralized way. There is no central authority that controls the topology of the network, how nodes join or leave the system, or in which way nodes communicate with each other. Also, many future distributed applications will be built using wireless devices that communicate via radio. The general objective of the proposed project is to improve our understanding of the algorithmic and theoretical foundations of decentralized distributed systems. From an algorithmic point of view, decentralized networks and computations pose a number of fascinating and unique challenges that are not present in sequential or more standard distributed systems. As communication is limited and mostly between nearby nodes, each node of a large network can only maintain a very restricted view of the global state of the system. This is particularly true if the network can change dynamically, either by nodes joining or leaving the system or if the topology changes over time, e.g., because of the mobility of the devices in case of a wireless network. Nevertheless, the nodes of a network need to coordinate in order to achieve some global goal. In particular, we plan to study algorithms and lower bounds for basic computation and information dissemination tasks in such systems. In addition, we are particularly interested in the complexity of distributed computations in dynamic and wireless networks."

1 148 000 €

Start date: 2013-11-01, End date: 2018-10-31

APPLAUSE’s aim is to produce a body of evidence that illustrates how young people with mental health problems currently interact with both formal mental health services and informal social and familial support structures. Careful analysis of data gathered in the UK and Brazil will allow formulation of globally relevant insights into mental health care delivery for young people, which will be presented internationally as a resource for future health care service design. APPLAUSE will allow the collection of an important data set that does not currently exist in this field, and will look to other disciplines for innovative approaches to data analysis. Whist standard analysis may allow for snapshots of health service use, using innovative life course methods will allow us to to characterise patterns of complete service use of each individual participant’s experience of accessing mental health care and social support. Adolescence is a critical period in mental health development, which has been largely neglected by public health efforts. Psychiatric disorders rank as the primary cause of disability among individuals aged 10-24 years, worldwide. Moreover, many health risk behaviours emerge during adolescence and 70% of adult psychiatric disorders are preceded by mental health problems during adolescent years. However, delays to receiving care for psychiatric disorders, following disorder onset, avreage more than ten years and little is known about factors which impede access to and continuity of care among young people with mental health problems. APPLAUSE will analyse current access models, reports of individual experiences of positive and negative interactions with health care services and the culturally embedded social factors that impact on such access. Addressing this complex problem from a global perspective will advance the development of a more diverse and innovative set of strategies for improving earlier access to care.

1 499 948 €

Start date: 2014-01-01, End date: 2018-12-31

Supramolecular assemblies – formed by the self-assembly of hundreds of protein subunits – are part of bacterial nanomachines involved in key cellular processes. Important examples in pathogenic bacteria are pili and type 3 secretion systems (T3SS) that mediate adhesion to host cells and injection of virulence proteins. Structure determination at atomic resolution of such assemblies by standard techniques such as X-ray crystallography or solution NMR is severely limited: Intact T3SSs or pili cannot be crystallized and are also inherently insoluble. Cryo-electron microscopy techniques have recently made it possible to obtain low- and medium-resolution models, but atomic details have not been accessible at the resolution obtained in these studies, leading sometimes to inaccurate models. I propose to use solid-state NMR (ssNMR) to fill this knowledge-gap. I could recently show that ssNMR on in vitro preparations of Salmonella T3SS needles constitutes a powerful approach to study the structure of this virulence factor. Our integrated approach also included results from electron microscopy and modeling as well as in vivo assays (Loquet et al., Nature 2012). This is the foundation of this application. I propose to extend ssNMR methodology to tackle the structures of even larger or more complex homo-oligomeric assemblies with up to 200 residues per monomeric subunit. We will apply such techniques to address the currently unknown 3D structures of type I pili and cytoskeletal bactofilin filaments. Furthermore, I want to develop strategies to directly study assemblies in a native-like setting. As a first application, I will study the 3D structure of T3SS needles when they are complemented with intact T3SSs purified from Salmonella or Shigella. The ultimate goal of this proposal is to establish ssNMR as a generally applicable method that allows solving the currently unknown structures of bacterial supramolecular assemblies at atomic resolution.

1 456 000 €

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

I suggest that perceptions of diversity and disagreement voiced in the on-line political discussion may play a key role in mobilizing citizens to voice their views and take action in authoritarian regimes. The empirical focus is the Chinese Internet. Subjective perceptions of group discussion among participants can significantly differ from the objective content of the discussion. These perceptions can have an independent effect on political engagement. Novel is also that I will study which technological settings (blogs, Weibo (Twitter), public hearings, etc) facilitate these perceptions. I will address these novel issues by specifying the conditions and causal mechanisms that facilitate the rise of online public opinion. As an expansion to prior work, I will study passive in addition to active participants in online discussion. This is of particular interest because passive participants outnumber active participants. My overall aim is to deepen our knowledge of how participants experience online political discussion in stabilizing or destabilizing authoritarian rule. To this end, I propose to work with one post-doc and two PhD research assistants on four objectives: Objective 1 is to explore what kinds of people engage in online discussions and differences between active and passive participants. Objective 2 is to understand how the technological settings that create the conditions for online discussion differ from each other. Objective 3 is to assess how active and passive participants see the diversity and disagreement in the discussion in these settings. Objective 4 is to assess whether citizens take action upon online political discussion depending on how they see it. I will produce the first nationally representative survey on the experiences of participants in online political discussion in China. In addition to academics, this knowledge is of interest to policy-makers, professionals, and journalists aiming to understand authoritarian politics and media

1 499 780 €

Start date: 2014-03-01, End date: 2019-02-28

This project investigates the cross-fertilisation of Anglo/American and German literature and film during the Allied Occupation of Germany. It will be the first study to survey the cultural landscape of the British and American zones of Occupied Germany in any detail. By doing so it will offer a new interpretative framework for postwar culture, in particular in three areas: the history of the Allied Occupation of Germany; the history of postwar Anglophone and Germanophone literature (arguing the two were more intertwined than has previously been suggested); and the history of the relationship between postwar and Cold War. Combining Anglo-American and German literature and film history with critical analysis, cultural history and life-writing, this is a necessarily ambitious, multidisciplinary study which will open up a major new field of research.

1 414 601 €

Start date: 2013-09-01, End date: 2019-02-28

"The body is ubiquitous in perceptual experience and is central to our sense of self and personal identity. Disordered body representations are central to several serious psychiatric and neurological disorders. Thus, identifying factors which contribute to the formation and maintenance of body representations is crucial for understanding how body representation goes awry in disease, and how it might be corrected by potential novel therapeutic interventions. Several types of sensory signals provide information about the body, making the body the multisensory object, par excellence. Little is known, however, about how information from somatosensation and from vision is integrated to construct the rich body representations we all experience. This project fills this gap in current understanding by determining how the brain builds body representations (BODYBUILDING). A hierarchical model of body representation is proposed, providing a novel theoretical framework for understanding the diversity of body representations and how they interact. The key motivating hypothesis is that body representation is determined by the dialectic between two major cognitive processes. First, from the bottom-up, somatosensation represents the body surface as a mosaic of discrete receptive fields, which become progressively agglomerated into larger and larger units of organisation, a process I call fusion. Second, from the top-down, vision starts out depicting the body as an undifferentiated whole, which is progressively broken into smaller parts, a process I call segmentation. Thus, body representation operates from the bottom-up as a process of fusion of primitive elements into larger complexes, as well as from the top-down as a process of segmentation of an initially undifferentiated whole into more basic parts. This project uses a combination of psychophysical, electrophysiological, and neuroimaging methods to provide fundamental insight into how we come to represent our body."

1 497 715 €

Start date: 2014-02-01, End date: 2019-01-31

Non-invasive genomic analysis of cancer can revolutionize the study of tumour evolution, heterogeneity, and drug resistance. Clinically applied, this can transform current practice in cancer diagnosis and management. Cell-free DNA in plasma contains tumour-specific sequences. This circulating tumour DNA (ctDNA) is a promising source of genomic and diagnostic information, readily accessible non-invasively. The study of ctDNA is therefore timely and of great importance. But it is also very challenging. Measurement can be complex, and high-quality samples are not easily obtained. Though progress has been made, much remains to be discovered. My lab pioneered the use of targeted sequencing to analyse mutations in ctDNA. We recently developed a ground-breaking paradigm for analysing evolving cancer genomes in plasma DNA, combining ctDNA quantification with exome-sequencing of serial plasma samples. Applied to extensive sets of clinical samples my lab has characterized, this will enable large-scale exploration of acquired drug resistance with unprecedented resolution. CancerExomesInPlasma aims to use ctDNA for genome-wide analysis of tumour evolution, as a means for non-invasive, unbiased discovery of genes and pathways involved in resistance to cancer therapy.

