ERC FUNDED PROJECTS

"The twin concepts of sustainability and conservation that are so pivotal within current debates regarding economic development and biodiversity protection both contain an inherent temporal dimension, since both refer to the need to balance short-term gains with long-term resource maintenance. Proponents of resilience theory and of development based on ‘indigenous knowledge’ have thus argued for the necessity of including archaeological, historical and palaeoenvironmental components within development project design. Indeed, some have argued that archaeology should lead these interdisciplinary projects on the grounds that it provides the necessary time depth and bridges the social and natural sciences. The project proposed here accepts this logic and endorses this renewed contemporary relevance of archaeological research. However, it also needs to be admitted that moving beyond critiques of the misuse of historical data presents significant hurdles. When presenting results outside the discipline, for example, archaeological projects tend to downplay the poor archaeological visibility of certain agricultural practices, and computer models designed to test sustainability struggle to adequately account for local cultural preferences. This field will therefore not progress unless there is a frank appraisal of archaeology’s strengths and weaknesses. This project will provide this assessment by employing a range of established and groundbreaking archaeological and modelling techniques to examine the development of two east Africa agricultural systems: one at the abandoned site of Engaruka in Tanzania, commonly seen as an example of resource mismanagement and ecological collapse; and another at the current agricultural landscape in Konso, Ethiopia, described by the UN FAO as one of a select few African “lessons from the past”. The project thus aims to assess the sustainability of these systems, but will also assess the role archaeology can play in such debates worldwide."

1 196 701 €

Start date: 2014-02-01, End date: 2018-01-31

The active target and time projection chamber (ACTAR TPC) is a novel gas-filled detection system that will permit new studies into the structure and decays of the most exotic nuclei. The use of a gas volume that acts as a sensitive detection medium and as the reaction target itself (an “active target”) offers considerable advantages over traditional nuclear physics detectors and techniques. In high-energy physics, TPC detectors have found profitable applications but their use in nuclear physics has been limited. With the ACTAR TPC design, individual detection pad sizes of 2 mm are the smallest ever attempted in either discipline but is a requirement for high-efficiency and high-resolution nuclear spectroscopy. The corresponding large number of electronic channels (16000 from a surface of only 25×25 cm) requires new developments in high-density electronics and data-acquisition systems that are not yet available in the nuclear physics domain. New experiments in regions of the nuclear chart that cannot be presently contemplated will become feasible with ACTAR TPC.

1 290 000 €

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

"In plants, receptor kinases form the largest family of plasma membrane (PM) receptors and they are involved in virtually all aspects of the plant life, including development, immunity and reproduction. In animals, key molecules that orchestrate the recruitment of signaling proteins to membranes are anionic phospholipids (e.g. phosphatidylinositol phosphate or PIPs). Besides, recent reports in animal and yeast cells suggest the existence of PM nanodomains that are independent of cholesterol and lipid phase and rely on anionic phospholipids as well as electrostatic protein/lipid interactions. Strikingly, we know very little on the role of anionic phospholipids in plant signaling. However, our preliminary data suggest that BKI1, an inhibitory protein of the steroid receptor kinase BRI1, interacts with various PIPs in vitro and is likely targeted to the PM by electrostatic interactions with these anionic lipids. These results open the possibility that BRI1, but also other receptor kinases, might be regulated by anionic phospholipids in plants. Here, we propose to analyze the function of anionic phospholipids in BRI1 signaling, using the root epidermis as a model system. First, we will ask what are the lipids that control membrane surface charge in this tissue and recruit BR-signaling component to the PM. Second, we will probe the presence of PIP-enriched nanodomains at the plant PM using super-resolution microscopy techniques and investigate the roles of these domains in BRI1 signaling. Finally, we will analyze the function of the BKI1-related plant-specific family of anionic phospholipid effectors in plant development. In summary, using a transversal approach ranging from in vitro studies to in vivo validation and whole organism physiology, this work will unravel the interplay between anionic phospholipids and receptor signaling in plants."

1 797 840 €

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

This proposal aims to unravel mysteries at the frontier of number theory and other areas of mathematics and physics. The main focus will be to understand and exploit “modularity” of q-hypergeometric series. “Modular forms are functions on the complex plane that are inordinately symmetric.” (Mazur) The motivation comes from the wide-reaching applications of modularity in combinatorics, percolation, Lie theory, and physics (black holes). The interplay between automorphic forms, q-series, and other areas of mathematics and physics is often two-sided. On the one hand, the other areas provide interesting examples of automorphic objects and predict their behavior. Sometimes these even motivate new classes of automorphic objects which have not been previously studied. On the other hand, knowing that certain generating functions are modular gives one access to deep theoretical tools to prove results in other areas. “Mathematics is a language, and we need that language to understand the physics of our universe.”(Ooguri) Understanding this interplay has attracted attention of researchers from a variety of areas. However, proofs of modularity of q-hypergeometric series currently fall far short of a comprehensive theory to describe the interplay between them and automorphic forms. A recent conjecture of W. Nahm relates the modularity of such series to K-theory. In this proposal I aim to fill this gap and provide a better understanding of this interplay by building a general structural framework enveloping these q-series. For this I will employ new kinds of automorphic objects and embed the functions of interest into bigger families A successful outcome of the proposed research will open further horizons and also answer open questions, even those in other areas which were not addressed in this proposal; for example the new theory could be applied to better understand Donaldson invariants.

1 240 500 €

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

At every moment in time, the brain receives a vast amount of sensory information about the environment. This makes attention, the process by which we select currently relevant stimuli for processing and ignore irrelevant input, a fundamentally important brain function. Studies in primates have yielded a detailed description of how attention to a stimulus modifies the responses of neuronal ensembles in visual cortex, but how this modulation is produced mechanistically in the circuit is not well understood. Neuronal circuits comprise a large variety of neuron types, and to gain mechanistic insights, and to treat specific diseases of the nervous system, it is crucial to characterize the contribution of different identified cell types to information processing. Inhibition supplied by a small yet highly diverse set of interneurons controls all aspects of cortical function, and the central hypothesis of this proposal is that differential modulation of genetically-defined interneuron types is a key mechanism of attention in visual cortex. To identify the interneuron types underlying attentional modulation and to investigate how this, in turn, affects computations in the circuit we will use an innovative multidisciplinary approach combining genetic targeting in mice with cutting-edge in vivo 2-photon microscopy-based recordings and selective optogenetic manipulation of activity. Importantly, a key set of experiments will test whether the observed neuronal mechanisms are causally involved in attention at the level of behavior, the ultimate readout of the computations we are interested in. The expected results will provide a detailed, mechanistic dissection of the neuronal basis of attention. Beyond attention, selection of different functional states of the same hard-wired circuit by modulatory input is a fundamental, but poorly understood, phenomenon in the brain, and we predict that our insights will elucidate similar mechanisms in other brain areas and functional contexts.

1 466 505 €

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

Can benefit-sharing address the equity deficit within the green economy? This project aims to investigate benefit-sharing as an under-theorised and little-implemented regulatory approach to the equity concerns (disregard for the special circumstances of developing countries and of indigenous peoples and local communities) in transitioning to the green economy. Although benefit-sharing is increasingly deployed in a variety of international environmental agreements and also in human rights and corporate accountability instruments, no comprehensive account exists of its conceptual and practical relevance to equitably address global environmental challenges. This project will be the first systematic evaluation of the conceptualisations and operationalisations of benefit-sharing as a tool for equitable change through the allocation among different stakeholders of economic and also socio-cultural and environmental advantages arising from natural resource use. The project will combine a comparative study of international law with empirical legal research, and include an inter-disciplinary study integrating political sociology in a legal enquiry on the role of “biocultural community protocols” that articulate and implement benefit-sharing at the intersection of international, transnational, national and indigenous communities’ customary law (global environmental law). The project aims to: 1. develop a comprehensive understanding of benefit-sharing in international law; 2. clarify whether and how benefit-sharing supports equity and the protection of human rights across key sectors of international environmental regulation (biodiversity, climate change, oceans, food and agriculture) that are seen as inter-related in the transition to the green economy; 3. understand the development of benefit-sharing in the context of global environmental law; and 4. clarify the role of transnational legal advisors (NGOs and bilateral cooperation partners) in the green economy.

1 481 708 €

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

High precision radiotherapy (RT) allows extremely flexible tumour treatments achieving highly conformal radiation doses while sparing surrounding organs at risk. Nevertheless, failure rates of up to 50% are reported for head and neck cancer (HNC) due to radiation resistance induced by pathophysiologic factors such as hypoxia and other clinical factors as HPV-status, stage and tumour volume. This project aims at developing a multi-parametric model for individualized RT (iRT) dose prescriptions in HNC based on biological markers and functional PET/MR imaging. This project goes far beyond current research standards and clinical practice as it aims for establishing hypoxia PET and f-MRI as well as biological markers in HNC as a role model for a novel concept from anatomy-based to biologically iRT. During this project, a multi-parametric model will be developed on a preclinical basis that combines biological markers such as different oncogenes and hypoxia gene classifier with functional PET/MR imaging, such as FMISO PET in combination with different f-MRI techniques, like DW-, DCE- and BOLD-MRI in addition to MR spectroscopy. The ultimate goal of this project is a multi-parametric model to predict therapy outcome and guide iRT. In a second part, a clinical study will be carried out to validate the preclinical model in patients. Based on the most informative radiobiological and imaging parameters as identified during the pre-clinical phase, biological markers and advanced PET/MR imaging will be evaluated in terms of their potential for iRT dose prescription. Successful development of a model for biologically iRT prescription on the basis of multi-parametric molecular profiling would provide a unique basis for personalized cancer treatment. A validated multi-parametric model for RT outcome would represent a paradigm shift from anatomy-based to biologically iRT concepts with the ultimate goal of improving cancer cure rates.