1 769 380 €

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

There is a large need for revitalization of the research on coronary heart disease (CHD) including: a) improved risk prediction and more adequate individually-tailored treatment; and b) new targets for drug development based on pathways previously unknown to be involved in CHD pathophysiology. The overall goal of this proposal is to improve prevention and treatment of CHD through better understanding of the biology underlying disease development, identification of new biomarkers for improved risk prediction, and discovery of novel targets for drug development. The specific aims are to: 1) Establish and characterize causal genes in known CHD loci (gene regions) through: a) resequencing of known CHD loci; b) expression profiling in liver, arteries, myocardium and skeletal muscle; c) high-throughput protein profiling; and d) experimental follow-up in zebrafish (Danio rerio) models. 2) Discover new proteins, metabolites and pathways involved in CHD pathophysiology using global proteomic and metabolomic profiling to provide new biomarkers and drug targets. We will integrate genomic, transcriptomic, metabolomic and proteomic data from five longitudinal, population-based cohort studies with detailed phenotyping and one study with tissue collections for expression studies. The cohort studies include 36,907 individuals; there are 3,093 prevalent CHD cases at baseline and the estimated number of incident (new) events in previously healthy by 2016 is 2,202. In addition, we work with zebrafish model systems to establish causal CHD genes and characterize their mechanisms of action. We have access to unique study materials, state-of-the art methods, and a strong track record of successful projects in this field. To our knowledge, there are no other groups combining -omics methods to elucidate the whole chain from DNA variation to overt CHD in such large and well-characterized study samples. Further, we are unaware of other groups using zebrafish models to screen for and characterize causal CHD genes. Our work is anticipated to lead to new important insights into the pathophysiology of CHD, identification of new biomarkers for improved risk prediction, and discovery of novel targets for drug development.

1 498 224 €

Start date: 2014-01-01, End date: 2018-12-31

Adhesion is a key event for eukaryotic cells to establish contact with the extracellular matrix and other cells. It allows cells to quickly adapt to mechanical changes in their environment by either adhesion reinforcement or release. Understanding and mimicking the interplay between adhesion reinforcement and release could result in novel cell-inspired adaptive materials. In order to ultimately be able to transfer functional principles of cell adhesion to a next generation of biomimetic materials, we will elucidate the biophysics of cell adhesion in response to external force. We have already obtained important results that have provided new insights into cell adhesion. For example, we have found that the nanoscale spacing of adhesion sites controls cell adhesion reinforcement. With the project proposed here I want to advance our understanding of cell adhesion by generating a comprehensive model of mechanotransduction-mediated cell adhesion. Therefore, my group will develop new force measurement methods based on atomic force microscopy and 2D force sensor arrays that allow for a systematic investigation of key parameters in the cell adhesion system, including the concept of cellular mechanosensing. My hypothesis is that there is a transition between adhesion reinforcement and release as a function of external mechanical stress, stress history, and the biofunctionalization of the adhesive surface. Transferring our biophysical knowledge into materials science promises new materials with a dynamic adaptive mechanical and adhesion response. This transfer of biological concepts into cell-inspired materials will follow the construction principles of cells: the proposed material will be based on polymer fibers that are reversibly cross-linked and reinforce adhesion upon mechanical stress. The ultimate goal of the proposed project is to develop an intelligent polymer material with an adaptive adhesive and mechanical response similar to that found in living cells.

1 467 483 €

Start date: 2013-09-01, End date: 2018-08-31

"Magnetism plays a profound role in stars and planets. In the Sun, magnetic fields are ultimately responsible for solar flares and coronal mass ejections that can impact our technological society. Earth's own magnetic field partly shields us from these events, but solar storms can still interrupt satellite communications, disrupt power grids, and pose a danger to astronauts on spacewalks. More generally, magnetic fields partly control the rotational evolution of stars, likely impact the habitability of extrasolar planets, and may modify the sizes and internal structures of low-mass stars and gaseous planets. In all cases, the magnetism is generally thought to arise from a convective dynamo -- but a detailed theoretical understanding of this process, and its influence on the overall evolution of stars and planets, has remained elusive. Particularly fascinating observational puzzles have recently come from the study of low-mass M-dwarf stars: the most numerous type of stars in our galaxy and perhaps the most likely to host habitable planets. We therefore propose to study how stars and sub-stellar objects build magnetic fields using 3-D magnetohydrodynamic simulations, and to quantify the effects of those fields on stellar structure and evolution. Using the Anelastic Spherical Harmonic (ASH) and Compressible Spherical Segment (CSS) codes, we will examine (a) how global magnetic field generation in these stars depends upon parameters like stellar mass, rotation rate, and the presence of a stable core, and (b) how the deep convection and magnetism imprints through (and is shaped by) the near-surface layers of these objects. We will (c) determine the impact of the resulting fields on the convective transport of heat and angular momentum, incorporate our results into state of the art 1-D evolutionary models of stars, and explore the consequences for stellar evolution. Separately, we will (d) develop and maintain a public database of 3-D convective dynamo models."

1 469 070 €

Start date: 2013-12-01, End date: 2018-11-30

The principle objective of this proposal is to validate fluorinated glyco-structures as effective carbohydrate mimics for the next frontier in pharmaceutical research. Herein we propose to capitalise on the major advances in statistical data analysis which are unravelling the complexity of mammalian and bacterial “glycospace”. Molecular mimicry is a powerful drug design approach. It is therefore envisaged to develop a focussed programme of research to validate fluorinated glycostructures, and in particular 2-fluoro sugars, as carbohydrate mimics for chemical biology, exploiting the ubiquitous role of carbohydrates in molecular recognition. Salient features of the 2-fluoro substituent include (i) enhanced hydrolytic stability to enzymatic degradation, (ii) the presence of a NMR active reporter nucleus (19F) for facile analysis, and (iii) the possibility for molecular imaging application when using 18F labelled glycostructures. Phase one of this project will aim to develop synthetic routes to the target fluoro-glycostructures. This will involve a substantial component of physical organic chemistry including conformational analysis, advanced 19F NMR spectroscopy and the possible isolation of oxo-carbenium analogues by exploiting advances in the development of large, weakly co-ordinating anions. From first principle reaction design and development, through a basic understanding of conformation and reactivity, phase 2 will focus on the application of these materials for chemical biology applications. Phase 2 will then heavily focus on the application of complex oligosaccharides containing the PET active 18F moiety. It is envisaged that by exploiting the ubiquitous role of carbohydrates in molecular recognition that this would conceivably lead to the development of selective imaging agents, thus bypassing the current problem of relying on the metabolically controlled distribution of the commonly used PET tracer 2-fluorodeoxy glucose (18F-FDG).

1 253 880 €

Start date: 2013-11-01, End date: 2018-10-31

Recent cancer genome analyses have led to the discovery of a process involving massive genome structural rearrangement (SR) formation in a one-step, cataclysmic event, coined chromothripsis. The term chromothripsis (chromo from chromosome; thripsis for shattering into pieces) stands for a hypothetical process in which individual chromosomes are pulverised, resulting in a multitude of fragments, some of which are lost to the cell whereas others are erroneously rejoined. Compelling evidence was presented that chromothripsis plays a crucial role in the development, or progression of a notable subset of human cancers – thus, tumorigensis models involving gradual acquisitions of alterations may need to be revised in these cancers. Presently, chromothripsis lacks a mechanistic basis. We recently showed that in childhood medulloblastoma brain tumours driven by Sonic Hedgehog (Shh) signalling, chromothripsis is linked with predisposing TP53 mutations. Thus, rather than occurring in isolation, chromothripsis appears to be prone to happen in conjunction with (or instigated by) gradually acquired alterations, or in the context of active signalling pathways, the inference of which may lead to further mechanistic insights. Using such rationale, I propose to dissect the mechanism behind chromothripsis using interdisciplinary approaches. First, we will develop a computational approach to accurately detect chromothripsis. Second, we will use this approach to link chromothripsis with novel factors and contexts. Third, we will develop highly controllable cell line-based systems to test concrete mechanistic hypotheses, thereby taking into account our data on linked factors and contexts. Fourth, we will generate transcriptome data to monitor pathways involved in inducing chromothripsis, and such involved in coping with the massive SRs occurring. We will also combine findings from all these approaches to build a comprehensive model of chromothripsis and its associated pathways.

1 471 964 €

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

"Bile synthesis and secretion are crucial to liver function and involve multiple proteins. Disorders due to defects in this process (Inherited Cholestatic Disorders, ICDs) lead to progressive liver disease. Many ICD patients do not respond to medical treatment and need liver transplantation (LT). Although ICDs are rare, multifactorial cholestatic diseases are common and many patients will benefit from ICD research. There is acute shortage of liver donors. 10% of patients die while waiting on the liver transplant list. Therefore alternatives to LT are urgently needed. Bioengineered tissues may reduce the need for donor organs but complexity of it's organisation makes generation of functional liver challenging. The OBJECTIVE of this project is to generate Cultured Liver Organoids (CLOs) using hepatocytes cultured on 3-D scaffolds as novel models for study of liver development and disease and potential treatment of ICDs. 3-D extracellular matrix (ECM) scaffolds derived from decellularised livers and polymeric matrices (PM) have been used to mimic liver architecture but further work is needed to establish functional bile flow. Human Induced Pluripotent Stem Cells (hIPSCs) derived from reprogrammed skin fibroblasts by overexpression of pluripotency factors can proliferate and be differentiated into various cell types including hepatocytes. hIPSCs enable production of patient specific cells, which are fully immuno-compatible. Genetically corrected mutant hIPSCs differentiated into hepatocytes have been used as cell therapy in animal models of inherited metabolic disorders but direct infusion of hepatocytes into the liver is unlikely to achieve polarised bile flow and correct ICDs. Therefore hIPSCs developed from ICD patients will be used to culture hepatocytes on decellularised mouse liver ECM to generate in vitro models of ICDs. CLOs containing hepatocytes from genetically corrected hIPSC will be tested in mouse models of ICDs as potential treatment."