1 370 799 €

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

"Conscious experiences normally result from the flow of external input into our sensory systems. However, our minds are also able to create conscious percepts in the absence of any sensory stimulation; these internally generated percepts are referred to as mental images, and they have many similarities with real visual percepts; consequently, mental imagery is often referred to as “seeing in the mind’s eye”. Mental imagery is also believed to be closely related to working memory, a mechanism which can maintain “offline” representations of visual stimuli no longer in the observer’s view, as both involve internal representations of previously seen visual attributes. Indeed, visual imagery is often thought of as a conscious window into the content of memory representations. Imagery, working memory, and conscious perception are thus thought to rely on very similar mechanisms. However, in everyday life we are generally able to keep apart the constructs of our imagination from real physical events; this begs the question of how the brain distinguishes internal mental images from externally induced visual percepts. To answer this question, the proposed work aims to isolate the cortical mechanisms associated uniquely with WM and imagery independently of each other and independently of the influence of external conscious percepts. Furthermore, by the use of neuroimaging and brain stimulation, we aim to determine the cortical mechanisms which keep apart internally generated and externally induced percepts, in both health and disease. This is a question of great clinical interest, as the ability to distinguish the perceived from the imagined is impoverished in psychotic disorders. In addition to revealing the mechanisms underlying this confusion, the present project aims to alleviate it in psychotic patients by the use of brain stimulation. The project will thus significantly improve our understanding of these cognitive processes and will also have clinical implications."

1 280 680 €

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

Because fossil resources are a limited feedstock and their use results in the accumulation of atmospheric CO2, the organic chemistry industry will face important challenges in the next decades to find alternative feedstocks. New methods for the recycling of CO2 are therefore needed, to use CO2 as a carbon source for the production of organic chemicals. Yet, CO2 is difficult to transform and only 3 chemical processes recycling CO2 have been industrialized to date. To tackle this problem, my idea is to design novel catalytic transformations where CO2 is reacted, in a single step, with a functionalizing reagent and a reductant that can be independently modified, to produce a large spectrum of molecules. The proof of concept for this new “diagonal approach” has been established in 2012, in my team, with a new reaction able to co-recycle CO2 and a chemical waste of the silicones industry (PMHS) to convert amines to formamides. The goal of this proposal is to develop new diagonal reactions to enable the use of CO2 for the synthesis of amines, esters and amides, which are currently obtained from fossil materials. The novel catalytic reactions will be applied to the production of important molecules: methylamines, acrylamide and methyladipic acid. The methodology will rely on the development of molecular catalysts able to promote the reductive functionalization of CO2 in the presence of H2 or hydrosilanes. Rational design of efficient catalysts will be performed based on theoretical and experimental mechanistic investigations and utilized for the production of industrially important chemicals. Overall, this proposal will contribute to achieving sustainability in the chemical industry. The results will also increase our understanding of CO2 activation and provide invaluable insights into the basic modes of action of organocatalysts in reduction chemistry. They will serve the scientific community involved in the field of organocatalysis, green chemistry and energy storage.

1 494 734 €

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

"With the ground-breaking discovery of a new, Higgs-like boson on July 4th, 2012, by the CMS and ATLAS collaborations at CERN, a new era of particle physics has begun. The discovery is the first step in answering an unsolved problem in particle physics, the question how fundamental bosons and fermions acquire their mass. One of the major goals in collider physics in the next few years will be the deeper insight into the nature of the new particle, its connection to the known fundamental particles and possible extensions beyond the standard model (SM) of particle physics. My project aims at a particular interesting field to study, the relation of the new particle with the heaviest known elementary particle, the top quark. I aim to develop new, innovative techniques and beyond state-of-the-art methods to extract the Yukawa coupling between the top quark and the Higgs boson, which is expected to be of the order of one - much higher than that of any other quark. I will analyse the only process where the top-Higgs Yukawa coupling can be measured, in associated production of top quark pairs and a Higgs boson. The Higgs boson mainly decays into a pair of b-quarks. This is one of the most challenging channels at the LHC, as huge background processes from gluon splitting contribute. In particular, I will develop and study color flow variables, which provide a unique, powerful technique to distinguish color singlet Higgs bosons from the main background, color octet gluons. The ultimate goal of the project is the first measurement of the top-Higgs Yukawa coupling and its confrontation with SM and beyond SM Higgs boson models, resulting in an unprecedented insight into the fundamental laws of nature. The LHC will soon reach a new energy frontier of 13 TeV starting in 2014. This new environment will provide never seen opportunities to study hints of new physics and precisely measure properties of the newly found particle. This sets the stage for the project."