1 500 000 €

Start date: 2014-01-01, End date: 2018-12-31

Cognition is a collective term for complex but sophisticated mental processes such as attention, learning, social interaction, language production, decision making and other executive functions. For normal brain function, these higher-order functions need to be aptly regulated and controlled, and the physiology and cellular substrates for cognitive functions are under intense investigation. The loss of cognitive control is intricately related to pathological states such as schizophrenia, depression, attention deficit hyperactive disorder and addiction. Synchronized neural activity can be observed when the brain performs several important functions, including cognitive processes. As an example, gamma activity (30-80 Hz) predicts the allocation of attention and theta activity (4-12 Hz) is tightly linked to memory processes. A large body of work indicates that the integrity of local and global neural synchrony is mediated by interneuron networks and actuated by the balance of different neuromodulators. However, much knowledge is still needed on the functional role interneurons play in cognitive processes, i.e. how the interneurons contribute to local and global network processes subserving cognition, and ultimately play a role in behavior. In addition, we need to understand how neuro-modulators, such as dopamine, regulate interneuron function. The proposed project aims to functionally determine the specific role the parvalbumin interneurons and the neuromodulator dopamine in aspects of cognition, and in behavior. In addition, we ask the question if cognition can be enhanced. We are employing a true multidisciplinary approach where brain activity is recorded in conjunctions with optogenetic manipulations of parvalbumin interneurons in animals performing cognitive tasks. In one set of experiments knock-down of dopamine receptors specifically in parvalbumin interneurons is employed to probe how this neuromodulator regulate network functions.

1 400 000 €

Start date: 2014-02-01, End date: 2019-01-31

"CON-HUMO focuses on novel concepts for automatic control based on data-driven human models and machine learning. This enables innovative control applications that are difficult if not impossible to realize using traditional control and identification methods, in particular in the challenging area of smart human-machine interaction. In order to achieve intuitive and efficient goal-oriented interaction, anticipation is key. For control selection based on prediction a dynamic model of the human interaction behavior is required, which, however, is difficult to obtain from first principles. In order to cope with the high complexity of human behavior with unknown inputs and only sparsely available training data we propose to use machine-learning techniques for statistical modeling of the dynamics. In this new field of human interaction modeling – data-driven and machine-learned – control methods with guaranteed properties do not exist. CON-HUMO addresses this niche. Key methodological innovation and breakthrough is the merger of probabilistic learning with model-based control concepts through model confidence and prediction uncertainty. For the sake of concreteness and evaluation the focus is on one of the most challenging problem classes, namely physical human-machine interaction: Because of the physical contact between the human and the machine not only information, but also energy is exchanged posing fundamental challenges for real-time human-adaptive and safe decision making/control and requiring provable stability and performance guarantees. The developed methods are a direct enabler for societally important applications such as machine-based physical rehabilitation, mobility and manipulation aids for elderly, and collaborative human-machine production systems. With its fundamental results CON-HUMO lays the ground for the systematic control design for smart human-machine/infrastructure interaction."

1 494 640 €

Start date: 2014-02-01, End date: 2019-01-31

Understanding how galaxies form in the early universe and how they evolve through cosmic time is a major goal of modern astrophysics. Panchromatic look-back sky surveys significantly advanced the field in the past decade, and we are now entering a 'golden age' of radio astronomy given an order of magnitude improved facilities like JVLA, ATCA and ALMA. I am leading two unique, state-of-the-art (JVLA/ATCA) radio surveys that will push to the next frontiers. The proposed ERC project will focus on the growth of stellar and black-hole mass in galaxies across cosmic time by: 1-probing various types of extremely faint radio sources over cosmic time, revealing the debated abundance of faint radio sources, 2-exploring star formation conditions at early cosmic times, allowing to access for the first time the dust-unbiased cosmic star formation history since the epoch of reionization, 3-performing the first census of high-redshift starbursting galaxies (SMGs), and their role in galaxy formation and evolution, and 4-performing a full census of galaxies hosting supermassive black holes (AGN), with different black-hole accretion modes, and their roles in galaxy evolution. The exploitation of these radio sky surveys is essential for the preparation and success of the future large facilities like ASKAP, and SKA as they will 1-provide best predictions of the to-date uncertain cosmic radio background seen with the SKA, and 2-optimize photometric redshift estimates, essential for the success of the first ASKAP sky survey (EMU, >2016). My radio surveys, expected to yield >100 refereed publications, carry an immense legacy value. The proposed ERC funding is essential for the success of these timely surveys, which I will conduct from Croatia. The ERC grant will allow me to lead my own research group working on this novel data, and to even more firmly establish myself as a leading survey scientist, and lead my group to internationally competitive levels, and enhance EU competitiveness.

1 500 000 €

Start date: 2014-02-01, End date: 2019-01-31

Cells must integrate output from multiple genetic circuits in order to correctly control cellular processes. Despite much work characterizing regulation in these circuits, how circuits interact to control global cellular programs remains unclear. This is particularly true given that recent research at the single cell level has revealed that genetic circuits often generate variable or stochastic regulation dynamics. In this proposal we will use a multi-disciplinary approach, combining modelling and time-lapse microscopy, to investigate how cells can robustly integrate signals from multiple dynamic genetic circuits. In particular we will answer the following questions: 1) What types of dynamic signal encoding strategies are available for the cell? 2) What are the benefits of dynamic gene activation, whether stochastic or oscillatory, to the cell? 3) How do cells couple and integrate output from diverse gene modules despite the noise and variability observed in gene circuit dynamics? We will study these questions using 2 key model systems. In Aim 1, we will examine stochastic pulse regulation dynamics and coupling between alternative sigma factors in B. subtilis. Our preliminary data has revealed that multiple B. subtilis sigma factors stochastically pulse under stress. We will look for evidence of any coupling or interactions between these stochastic pulse circuits. This system will serve as a model for how a cell uses stochastic pulsing to control diverse cellular processes. In Aim 2, we will examine coupling between a deterministic oscillator, the circadian clock, and multiple other key pathways in Cyanobacteria. We will examine how the cell can dynamically couple multiple cellular processes using an oscillating signal. This work will provide an excellent base for Aim 3, in which we will use synthetic biology approaches to develop ‘bottom up’ tests of generation of novel dynamic coupling strategies.

1 499 571 €

Start date: 2014-02-01, End date: 2019-01-31

Research on Muslims in Europe or in the Muslim majority countries has since September 11, mainly focused on understanding the causes of religious radicalization. Largely ignored in the public debates, as well as in academic scholarship, is recognition of the rapid growth in a number of prominent initiatives emerging within Muslims in the west that are aimed at initiating intellectual revival within Islam. Drawing inspiration from the thinkers such as Al-Ghazali or Ibn-Rushd (associated with the ‘rationalist tradition’ in Islam), the Muslim intellectuals and scholars at the center of this movement for intellectual revival in Islam are arguing for ‘indigenizing Islam in the West.’ This project is aimed at understanding the emergence and growth of this movement, the methodology different actors within this movement adopt to initiate reform while remaining loyal to the Islamic ethical spirit, and the implications of these attempts at intellectual reform for individual behavior and social change within Muslims in the west as well as in Muslim majority countries. The project will situate the emergence of this movement within the broader shifts being witnessed in the traditional structures of Islamic authority— such as Al-Azhar University, Dar-ul Uloom, Deoband, Diyanat, and Al-Medina University— that dominate the teaching and interpretation of Islam globally but are under pressure to reform. By developing detailed ethnographic accounts of these new and old institutions of Islamic authority, examining the intellectual discourse of their scholars, observing the argumentations through which they socially advance their conception of Islam, and analyzing how these discourses impact real life choices, this project will shed light on the complexity of Islamic thought and changes in contemporary Muslim societies. It will also highlight the spaces that are emerging for engagement between the Islamic and western tradition and inform theory of religious behavior.

1 376 704 €

Start date: 2014-03-01, End date: 2019-12-31

"This project aims to develop a new ‘philosophy of data-intensive science’ that clarifies how research practices are changing in the digital age, and examines how this affects current understandings of scientific epistemology within the philosophy of science and beyond. The scale of scientific data production has massively increased in recent times, raising urgent questions about how scientists are to transform the resulting masses of data into useful knowledge. A technical solution to this problem is offered by technologies for the storage, dissemination and handling of data over the internet, including online databases that enable scientists to retrieve and analyse vast amounts of data of potential relevance to their research. These technologies are having a profound effect on what counts as scientific knowledge and on how that knowledge is obtained and used. This is a step change in scientific methods, which scientists refer to as ‘data-intensive’ research. Surprisingly, the characteristics and philosophical implications of this emerging way of doing science have not yet been extensively and systematically analysed. This project aims to fill this gap by combining the analytic apparatus developed by philosophers of science with empirical, qualitative methods used by social scientists to investigate cutting-edge scientific practices. Accordingly, Phase 1 of the project will investigate how the use of online databases is currently affecting research practices and outcomes in two areas: plant science and biomedicine. Phase 2 will then build on these empirical results to analyse how data-intensive methods challenge existing philosophical understandings of the epistemic role of data, theory, experiments and division of labour in science. Through the analysis of how these four key components, the PI will produce a systematic assessment of the implications of the rise of data-intensive research for how science is organised, conducted and assessed."

1 046 000 €

Start date: 2014-03-01, End date: 2019-02-28

High-throughput (HT) screening of live cells is crucial to accelerate both fundamental biological research and discovery of new drugs. Current methods for HT cell screenings, however, either require a large number of microplates, are prone to cross-contaminations and are limited to adherent cells (cell microarrays), or are not compatible with adherent cells as well as with spatial indexing (droplet microfluidics). We recently demonstrated the use of superhydrophobic-superhydrophilic microarrays to create high-density arrays of microdroplets or hydrogel micropads. We propose here to develop a new platform for HT cell screening experiments using the unique properties of the superhydrophilic microarrays separated by superhydrophobic thin barriers. The new technology will allow us to perform up to 300K cell experiments in parallel using a single chip. Individual cell experiments will be performed in thousands of completely isolated microdroplet at defined locations on the chip. This will enable spatial indexing, time-lapse measurements and screening of either adherent or non-adherent cells. Parallel manipulations within individual microreservoirs, such as washing, addition of chemical libraries, or staining will be developed to open new possibilities in the field of live cell studies. Superhydrophobic barriers will allow complete isolation of the microreservoirs, thus preventing cross-contamination and cell migration. We will also develop a technology for the HT screening of cells in 3D hydrogel micropads. We will use these methods to gain better understanding of how different parameters of the 3D cell microenvironment influence various aspects of cell behavior. The project will require the development of new technological tools which can later be applied to a wide range of cell screening experiments and biological problems. Our long term aim is to replace the outdated microplate technology with a more powerful and convenient method for cell screening experiments.

1 499 820 €

Start date: 2014-02-01, End date: 2019-01-31

Fire has played a key role in the evolutionary success of our species and has shaped the abundance of life that we see on our planet today. Wildfires have influenced the history of plant life for 410 million years where 5 key plant evolutionary events have occurred that led to variations in fire behaviour. Variations in fire behaviour determine a fire’s severity and its impact on an ecosystem. In order to assess palaeofire severity the heat delivered by a fire and the duration for which it remains at a site must be estimated. Currently we are unable to estimate palaeofire behaviour and are therefore unable to predict the ecological impact of palaeofires. ECOFLAM will change this by combining for the first time state-of-the-art flammability experiments with innovative modelling approaches to reconstruct variations in palaeofire behaviour due to plant innovations. ECOFLAM will establish relationships between plant traits that are measurable in the fossil record, and their flammability. It will construct simple metrics that can be applied to assess the nature of fires occurring in a fossil flora. Then using a frontier approach ECOFLAM will apply mathematical models to create the first ever estimates of palaeofire behaviour. ECOFLAM will: 1) estimate fire behaviour in Earth’s earliest forests, 2) assess the impact of the evolution of gymnosperm conifers on changes in fire regime and fire behaviour 3) test the hypothesis that early angiosperms utilised fire to invade and out compete gymnosperm forests, 4) test the hypothesis that expansion of neotropical forests led to suppression of fire and 5) track the ability of increases in grass fuel to enhance ecosystem flammability enabling expansion of the savanna biome. ECOFLAM will collaborate with an artist to visually express the relationship between fire and plants to bring fire science to the arts and public. Finally via an exciting link with Morgan Stanley, London ECOFLAM will explore the economic impact of wildfires.

1 519 640 €

Start date: 2013-10-01, End date: 2018-09-30

Imparting chirality to non-chiral metal surfaces by adsorption of chiral modifiers is a highly promising route to create effective heterogeneously catalyzed processes for production of enantiopure pharmaceuticals. A molecular-level understanding of enantioselective processes on chiral surfaces is an importance prerequisite for the rational design of new enantiospecific catalysts. With the research outlined in this proposal we are aiming at a fundamental level understanding of the structure of chirally modified surfaces, the bonding of the prochiral substrate on the chiral media and the details of the kinetics and dynamics of enantioselective surface reactions. A full mechanistic picture can be obtained if these aspects will be understood both on the extended single crystal surfaces, mimicking a local interaction of the modifier-substrate complexes with a metal, as well as on the small chirally modified nanoparticles that more accurately resemble the structural properties and high catalytic activity of practically relevant powdered supported catalyst. To achieve these atomistic insights, we propose to apply a combination of ultrahigh vacuum (UHV) based methods for studying reaction kinetics and dynamics (multi-molecular beam techniques) and in-situ surface spectroscopic and microscopic tools on well-defined model surfaces consisting of metal nanoparticles supported on thin single crystalline oxide films. Complementary, the catalytic behaviour of these chirally modified model surfaces will be investigated under ambient pressure conditions with enantiospecific detection of the reaction products that will enable detailed atomistic insights into structure-reactivity relationships.

1 589 736 €

Start date: 2014-01-01, End date: 2018-12-31

It is the unprecedented access to genome wide data that highlights the potential of current evolutionary studies and this proposal aims at exploiting this progress to analyze evolutionary processes in a well-established fish system of hybrid speciation. We study natural populations of freshwater fish referred to as sculpins (Cottus). In these we have identified species that have recently (<200 years) hybridized as a result of secondary contact through man-made canals between river systems. This gave rise to a new lineage with new adaptations that have allowed it to invade habitats that were not used by the parental species before. We are thus also dealing with evolutionary change that is associated with man-made ecological perturbations, the analysis of which is particularly timely. It is now possible to perform a near exhaustive search to identify genes and to study gene expression as a measure of evolutionary change in Cottus. A combination of genetic mapping experiments and screens for genotypic selection can reveal loci and functions as targets of selection in the adaptive evolution of invasive Cottus. This proposal specifically aims at identifying genomic traits such as copy number changes of coding sequences or changes in the gene regulatory architecture that have evolved as a direct consequence of hybridization and to explore their implication in adaptive evolution. The results will contribute to our understanding of the genetics of adaptation and the invasion of a new environment. With respect to hybrid zones and the evolution of new species, we will identify candidate genes and functions that can explain barriers to reproduction in the wild. Finally, we will be able to make significant progress with respect to the genetics associated with hybrid speciation.

1 377 162 €

Start date: 2014-02-01, End date: 2019-01-31

"Inflammasomes are intracellular danger-sensing protein complexes that are important for host protection. They initiate inflammation by controlling the activity of the proinflammatory cytokine interleukin-1β (IL-1β). Unlike most other cytokines, IL-1β is produced and retained in the cytoplasm in an inactive pro-form. Inflammasome-dependent maturation of proIL-1β is mediated by the common component of all inflammasomes, the protease caspase-1. Caspase-1 also controls the secretion of IL-1β, but the mechanism and route of secretion are unknown. We have recently demonstrated that the ability of caspase-1 to control IL-1β secretion is not dependent on its protease activity, but rather on a scaffold or adapter function of caspase-1. Furthermore, we and others could show that caspase-1 can control the secretion of non-substrates like IL-1α. These insights provide us with new and potentially revealing means to investigate the downstream effector functions of caspase-1, including the route and mechanism of IL-1 secretion. We will develop new tools to study the process of IL-1 secretion by microscopy and the novel mode-of-action of caspase-1 through the generation of transgenic models. Despite the important role of IL-1 in host defence against infection, dysregulated inflammasome activation and IL-1 production has a causal role in a number of acquired and hereditary auto-inflammatory conditions. These include particle-induced sterile inflammation (as is seen in gout and asbestosis), hereditary periodic fever syndromes, and metabolic diseases like diabetes and atherosclerosis. Currently, recombinant proteins that block the IL-1 receptor or deplete secreted IL-1 are used to treat IL-1-dependent diseases. These are costly treatments, and are also therapeutically cumbersome since they are not orally available. We hope that a better understanding of caspase-1-mediated secretion of IL-1 will unveil mechanisms that may serve as targets for future therapies for these diseases."

1 495 533 €

Start date: 2014-03-01, End date: 2019-02-28

"The financial crisis, since its start in 2008 has exposed enormous fractures both in the financial architecture and in the structure of the global economy. Although with some notable exceptions, the magnitude of the events caught the finance profession largely by surprise. Clearly, we have to understand better the institutional mechanism channeling savings towards the best uses of capital, and to what extent this mechanism can sometimes fail. The projects in this proposal will push the boundaries of our knowledge in this direction. I suggest a dual approach to achieve this goal. First, we have to improve our understanding of which frictions are the crucial impediments of the efficient functioning of markets. As this approach focuses on particular markets in isolation, I call this the micro approach. I propose three projects within this approach: trading and information diffusion in OTC markets, the crowdedness in limits-to-arbitrage, and the interaction of political uncertainty and sovereign bond prices. Second, from the frictions emerging from the micro approach, we have to select the ones which determine the aggregate liquidity fluctuations in the economy. I use this concept in a broad sense; referring to the changing efficiency with which the financial system allocates resources across investment opportunities. As this approach focuses on the functionality of the financial system as a whole, I call this the macro approach. I propose two projects within this approach. The first project focuses on the determinants of the differences in the financial architecture of different economies. It builds a novel framework to study the dynamics of the financial sector of an economy. The second project studies the role of shadow banking in the fluctuation of aggregate liquidity. In particular, this project concentrates on the fluctuation of the efficiency of private liquidity creation as the state of the economy changes."