1 163 755 €

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

Participation – defined in this project as the social practice of engaging in personal and social change – links private and public life, biography and history, and forms a mechanism for social action. Twenty years after the ratification of the United Nations Convention for the Rights of the Child (1989) the international community is no closer to identifying what constitutes a ‘good enough’ model for understanding and supporting the development of children’s participation in public life. The project asks game changing questions about the emergence of children’s orientation towards social action through qualitative, longitudinal and cross-national research. Building on biographical interviews with children, relational and geographical mapping techniques, selective participant-observation with children, and children social research workshops in three cities (London, Athens, Mumbai), the project examines the meaning of personal and social change in middle childhood (6-11 year olds), the circuits of social action that children tap into in an attempt to make changes real, the extent to which privilege, marginalization and economic crisis shape children’s practices of participation, and the ways in which encounters with difference (gender, ethnicity, race, religion) challenge children’s orientation towards social action. By sampling children from a diverse cross-section of each city the project will collect and follow a total of 100 children over a five-year period. The project will provide a rich data sources for making within and between country comparisons and in doing so enable the development a theoretical paradigm for understanding children’s participation that is derived from the bottom-up, that is generated in diverse settings, including non-Western, and that takes advantage of the current rupture to established socio-economic realities to ask questions about the future of social action.

1 469 296 €

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

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

"Rarely in astrophysics are there opportunities to spectrally classify a completely new group of astrophysical objects. This is the challenge facing the exoplanets christened “hot Jupiters”. The detection and subsequent spectroscopic information now achievable for a large number of these exoplanets are now allowing for detailed comparative exoplanetology. This project uses a twofold approach to advance both the theory and observation of these exoplanets beyond their current limitations. Hot Jupiter atmospheric spectra are built from two large observational survey programmes headed by Dr. Sing to obtain a vast amount of high quality data on transmission spectra. One large programme uses the HST which alone will quadruple the number of broadband exoplanet transmission spectra. The Hubble survey will be augmented by a large programme on the GTC telescope, where we will put efforts into pioneering multi-object spectroscopy, capable of delivering space-like quality spectra. Both large programmes will be further complemented by followup observations, as well as existing near-IR spectroscopy. This project will combine this plethora of data in a coherent fashion, enabling studies of nearly the entire planetary atmosphere. Our observational efforts will be combined with a broad and inclusive theoretical modeling programme, where we will incorporate clouds and hazes, modelling the complete atmosphere in a self-consistent manner with a 3D global circulation model. Our library of transmission spectra across the hot-Jupiter class will be used to address long outstanding and complex issues. We will focus our efforts on two key areas, addressing why some hot Jupiters have hazes & clouds while others do not, and the outstanding issue on the presence or absence of stratospheres. For the first time a comprehensive set of high quality exoplanet spectra will be available with which to inter-compare using the required set of theoretical tools."

1 495 824 €

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

Nearly all desirable biological activities, whether for the purposes of nutrition, pharmacology, biofuel production, or waste disposal, can be carried out by proteins. Nature has furnished a vast array of bioactive and biocatalytic tools, and with the advent of rational protein design nearly any imaginable bioactivity is at our fingertips. There is, therefore, a pressing need for cost-effective, safe, and easily scalable strategies for generating Recombinant Proteins (rProteins). The main bottleneck for mass-producing a whole host of valuable biologically active rProteins is the difficulty of recovering functional proteins from expression hosts. This difficulty stems largely from the lack of sufficient know-how for manipulating protein biogenesis in the cell. The key component of protein biology, whether in the context of rProtein production or cell viability, is enabling a protein to achieve its proper folding state. Most proteins do not fold on their own – they require the assistance of a vast network of folding managers, or chaperones. The cellular chaperone machinery not only assists protein folding, it also carries out quality control, ensuring that proteins that are damaged or unable to fold for other reasons are properly disposed of through degradation or protective aggregation. The aim of this proposal is to understand the protein biosynthetic pathway in sufficient detail, so as to be able to manipulate its overall function. My eventual goal is to exert control over folding and aggregation in order to produce higher yields of functional rProteins in eukaryotes. The biotechnological strategy will consist of: 1. Manipulating aggregation to remove damaged endogenous proteins from the folding proteome, thus diverting more resources to the folding of rProteins; 2. Manipulating the allocation of cellular chaperone resources between folding, degradation, and aggregation; 3. Utilizing aggregates to produce substantially higher amounts of functional rProteins.