1 122 883 €

Start date: 2013-12-01, End date: 2018-11-30

Until recently, access to telecommunication technologies was out of reach for all but the most privileged citizens in Sub-Saharan Africa (SSA). However, recent radical changes that have connected hundreds of millions have encouraged politicians, journalists, academics, and citizens to speak of an IT-fuelled economic revolution happening on the continent. Many see potentials to move away from primary industries and towards a focus on quaternary and quinary sectors (the knowledge-based parts of the economy). Yet, it remains that there is surprisingly little research into the emergence of a new knowledge economy in Africa. As such, it is precisely now that we urgently need groundbreaking frontier research to understand precisely what impacts are observable, who benefits, and how these changes match up to our expectations for change. We should therefore ask if we are seeing a new era of development on the continent fuelled by ICTs, or whether SSA’s engagement with the global knowledge economy continues to be on terms that reinforce dependence, underdevelopment, and economic extraversion. This research project tackles this broad line of inquiry by focusing on the geographies, causes, and effects of SSA’s emerging knowledge economies at this crucial moment of change. We do so through three key research contexts: economic geographies of knowledge production; outsourcing and bottom-of-the-pyramid labour; and the creative service sector. Using a mixed-methods approach, we will document the unexpected challenges and the unanticipated innovative uses of this changing connectivity, and cut through through the hype by empirically evaluating benefits and impacts of new communication technologies in Africa. This project will thus contribute not only to academic and policy debates surrounding connectivity and Internet access, but will also provide a robust evidence base crucial in shaping future rounds of ICT related development projects in low-income countries.

1 499 110 €

Start date: 2014-07-01, End date: 2019-06-30

The unique manipulative abilities of the human hand have fascinated scientists since the time of Darwin. However, we know little about how these unique abilities evolved because we have lacked, (1) the necessary fossil human (hominin) evidence and (2) the appropriate methods to investigate if, when and how our early ancestors used their hands for locomotion (climbing) and manipulation (tool-use). The GRASP project will use novel morphological, experimental and biomechanical methods to investigate different locomotor and manipulative behaviours in humans and other apes, and will use this knowledge to reconstruct hand use in the most complete early hominin hand fossils, those of Australopithecus sediba. The goal of GRASP is to determine the evolutionary history of the human hand by addressing two fundamental, yet unresolved, questions: (1) Were our fossil hominin ancestors still using their hands for climbing? (2) When and in which fossil hominin species did stone tool-use and tool-making first evolve? These questions will be addressed via three objectives: First, microtomography and a novel, holistic method (MedTool®) will be used to analyse the internal bony structure of human, ape and fossil hominin hand bones. Second, collection of the necessary biomechanical data on (a) the loads experienced by the human hand during tool-use and tool-making, (b) hand use and hand postures used by African apes during locomotion in the wild and, (c) the loads experienced by the bonobo hand during arboreal locomotion. Third, data from the first two objectives will be used to adapt musculoskeletal models of the human and bonobo hand and, through the creation of 3D biomechanical (finite-element) models, simulate natural loading of individual hand bones in humans, bonobos and fossil hominins. With this detailed understanding of hand function, we will determine how the locomotor and manipulative behaviours of Au. sediba and other early hominins shaped the evolution of the human hand.

1 618 253 €

Start date: 2014-03-01, End date: 2019-02-28

"Over the past years, carbon nanomaterial such as graphene and carbon nanotubes (CNTs) have attracted the interest of scientists, because some of their properties are unlike any other engineering material. Individual graphene sheets and CNTs have shown a Youngs Modulus of 1 TPa and a tensile strength of 100 GPa, hereby exceeding steel at only a fraction of its weight. Further, they offer high currents carrying capacities of 10^9 A/cm², and thermal conductivities up to 3500 W/mK, exceeding diamond. Importantly, these off-the-chart properties are only valid for high quality individualized nanotubes or sheets. However, most engineering applications require the assembly of tens to millions of these nanoparticles into one device. Unfortunately, the mechanical and electronic figures of merit of such assembled materials typically drop by at least an order of magnitude in comparison to the constituent nanoparticles. In this ERC project, we aim at the development of new techniques to create structured assemblies of carbon nanoparticles. Herein we emphasize the importance of controlling hierarchical arrangement at different length scales in order to engineer the properties of the final device. The project will follow a methodical approach, bringing together different fields of expertise ranging from macro- and microscale manufacturing, to nanoscale material synthesis and mesoscale chemical surface modification. For instance, we will pursue combined top-down microfabrication and bottom-up self-assembly, accompanied with surface modification through hydrothermal processing. This research will impact scientific understanding of how nanotubes and nanosheets interact, and will create new hierarchical assembly techniques for nanomaterials. Further, this ERC project pursues applications with high societal impact, including energy storage and water filtration. Finally, HIENA will tie relations with EU’s rich CNT industry to disseminate its technologic achievements."

1 496 379 €

Start date: 2014-01-01, End date: 2018-12-31

A long term goal of synthetic biology is the assembly of a cell from its individual components. A genetic element based on synthetic nucleic acids capable of stable propagation, a synthetic episome, is the minimal genetic element required for the systematic development of all cellular components of a synthetic organism based on artificial nucleic acids. Recent progress in DNA polymerase engineering has successfully isolated variants with expanded substrate spectra capable of efficiently synthesising hexitol nucleic acids (HNA) from DNA templates, and capable of synthesising DNA from HNA templates. Together, they demonstrate that HNA can serve as a genetic material. However, the unavoidable DNA intermediate in HNA replication and their limited processivity greatly limit the potential of these polymerases for the development of an HNA episome. To establish an HNA episome, processive HNA-directed HNA polymerases as well as accessory proteins to support episome maintenance and replication are required. The bacteriophage phi29 requires only four proteins (including polymerase, terminal protein, single-stranded and double-stranded DNA binding proteins) and two DNA elements (origin of replication and high affinity sites for its double-stranded DNA binding protein) to replicate and maintain its linear genome, making it a suitable starting point for the development of an HNA episome. We propose to develop novel in vitro selection methodologies that will allow the directed evolution of a minimal HNA episome based on the phi29 system – including the isolation of an HNA-dependent HNA polymerase, a modified terminal protein and single-stranded as well as double-stranded HNA binding proteins. In addition to being a landmark result in synthetic biology, such HNA episome can form the basis of safer genetically modified organisms, in which the traits are encoded outside biology in an HNA episome dependent on the continued supply of artificial substrates for its maintenance.

1 188 594 €

Start date: 2014-02-01, End date: 2019-01-31

In spite of their small areal extent, inland waters play a vital role in the carbon cycle of the continents, as they emit significant amounts of the greenhouse gases (GHG) carbon dioxide (CO2) and methane (CH4) to the atmosphere, and simultaneously bury more organic carbon (OC) in their sediments than the entire ocean. Particularly in tropical hydropower reservoirs, GHG emissions can be large, mainly owing to high CH4 emission. Moreover, the number of tropical hydropower reservoirs will continue to increase dramatically, due to an urgent need for economic growth and a vast unused hydropower potential in many tropical countries. However, the current understanding of the magnitude of GHG emission, and of the processes regulating it, is insufficient. Here I propose a research program on tropical reservoirs in Brazil that takes advantage of recent developments in both concepts and methodologies to provide unique evaluations of GHG emission and OC burial in tropical reservoirs. In particular, I will test the following hypotheses: 1) Current estimates of reservoir CH4 emission are at least one order of magnitude too low, since they have completely missed the recently discovered existence of gas bubble emission hot spots; 2) The burial of land-derived OC in reservoir sediments offsets a significant share of the GHG emissions; and 3) The sustained, long-term CH4 emission from reservoirs is to a large degree fuelled by primary production of new OC within the reservoir, and may therefore be reduced by management of nutrient supply. The new understanding and the cross-disciplinary methodological approach will constitute a major advance to aquatic science in general, and have strong impacts on the understanding of other aquatic systems at other latitudes as well. In addition, the results will be merged into an existing reservoir GHG risk assessment tool to improve planning, design, management and judgment of hydropower reservoirs.

1 798 227 €

Start date: 2013-09-01, End date: 2019-08-31

This project examines how changing notions of animated film emerged during the period of its consolidation, from the introduction of animated films in cinema programmes in the mid-1910s to the surge in interest in animation and the global prominence of Walt Disney studios in the 1930s. The project investigates how a changing cultural and aesthetic identity of animated film was negotiated within films and articulated in the discourse surrounding cinema. As a new medium, animated film was marked by shifting understandings of its identity, with animated films themselves often experimenting with and reflecting on the form. Sometimes situating themselves within contexts of modernity and modernism, animated films negotiated the place of animation as a medium within a wider cultural and social field. Animation was also closely entwined with other media and arts; in addition to live action film, music, comic strips, illustrated books and theatre all played a prominent role in the constitution and development of animated film. Further shaping its identity, the reception and discourse of animation – including marketing, theorizations and discussions in the popular press – contributed to an emerging sense of what animation was, what it could (or should) do, and what its place in a wider context of visual culture entailed. In order to trace these various facets of animated film, the project will focus on three of the most significant national contexts of exhibition and production during the period: the United States, England and France. This will allow for a comparative examination of ideas of animation, linked to national and transnational spheres of production, exhibition and reception. In doing so, the project will develop new approaches to the historiography of animation that enlarge our perspective on this crucial subject in the history of twentieth century visual culture, during an under-researched period in its development.