1 639 400 €

Start date: 2013-11-01, End date: 2019-10-31

Cilia are microtubule-based protrusions of the plasma membrane found on many eukaryotic cells, including most cell types of the human body. Whereas the functions of motile cilia were immediately obvious, the role of the immotile or so-called primary cilia remained largely unrecognized for many decades. Once referred to as aberrant solitary cilia with no obvious function, these ancient structures now hold the promise of revealing no less than the secrets of multicellularity and development. Even though the importance of primary cilia is now evident, molecular mechanisms underlying their assembly and function are far from being understood. The construction and maintenance of cilia relies on an ancient, universally conserved machinery termed IntraFlagellar Transport (IFT). IFT requires a multi-subunit, non-membranous protein complex assembled from more than 20 distinct subunits. At the heart of IFT are the microtubule-associated motors, -kinesin and dynein-, that continuously ferry cargo in a bi-directional fashion needed for ciliary assembly and function. To pave the way towards a molecular understanding of this fascinating organelle, we propose to employ a bottom-up approach in which we stepwise reconstitute the IFT complex from recombinantly expressed subunits of the so far best understood primary cilium from C.elegans. The structural integrity and stability of the IFT complex will be characterized using multifaceted approaches such as chemical crosslinking or thermophoresis. To mechanistically dissect the kinesin-dependent transport in vitro, we will make use of enzymatic bulk and single-molecule assays. Collectively, these results will provide a quantitative understanding of the assembly and kinesin-dependent motility of the IFT machinery. Given that cells mobilize ~600 components to build their cilia, this experimental platform will significantly streamline future efforts to identify novel cargoes and the effects of putative regulators of the IFT machinery.

1 497 740 €

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

"Although protein dynamics plays an essential role in function, it is rarely considered explicitly in current structure-based approaches to drug design. Here I propose the computer-aided design of ligands by modulation of protein dynamics, or equivalently, protein structural ensembles. The detailed understanding of ligand-induced perturbations of protein dynamics that will result from this study is crucial not just to accurately predicting binding affinities and tackling ""undruggable"" targets, but also to understanding protein allostery. Three major aims will be pursued during this project. First, I will combine concepts from chemoinformatics and non-equilibrium thermodynamics to detect cryptic ""druggable"" small molecule binding sites in computed structural ensembles. New computational methods will be developed to predict how binding at these putative sites is likely to influence protein function. This will enable rational approaches to allosteric control of protein function. Second, new classes of non-equilibrium sampling algorithms will be developed to improve by 2-3 orders of magnitude the speed of computation of protein/ligand structural ensembles by molecular simulations. This will enable routine consideration of protein flexibility in ligand optimisation problems. Third, I will address with the above methods a frontier problem in molecular recognition: the rational design of protein isoform-specific ligands. To achieve this goal, I will integrate computation with experiments and focus efforts on the therapeutically relevant cyclophilin protein family. Experimental work will involve the use of purchased or custom-synthesized competitive and allosteric ligands in enzymatic assays, calorimetry and crystal structure analyses. Overall, this project proposes fundamental advances in our ability to quantify and engineer protein-ligand interactions, therefore expanding opportunities for the development of future small molecule therapeutics."

1 382 202 €

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

"My project consists of two lines of work. 1.Empirical Macro-Finance: Asset prices are informative about the macro-economic risks that matter to investors and about the welfare costs of economic fluctuations. However, recent empirical evidence suggests that leading asset pricing models cannot explain how risks are priced across maturities in equity markets, which is a key input to measuring the costs of business cycles. An analysis of what leading models miss will vastly improve our understanding of how the real economy and asset prices are related. Also, by expanding our empirical evidence about the term structure of equity to the firm-level, I plan to study how investment decisions relate to asset prices. My goal is to measure the firms' incentives to invest and how this impacts economic growth more broadly. 2.Financial Economics of Insurance Markets: Households in Europe and the US can choose from a wide variety of insurance products that insure health and mortality risks. Choosing between these products is no easy task and the costs from sub-optimal insurance choices are estimated to be large. My plan is to develop a comprehensive life-cycle theory of insurance choice that accounts for family structure, risk factors such as labor income and housing, and different institutional settings across countries. I also plan to study the supply side of insurance markets. The traditional view is that insurance prices are driven by life-cycle demand or informational frictions. However, as is clear from evidence during the financial crisis, insurance companies are in fact financial institutions. If financial constraints bind, it may affect insurance prices and ultimately consumers' welfare. My goal is to understand how financial frictions affect insurance companies. A policy implication of my research may be that the private supply of insurance is an imperfect substitute for public supply as insurance companies face different incentives and constraints than the government."

1 077 765 €

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

Protection of genome integrity is crucial for maintaining cell identity and viability. However, the organisation of DNA with histone proteins into chromatin in eukaryotic cell nuclei poses structural constraints to the detection and repair of DNA lesions. Dynamic and tightly controlled changes in chromatin organisation are thus critical for an efficient response to DNA damage, while at the same time preserving chromatin integrity. Yet, the underlying regulatory mechanisms are still poorly characterised, particularly in higher eukaryotes. Here, we describe a range of complementary approaches using cutting-edge imaging to address this issue in mammalian cells. Our aim is to investigate DNA damage-induced alterations at distinct levels of chromatin organisation, from histone proteins up to higher-order chromatin structure, and to explore the underlying mechanisms. (1) We first intend to provide a detailed analysis of histone variant dynamics at DNA damage sites by combining local induction of DNA lesions with pulse-chase imaging of histone proteins. (2) To examine how these dynamics are reflected at the level of higher-order chromatin folding, we will quantitatively visualise changes in chromatin compaction in cells exposed to genotoxic stress. For this, we will implement a recent FLIM-FRET-based approach and also exploit super-resolution fluorescence microscopy. (3) We will examine the spatio-temporal regulation of damaged chromatin reorganisation, analyse how it connects with DNA damage signalling and repair pathways, and characterise the histone chaperones and chromatin remodelling factors involved. (4) To broaden the range of candidate regulatory factors, we will screen for novel players in the DNA damage response among chromatin-associated proteins using laser micro-irradiation induced damage. Altogether, these integrated approaches should provide new insights into the molecular mechanisms that coordinate the maintenance of genome and epigenome integrity.

1 500 000 €

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

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

Food poverty in the global North is emerging as an urgent social and moral concern, increasingly recognized as a central issue in the field of health inequalities in industrialized countries. With widening income disparity in Austerity Europe and ‘the end of cheap food’, these effects are being exacerbated. International media report an increase in the number of children arriving at school hungry, a dramatic rise in the number of food banks handing out food parcels to families and parents forced to choose between ‘heating and eating’. However, little is known about how food practices are negotiated in low-income families, children’s and young people’s perspectives of food poverty and how it affects their lives, or how food poverty manifests and is addressed in different places. The proposed interdisciplinary, ambitious and innovative study will answer such questions, breaking new ground by: a) applying a mixed method international comparative case study design to the study of household food poverty b) including the experiences of children and young people using both extensive and intensive data and c) drawing on methodological developments in the sociology of food and consumption to elucidate habitual behaviour. Providing for ‘a contrast of contexts’ in relation to conditions of austerity, the study focuses on Portugal, where poor families with children have been most affected by economic retrenchment, the UK, which is experiencing substantial cuts in benefits to poor families, and Norway which, in comparison with most societies, is highly egalitarian and has not been subject to austerity measures. Building on the Principal Investigator’s (PI’s) current mixed-methods UK research on families, food and paid work, the project will develop the PI’s research skills, publication record and international reputation. Engaging academic and non-academic beneficiaries at various stages of analysis and dissemination the study will achieve societal as well as scientific impact.

1 370 937 €

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

Genome-wide studies have revealed that the majority of vertebrate genomes are transcribed and generate large numbers of long intervening noncoding RNAs (lincRNAs). While there is growing evidence that these molecules have functional importance for diverse cellular processes, such as dosage compensation, transcriptional regulation, and reprogramming, the role of lincRNAs in normal development remains elusive. To better understand the function and evolution of lincRNAs, we previously identified over 550 lincRNAs expressed during zebrafish embryonic development. We demonstrated that at least two of these novel lincRNAs, megamind and cyrano, are required for proper embryonic development, in particular for brain morphogenesis and neurogenesis. Remarkably, lincRNA functionality is retained in mammalian orthologs despite rapid evolution and little sequence conservation between human and zebrafish lincRNAs (Ulitsky*, Shkumatava* et al., Cell, 2011). This proposal aims to identify conserved developmental functions of novel lincRNAs and to determine the molecular mechanisms that drive these lincRNA functions (Aims 1 and 2). For mechanistic studies, the initial focus will be on cyrano and megamind. Preliminary evidence suggests that one of these novel molecular mechanisms is through a non-canonical interaction between cyrano and the miRNA pathway (Aim 3). Furthermore, we will investigate the relationship between conserved genomic positions of lincRNAs across vertebrate genomes and their conserved biological functions (Aim 4). The specific aims outlined in this proposal will identify novel regulatory RNAs with important and potentially conserved roles in vertebrate embryonic development, and provide mechanistic insights into how specific lincRNA contribute to normal development. Moreover, we anticipate that this project will contribute to a new synthesis of knowledge of genome function and regulation.