560 734 €

Start date: 2014-01-01, End date: 2018-12-31

Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer. One hypothesis is that the same factors important for wound healing, if left unchecked, also promote tumorigenesis. Tight control by a sensor of tissue damage should induce these factors to promote tissue repair, while limiting their activity to prevent development of cancer. IL-22, a prototypical tissue repair factor, plays an important role in a wide variety of intestinal disease including infection, wound healing, colitis, and cancer. Indeed, IL-22 has protective and detrimental effects dependent on the milieu and disease suggesting that proper regulation is required. IL-22 expression is directly regulated, additionally a soluble IL-22 receptor (IL-22 binding protein; IL-22bp), can bind and neutralize IL-22. We reported recently that sensing of intestinal tissue damage and components of the microbiota via the NLRP3 or NLRP6 inflammasomes led to a down regulation of IL-22bp, thereby increasing bioavailability of IL-22. IL-22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumor development if not controlled by IL-22bp during the recovery phase. Accordingly a spatial and temporal regulation of IL-22 is crucial. Hence, global administration or blockade of IL-22 is unlikely to be therapeutically beneficial. We are using several newly generated conditional knock-out (cCasp1-/-, cIL-18R-/-, cIL-18-/-, cIL-22R1-/-), knock-in (IL-22 BFP), and gnotobiotic mice, aiming to analyze the cellular and microbial network regulating the IL-22 – IL-22bp axis at a resolution previously unfeasible. Our results will provide novel insights into the network between microflora, epithelium, and immune system regulating tissue regeneration and tumor development, and can lead to therapies for potentially a wide variety of intestinal diseases, such as infection, colon cancer, IBD, or wound healing.

1 498 392 €

Start date: 2014-01-01, End date: 2018-12-31

"This ERC Starter Grant project will fund an interdisciplinary, transnational and groundbreaking study of the Jagiellonian dynasty (c.1386-1596) and its role, and legacy, in the development of identity in what we now call Central Europe. One of the most spectacularly successful of early modern dynasties, comparable only to the Habsburgs, in 1500 the Jagiellonians ruled a third of continental Europe, an area comprising no fewer than 14 present-day states. Uniquely among European dynasties in this period, the Jagiellonians created a dynastic regional hegemony, a geographical ‘bloc’ of neighbouring monarchies. Our knowledge of the Jagiellonians is, however, limited and highly fragmented along both national and disciplinary lines. The project will provide the first treatment of this leading Renaissance-era dynasty as a supra-national entity; it will offer a major new investigation of Renaissance dynasty itself as a political and cultural institution; explore the part played by the Jagiellonians in the evolution of pre-modern local or 'national' and regional identities, and investigate the ways in which divergent memories of their rule have, from 1596 onwards, shaped modern national identities in Central Europe. The project will transcend scholarly divisions – between disciplines (e.g. art history, anthropology, political history), between period specialisations (late medieval, early modern, modern) and between individual national historiographies (Polish, German, Czech etc.), to offer a metahistory of the meanings attributed to this landmark European dynasty, from the founder Jogaila (d.1434) to Radek Sikorski, Poland’s current foreign minister. The research will be undertaken by a multi-lingual team of 5 post-doctoral researchers, led by the PI, drawing on a range of written and visual sources produced by and about the Jagiellonians over six centuries."

1 407 037 €

Start date: 2013-10-01, End date: 2018-09-30

Mathematical competence is essential for an individual’s functioning in society and for societal prosperity and progress in general. Crucially, the specific cognitive and biological factors that determine high, average, or low mathematical achievement are still poorly understood. The current project aims to address this gap by examining the link between mathematical achievement (cognitive factors) and brain indices (biological factors) across the developmental trajectory and for different competency levels. Specifically, the projects objectives are: 1) identify the critical cognitive and biological components, as well as the dynamic developmental sequence, necessary for the normal development of mathematical abilities; 2) unravel the cognitive and biological factors that contribute to and/or restrict neuroplasticity in mathematical learning. This knowledge may be used in the future to improve prevention, identification, and classification of children with impaired numeracy such as developmental dyscalculia; and 3) develop and test well-defined, evidence-based methods for improving mathematical learning. In addition, one of the objectives of the proposed project is to provide experimental knowledge that will have high ecological validity, by examining mathematical learning and achievement while subjects are studying in a classroom setting. I will use an innovative multimethod approach that integrates cognitive and developmental psychology together with neuromodulation, neurophysiology, and neurochemistry, which will provide a comprehensive understanding of the cognitive and brain bases of mathematical learning and cognition. While such knowledge will offer substantive advances for the fields of psychology, education, and neuroscience, it also has broad societal implications, as the high ecological validity provides insights in translational approaches for improving the lives of children and adults with low mathematical abilities.

1 999 859 €

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

"A modern economy is an intricately linked web of specialized production units, each relying on the flow of inputs from their suppliers to produce their own output which, in turn, is routed towards other downstream units. Recent work in economics stresses that the structure of this production network is key in determining whether and how microeconomic shocks can propagate throughout the economy and shape aggregate outcomes. This project has two main goals. First, it aims to provide novel evidence that we can trace back the origins of business cycles and asset price fluctuations to individual technologies interconnected by input-supply relations. The particular questions it tries to answer are: (1) Can we have more direct, causal, evidence that these micro shocks do matter in practice for the evolution of aggregates? What are examples of these micro shocks in reality, how can we identify them and how do they propagate through input chains? (2) What are the asset pricing implications of this perspective on the micro origins of aggregate fluctuations? What is the relation between changes in the technology portfolio of an economy and the evolution of asset prices? The second aim of this project is to improve our understanding of the structure and evolution of these production networks by asking the following questions: (3) At the firm level, do more productive suppliers match with more productive customers and, if so, why? What is the typical duration of a supplier-customer match and does this vary across matches? What is the firm-level impact of matching with better suppliers or more productive customers? (4) How do inputs diffuse on a network of interconnected technologies? Do linkages across sectors facilitate input adoption and the diffusion of General Purpose Technologies? Can linkages across sectors help us understand not only which sectors will adopt a given input but also the order in which these sectors adopt it?"

940 200 €

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

The proposed research project breaks important new ground by analyzing and documenting how the Chinese Communist Party (CCP) dealt with the legacy of mass atrocities committed under Maoist rule. Most accounts of the period mention the trial against the “Gang of Four” and the accompanying resolution on party history from 1981, which held former party chairman Mao Zedong accountable for grave political errors but not for criminal deeds. However, as yet there has been no in-depth analysis of the roughly five million cases and the over ten million petitions handled by courts and party committees between 1978 and 1987 in order to right previous injustices. Despite its enormous scale and relevance to societal stability, this so-called “revision of unjust, wrong, and false verdicts” has been virtually left unattended to by scholarly research. The project aims at diminishing this gap by studying the CCP’s strategies and the societal consequences of this major policy change. It proposes to analyze the partial break from the Maoist legacy as an important, yet by and large overlooked example of transitional justice, albeit confined by the party dictatorship’s overarching aim to stay in power. By way of relying on a wide array of recently available official and non-official sources, the project analyzes and documents how the CCP selectively dealt with the towering injustices of the past. The project will significantly contribute to current research on China’s transformation process and the Maoist legacy in at least four different areas: First, it will detail the CCP’s standards, institutions, and processes of administrating historical justice; second, it will show the great regional variances in implementing these policies between center and periphery; third, it will offer new explanations for the persistence of CCP rule despite the horrors of Maoism; and fourth, it will document both the revisal of verdicts and past atrocities in an electronic database to ease future research.

1 443 756 €

Start date: 2014-03-01, End date: 2019-02-28

In recent breakthrough publications, the effect of fluctuations on the affinity of membrane-confined molecules has been evaluated, and a quantitative model for the time evolution of small adhesion domains has been developed under my leadership. Now I propose to bring my research to a new level by tackling the problem of active and passive organisation of proteins into macromolecular structures on fluctuating fluid membranes, using a physicist’s approach across established disciplinary boundaries. The formation and transport of supramolecular complexes in membranes is ubiquitous to nearly all functions of biological cells. Today, there is a variety of experiments suggesting that macromolecular complexes act as scaffolds for free proteins, overall yielding obstructed diffusion, counterbalanced by active transport by molecular motors. However, an integrative view connecting complexation and transport is largely missing. Furthermore, the effects of membrane mediated interactions and (non)-thermal fluctuations were so far overlooked. Gaining a quantitative insight into these processes is key to understanding the fundamental functioning of cells. Together with my carefully selected team, I will address these intrinsically biological problems, by means of theoretical physics. Phenomena such as active and anomalous transport, as well as complexation are also currently subject to intense research in the statistical and soft matter physics communities. In this context, the aim of this proposal is to bridge the divide between the two worlds and significantly contribute to both physics and the life sciences by developing general principles that can be applied to processes in cells. Resolving these issues is of fundamental importance since it would identify how interactions on the cell surface arise, and may translate directly into pharmaceutical applications.

1 500 000 €

Start date: 2013-10-01, End date: 2019-09-30

"A fundamental research question of several disciplines concerns the description, explanation and prediction of human behavior in social contexts. While significant research had been devoted to higher order social capabilities, much less is known about basic principles that are underlying these functions. This is especially true for social attention which is at the heart of every higher order social function but has neither been systematically examined in naturalistic environments before nor has it been linked to the extensive body of psychological and neuroscientific research on basic principles of attention. As a consequence, it is unknown whether the neural computation and the behavioral expression of social attention is similar or divergent to other forms of non-social attention. The current project will fill this gap by comprehensively characterizing the distinctive features of social attention on the behavioral and neural level using a multimodal approach involving eye tracking measures, neuropeptidergic manipulations, fMRI and EEG. I propose that social elements in complex environments are automatically selected and preferentially processed which is mediated by a specialized subcortico-cortical system that allows for tagging social cues in the visual field. These hypotheses will be tested in healthy volunteers and in clinical disorders with well-described impairments in social functioning. Finally, immersive virtual reality environments will be used that allow for examining active behavior and attentional allocation in complex social situations which approximate naturalistic field settings. By highlighting ecological validity, this project will provide unique insights into the mechanisms of social attention in healthy individuals and it will identify maladaptive attentional processes in individuals with impaired social functioning. Building on these data, the proposed research will provide a new framework for understanding human behavior in social situations."

1 379 710 €

Start date: 2014-02-01, End date: 2019-01-31

Currently available enzyme technology is insufficient to economically degrade plant biomass, and presumably will remain so whilst fundamental questions are inadequately answered, the most evident being: “how do microbes and their enzymes interact with plant cell walls?” Compounding these difficulties is the “cultivability bottleneck”. The microbes that harbor the answers to these questions are largely irrecoverable in isolate form, which restricts access to their genetic and metabolic machinery. The present project will address these issues by applying a progressive interdisciplinary approach to study and compare natural and engineered digestive ecosystems that are linked together via overlapping phenotypic and functional traits (i.e. biomass degradation). The project aims to generate insight into diverse uncultured microbial lineages and uncover core enzyme systems for biomass degradation that are present in multiple environments. To achieve its objectives the project will employ a combination of predictive genome-reconstruction technologies, as well as metagenome-directed isolation strategies to target dominant and novel saccharolytic species. Furthermore we will develop and take advantage of advanced software for enzyme annotation and phylogenetic binning as it is being developed. Relevant genes identified from reconstructed genomes and/or transcriptome data for isolates will be cloned, over-expressed and their gene products tested using state-of-the-art carbohydrate microarray technologies, prior to being characterized in detail. The project will complement existing activities at the PI’s university on (1) polysaccharide converting enzymes in a biorefining context, (2) the impact of intestinal fiber deconstruction on satiety and (3) enhanced production of biogas. We expect to unravel novel aspects of the microbial ecology within these systems/processes. Furthermore, it is envisaged that novel isolates and enzymes will enter into live bioenergy projects.

1 467 176 €

Start date: 2014-02-01, End date: 2019-01-31

"While conventionally effects of a chemical structure on a biological system have been determined for individual compounds, one at a time, it is now becoming apparent that biological effects of compound combination are not additive, but often conditional (antagonistic or synergistic) in nature. This phenomenon is of relevance both in the medicinal context (where drugs can be combined to have a synergistic effect), as well as the area of toxicology (where the simultaneous application of compounds shows a toxicity that is non-additive). However, it is not yet clear how to model, and anticipate, which compound combinations show this type of effect. Hence, in this work I will derive models of synergistic compound combinations, which will be prospectively validated in experiments. Furthermore, I will describe how to capture the effect of a chemical structure on a biological system on multiple levels, namely by considering structural features of the compound, its bioactivity profile, and pathway annotations and their relationship to the phenotypic effect observed. By integrating the data generated in a biologically meaningful way, this allows us to generate predictive models for the bioactivity of compound combinations. The relevance of this work ranges from the question which drugs can be combined in a synergistic manner and which combinations should rather be avoided to the safety assessment of chemicals. Hence, with this work I will be able to improve upon the current state-of-the-art in bioactivity data integration and modelling approaches, as well as deliver concrete models for the bioactivity assessment of compound combinations."

1 499 558 €

Start date: 2014-02-01, End date: 2019-01-31

I propose to develop and apply a novel approach to optical microscopy to enable the direct visualization and study of dynamics on the nanoscale in biological and condensed matter physics. Given the speed with which nanoscopic objects move at ambient condition, this requires simultaneously very fast (ms) and precise (nm) imaging. The challenge is to avoid excessive perturbation of the system and enable imaging in biologically compatible environments without compromising imaging performance by pushing interferometric scattering to its theoretical limits. Using these advanced capabilities, I will study the dynamics and thereby the structure-function relationships in three fundamental systems that are currently not captured by even the most advanced biophysical approaches. These include: (1) the flexibility of DNA on short length scales, (2) diffusion in artificial and cellular membranes and (3) the three-dimensional power stroke of molecular motors such as myosin and kinesin. Fundamentally, this work aims to develop and establish a high-speed, non-invasive camera on the nanoscale that will enable us to study and eventually understand nanoscopic motion, dynamics and potentials on the relevant, rather than currently achievable, size and time scales.

1 498 352 €

Start date: 2014-01-01, End date: 2018-12-31

Semiconductor nanowires composed of III-V materials have enormous potential to add new functionality to electronics and optical applications. However, integration of these promising structures into applications is severely limited by the current near-universal reliance on gold nanoparticles as seeds for nanowire fabrication. Although highly controlled fabrication is achieved, this metal is entirely incompatible with the Si-based electronics industry. It also presents limitations for the extension of nanowire research towards novel materials not existing in bulk. To date, exploration of alternatives has been limited to selective-area and self-seeded processes, both of which have major limitations in terms of size and morphology control, potential to combine materials, and crystal structure tuning. There is also very little understanding of precisely why gold has proven so successful for nanowire growth, and which alternatives may yield comparable or better results. The aim of this project will be to explore alternative nanoparticle seed materials to go beyond the use of gold in III-V nanowire fabrication. This will be achieved using a unique and recently developed capability for aerosol-phase fabrication of highly controlled nanoparticles directly integrated with conventional nanowire fabrication equipment. The primary goal will be to deepen the understanding of the nanowire fabrication process, and the specific advantages (and limitations) of gold as a seed material, in order to develop and optimize alternatives. The use of a wide variety of seed particle materials in nanowire fabrication will greatly broaden the variety of novel structures that can be fabricated. The results will also transform the nanowire fabrication research field, in order to develop important connections between nanowire research and the semiconductor industry, and to greatly improve the viability of nanowire integration into future devices.

1 496 246 €

Start date: 2013-09-01, End date: 2018-08-31

"First observed by the physicist and musician Ernst Chladni in the 18th century, the nodal lines (also referred to as the Chladni Plates or Chladni Modes) appear in many problems in engineering, physics and natural sciences. Nodal lines describe sets that remain stationary during membrane vibrations, hence their importance in such diverse areas as musical instruments industry, mechanical structures, earthquake study and other fields. My proposed research aims at the nodal patterns and question arising from them with mathematical rigour. So far, the nodal structures have been mainly addressed in the physics literature, whose statement are lacking the mathematical precision; most of their results are based on numerical experiments and heuristic computations rather than analytic methods typical for mathematics. In his seminal paper, Michael Berry (1977) suggested that the behaviour of the deterministic nodal patterns corresponding to the high frequency vibration on generic membranes is universal, and may be ""miraculously"" explained by a random ensemble of monochromatic waves. Extensive numerical experiments confirm Berry's predictions, however no rigorous statement is known (or even formulated) to date. In this research I propose to investigate the nodal structures in depth arising for various random ensembles. These kind of questions, very natural, especially in light of the proposed random models, were studied empirically in physics literature, and in the last few years analytically in the mathematics literature, mainly by Nazarov and Sodin, and the PI in various collaborations. The questions arising are of fundamental importance in mathematical physics, probability theory, mathematical analysis, and, as was recently discovered, number theory. The proposed research aims at rigorously answering some of the related open questions."