1 499 976 €

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

Hydrogen produced by sunlight is a very promising, environmentally-friendly energy source as an alternative for increasingly scarce and polluting fossil fuels. Since the discovery of hydrogen production by photocatalytic water dissociation on a titanium dioxide (TiO2) electrode 40 years ago, much research has been aimed at increasing the process efficiency. Remarkably, insights into how water is bound to the catalyst and into the dynamics of the photodissociation reaction, have been scarce up to now, due to the lack of suitable techniques to interrogate water at the interface. The aim of this proposal is to provide these insights by looking at specifically the molecules at the interface, before, during and after their photo-reaction. With the surface sensitive spectroscopic technique sum-frequency generation (SFG) we can determine binding motifs of the ~monolayer of water at the interface, quantify the heterogeneity of the water molecules at the interface and follow changes in water molecular structure and dynamics at the interface during the reaction. The structure of interfacial water will be studied using steady-state SFG; the dynamics of the water photodissociation will be investigated using pump-SFG probe spectroscopy. At variable delay times after the pump pulse the probe pulses will interrogate the interface and detect the reaction intermediates and products. Thanks to recent developments of SFG it should now be possible to determine the structure of water at the TiO2 interface and to unravel the dynamics of the photodissocation process. These insights will allow us to relate the interfacial TiO2-water structure and dynamics to reactivity of the photocatalyst, and to bridge the gap between the fundamentals of the process at the molecular level to the efficiency of the photocatalys. The results will be essential for developing cheaper and more efficient photocatalysts for the production of hydrogen.

1 498 800 €

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

More than 150 years after the seminal works of Charles Darwin on speciation, we are beginning to unravel the genetic underpinnings of the splitting process (Ellegren H [..] JBW Wolf, Nature, in press). The genomic revolution is progressing at full speed, and for the first time in history we are equipped with the necessary tools to investigate the genomic architecture of speciation at base-pair resolution in any organisms of our choice. When integrated to the mature theoretical framework of the evolutionary sciences, this wealth of genome-scale data will produce fundamental insights into the processes governing adaptation and speciation. Here, I identify a novel evolutionary model system - crows and ravens of the genus Corvus - and demonstrate its potential for speciation genetic and functional genomic research. Central to this system is the phylogenetically independent recurrence of a pied colour-pattern in several species that stands in contrasts to the predominant all-black plumage in the clade. Building on the idea that colour polymorphism can promote speciation through sexual selection, I choose a number of black and pied species pairs that can be positioned along a time line representing different stages of the speciation process. This comparative framework is unrivalled in its setup and is uniquely suited to study the genetics of speciation across different stages of species divergence. It also provides a promising entry point to the fascinating theme of parallel evolution. This research program is among the first to harness the possibilities of the post-genomic era in a wild organism. Using a combination of population- and phylo-genomic approaches, single sperm sequencing, experimental work in a breeding population, systems biology approaches and in situ mRNA quantification at cellular resolution, this interdisciplinary program covers novel ground in the nascent field of functional avian genomics and pushes the boundaries of speciation genetic research.

1 494 300 €

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

GeopolyConc will provide the necessary scientific basis for the prediction of the long-term durability performance of alkali-activated ‘geopolymer’ concretes. These materials can be synthesised from industrial by-products and widely-available natural resources, and provide the opportunity for a highly significant reduction in the environmental footprint of the global construction materials industry, as it expands to meet the infrastructure needs of 21st century society. Experimental and modelling approaches will be coupled to provide major advances in the state of the art in the science and engineering of geopolymer concretes. The key scientific focus areas will be: (a) the development of the first ever rigorous mathematical description of the factors influencing the transport properties of alkali-activated concretes, and (b) ground-breaking work in understanding and controlling the factors which lead to the onset of corrosion of steel reinforcing embedded in alkali-activated concretes. This project will generate confidence in geopolymer concrete durability, which is essential to the application of these materials in reducing EU and global CO2 emissions. The GeopolyConc project will also be integrated with leading multinational collaborative test programmes coordinated through a RILEM Technical Committee (TC DTA) which is chaired by the PI, providing a route to direct international utilisation of the project outcomes.