966 361 €

Start date: 2014-02-01, End date: 2019-01-31

A revolution is underway, as molecular magnets are establishing a fundamental link between spintronics, molecular electronics and quantum computation. On the other hand, we know almost nothing on how a magnetic molecule is affected by electrons flowing through it or by the excitation of a molecular group. OptoQMol will investigate these uncharted waters by developing innovative, ultra-clean methods that will provide information inaccessible to established procedures. This will allow an unprecedented study of the interplay of electronic and spin degrees of freedom in magnetic molecules and of its possible use for quantum logic. OptoQMol is a strongly multidisciplinary project, and makes use of an innovative mix of chemical and physical methods to overcome present experimental limitations, both in terms of time resolution and cleanliness. Instead of placing a magnetic molecule between bulk electrodes, we will directly grow photoactive groups on the molecule, so that electrons will flow through or close to the spin centers after a light pulse. This affords an ultra-clean system that can be studied in bulk, with a perfectly defined geometry of the magnetic and electronic elements. We will then combine optical and electron paramagnetic resonance techniques with ns time resolution, so as to observe the effect of electron flow on the spins in real time and measure the spin quantum coherence. Eventually we will use these innovative methods to control the interactions among spins and perform quantum logic operations. The success of OptoQMol will answer two fundamental questions: How do molecular spins interact with flowing electrons? How can we use electronic excitations to perform quantum logic operations between multiple electron spins? The results will open a totally new area of experimental and theoretical investigation. Moreover they will redefine the limits and possibilities of molecular spintronics and allow quantum logic operations among multiple electron spins.

1 498 300 €

Start date: 2014-01-01, End date: 2018-12-31

The Earth’s oceans absorb about 11 billion tonnes of carbon dioxide (CO2) each year, about 25% of all anthropogenic CO2. The oceans are huge reservoirs of CO2, and a better understanding on how the oceans absorb CO2 is critical for predicting climate change. The sea-surface microlayer (SML), the aqueous boundary layer between the ocean and atmosphere, plays an important role in the exchange of gases between the ocean and atmosphere. The effects of the SML on air-sea gas exchange have been widely ignored by past and current research efforts due to uncertainties to what extent the SML covers the oceans. However, we recently reported the ubiquitous coverage of the oceans with SML, which pushes the SML into a new and wider context that is relevant to many ocean and climate sciences. I propose experiments at multiple scales, i.e. in laboratory tanks, wind wave tunnel, mesocosm and during a long-term field study. I propose a systematic field study measuring air-sea CO2 fluxes and mapping chemical, biological and physical properties of the SML. With the experiments on smaller scales, such measurements will allow for the first time (i) to define new parameters controlling gas fluxes, (ii) to quantify short-time and seasonal variability, (iii) to define global proxies for the effects of the SML, and (iv) to develop and apply a new parameterization for the correction of global CO2 flux data. For the first time, biogeochemical processes relevant to carbon cycling are investigated on the ocean’s surface at an interfacial level. Furthermore, I aim to reconstruct the natural composition of the SML in a wind-wave tunnel to study its ability to modify the ocean’s surface at well-defined wind regimes. The results from the proposed studies can form the basis for an improvement of current assessments of CO2 fluxes, and oceanic uptake rates. A better understanding in the oceanic uptake of atmospheric CO2 is critical in predicting climate trends and establishing policies.

1 485 797 €

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

The objective of this proposal is to probe in aqueous solution protein complexes which are both heterogeneous and possess highly variable stoichiometries. The study of heterogeneous protein systems by conventional means is very challenging since most current biophysical methods perform best for pure solutions of isolated components - yet proteins exert in the majority of cases their biological functionality through forming complexes. We propose in this application that the key to study such systems is to operate in much smaller volumes than in conventional biophysical experiments. We will use microfluidics to obtain information about the physical properties of protein complexes in real time through quantitative micron-scale measurements of mass transport of molecular species under the action of diffusion and electric or centrifugal fields. Furthermore, by working in small volumes, we will study nucleation phenomena inherent to many protein self-assembly phenomena on the level of single nucleation events by segregating individual nuclei into spatially distinct compartments. Modern microfabrication techniques that allow for the manipulation of liquids on the picolitre scales required for this project are available and will be exploited, but the potential of this technology to define experimentally highly heterogeneous protein complexes in terms of their key fundamental physical properties, such as the hydrodynamic radius, charge and mass, and shed light on the physical basis of protein self-assembly, have remained unexploited. Using this approach, we will explore biological problems of fundamental and practical importance characterised by heterogeneity, including functional chaperone complexes, formation and detection of amyloid oligomers and studies of complex biomolecular mixtures. This programme will deliver fundamentally new approaches to study heterogeneous protein complexes and will shed light on the physical principles that govern protein self-assembly.

1 499 895 €

Start date: 2014-02-01, End date: 2019-01-31

Protein serine/threonine phosphatases (PSTPs) are considered undruggable although they are involved in the most prominent post-translational modifications. This is mainly due to an apparent lack of substrate specificity. One important PSTP is protein phosphatase-1 (PP1), a ubiquitous PSTP that is predicted to catalyze about 1/3rd of Ser and Thr dephosphorylations in eukaryotic cells, counteracting hundreds of kinases. PP1 has broad substrate specificity but is restrained in vivo by numerous PP1-interacting proteins functioning for example as substrate-targeting proteins and forming specific holoenzymes with PP1. PP1 holoenzymes play a role in many different diseases such as cancer (counteracting oncogenic kinases), diabetes (insulin release), Alzheimer’s (dephosphorylation of Tau protein) and HIV (viral translation). Currently, there are no chemical modulators available that target PP1 selectively, except that we recently developed the first compound that selectively activates PP1 in intact cells, leading to rapid dephosphorylation of PP1 substrates. The activator does not act on the most closely related protein phosphatase-2A. This proposal aims to generate and apply tools for the investigation of PP1, in part based on our previously developed activator. The tools include selective, photo- and enzymatically releasable chemical inhibitors and activators and semisynthetic proteins, and they will be applied to study PP1–substrate interactions and help identify the correlating interacting proteins. The proposed research will provide long-sought selective chemical tools to study PP1 by applying new concepts of activator and inhibitor design using peptide and small molecule chemistry to an enzyme class that is difficult to be targeted chemically. This research program will contribute to a much more detailed understanding of PP1 biology, and will open doors to investigate PP1 and its holoenzymes as drug targets.

1 164 516 €

Start date: 2014-01-01, End date: 2018-12-31

"This proposal aims to apply ion-trap quantum logic techniques to precision measurements on individual (anti-)protons for fundamental physics tests. In particular, we aim to measure g-factors of single (anti-)protons as a precise test of CPT symmetry. This requires a method to detect single (anti-)proton spin flips. Current efforts based on classical “magnetic bottle” techniques are hurt by the extreme difficulty and slowness of the spin state detection. Discrete and direct state measurement is a prerequisite for inaccuracies below 10-6 and has not been achieved yet. Towards this end, we will employ a radically different approach and use quantum logic techniques developed by the PI in the NIST ion storage group of D. J. Wineland [Nature 476, 181(2011); Nature 471, 196(2011)]. This will allow us to transfer the (anti-)proton’s spin state to a nearby trapped atomic “logic” ion and subsequently read it out using standard quantum logic detection techniques along the lines of Heinzen and Wineland [PRA 42, 2977; J. Res. NIST 103, 259 (1998)]. The same ideas are also at the root of NIST’s world-record single-ion Al+ frequency standard. Ultimately, this quantum logic technique will lead to a precise test of CPT symmetry, a fundamental symmetry within the standard model of particle physics, by comparing the proton’s and the antiproton’s g-factor with fast detection and single spin-flip resolution. It thus has the potential to reach inaccuracies below 10-9, exceeding the state-of-the-art for the antiproton g-factor by six orders of magnitude. Such a measurement is urgently needed to complement ongoing tests with electrons and positrons. It is closely intertwined with our desire to understand the observed matter-antimatter imbalance in the universe and to obtain a unified description of matter and interactions. Further, the project will considerably broaden the arsenal of quantum state manipulation techniques in Penning traps and possibly impact high precision mass measurement."

1 619 640 €

Start date: 2013-09-01, End date: 2018-08-31

The posterior parietal cortex (PPC) mediates cognitive motor functions including motor planning and action understanding. The latter process is thought to occur via ‘mirror’ neurons, which fire both when an animal performs an action and when it observes a cohort performing the same action. The extraordinary tuning properties of PPC cells require the convergence of sensory and motor inputs from several areas, but the function of these inputs is ill-defined since it is not yet feasible in humans or primates to reversibly inhibit targeted anatomical projections. I propose to overcome this by studying PPC in rodents, and will apply optogenetic tools and multi-tetrode recordings to characterize the function of selected cortical inputs to PPC. Similar to motor planning functions for hand or eye movements in primates, the rodent PPC encodes upcoming locomotor movements, and a growing literature suggests that rodents have a mirror system. I thus propose two related research programmes focusing on action planning and the mirror mechanism. The first project will determine if behavioral coding in PPC changes between a foraging task, in which behavior is spontaneous, and during navigational planning in a working memory-based T-maze. I will then determine if silencing fronto-parietal anatomical connections at different phases of the T-maze tasks disrupts motor planning and decision making functions in PPC. Next, I will record from PPC while rats observe cohorts performing the T-maze task to determine if the rat PPC contains mirror neurons. If I find mirror cells in rats, I will optically silence visual and frontal inputs to PPC to determine if they confer mirror selectivity to PPC. These experiments will reveal the anatomical circuitry underlying action planning and the mirror system in a way which cannot be achieved in primate models, and will open the door for studying mirror cells in rodent models of human mental disorders, including autism and Fragile-X syndrome.

1 500 000 €

Start date: 2014-01-01, End date: 2018-12-31