1 495 458 €

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

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

Haematopoietic stem cells (HSC) reside in the bone marrow, from where they maintain immune cells, erythrocytes and platelets. To function correctly, they depend on their localisation within highly specialised niches, where cell-cell and -matrix interactions as well as medium- and long-range molecular signals are integrated to instruct them to either remain quiescent, or to generate progeny that will maintain both the stem cell pool and the differentiated lineages. Studies based on HSC transplantation assays have identified several signalling pathways and bone marrow cell types as regulators of HSC function; however the full picture of the cellular and molecular components of the HSC niche remains elusive because of lack of direct observation over time. HSC subpopulations have been identified based on their proliferative behaviour and it is likely that either migration between different microenvironments or transient modifications of the niche structure mediate changes in HSC fate in response to perturbations such as infection or leukaemia development. I pioneered the combination of confocal and two-photon microscopy to visualise single HSC and their progeny within the bone marrow of live mice and here I propose to combine advanced microscopy techniques with multi-colour genetic lineage marking and highly sensitive expression profiling to track HSC and their clonal progeny in vivo in real time and to study the cellular and molecular composition of their niches during steady state and when responding to infection and leukaemia development. This work will uncover whether functionally distinct HSC subpopulations reside in anatomically distinct niches or rather all HSC niches are in principle equivalent, but change over time to mediate changes in HSC fate balance. The results obtained will provide a comprehensive picture of HSC niche dynamics, which will be critical for the development of regenerative medicine approaches based on in vivo or ex vivo expansion of HSC.

1 699 724 €

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

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

Financial globalization has led to a large increase in capital flows together with increasing global imbalances. Understanding how investors structure their international portfolios and how such decisions interact with the real side of the economy has become a critical macro issue. Recently, policy makers have been advocating the understanding of capital flows and global imbalances as a necessary step to analyze the roots of the last financial crisis and its international transmission. Another important evolution is the larger role played by fast growing emerging markets. The world is getting more asymmetric as they feature very different characteristics compared to developed countries. INFINHET aims at developing new dynamic multi-country macro-models to better account for the heterogeneity across agents and across countries in order to answer age-old questions in international macro such as the benefits from financial integration, the adjustment of global imbalances, the dynamics of exchange rates and asset prices, international financial contagion, the international dimension of tax policies. The first part of INFINHET deals with new methods for dynamic stochastic models with heterogeneous agents/countries. Applications include normative questions regarding the welfare impact of policies in open economies and positive questions regarding the dynamics of asset prices and capital flows. The second part focuses on long-term issues in multi-country overlapping generations models. It analyzes the importance of asymmetries between countries on macroeconomic outcomes in a globalized world. Besides differences in growth and demographics, asymmetries in financial institutions, insurance mechanisms and welfare states are emphasized, with a particular focus on the specificities of China. The theoretical predictions will be tested empirically. This will require the development of panel data based on cross-country aggregates and the use of micro data based on individuals.

1 176 938 €

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

The hippocampus is an important structure for spatial memory in rodents and episodic memory in humans. The hippocampus uses a sparse coding scheme where a given environment is represented by the place selective firing of a small group of cells, (called place cells) among a larger population of silent neurons. Thus a given environment is not only coded by the firing rate and timing of active cells but also by the very identity of these cells that fire or stay silent in that environment. Similarly, in humans, specific items or episodes are coded by the selective firing of particular cells in the temporal lobe among a larger population of silent neurons. Thus understanding the mechanisms involved in the selection of which cells will be active in a particular environment is one of the most important to understand the formation of spatial memories in rodents and episodic memories in humans. This question is at the core of our research project. Place cells have been extensively studied at the system level using extracellular recording which can only record the spiking output of neurons but not the intracellular mechanisms leading to that spiking. This is why I recently contributed to the development of a new technique allowing intracellular recordings in freely behaving animals. Using this technique we found an important role for intrinsic neuronal properties in the distinction between place and silent cells. Intriguingly, these differences were observed even before the new exploration began. Based on these findings we will address three objectives: 1) determine the role of intrinsic excitability in the initial selection of place cells, 2) test whether a similar coding scheme are valid for the other major hippocampal area for spatial coding: the CA3 area and last 3) determine whether these intrinsic mechanisms play a role in another major function of the hippocampus the remapping.

1 497 163 €

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

"A unique and innovative test of a cornerstone principle of the Standard Model of particle physics, the Lepton Favour (LF) conservation, is proposed in the framework of the NA62 experiment at CERN. The search for nine decay modes of the charged kaon and the neutral pion forbidden in the Standard Model by LF conservation will be carried out at a record sensitivity of one part in a trillion. Such sensitivity will be achieved due to the uniquely intense kaon beam that will become available to the experiment in 2014, as well as a range of novel particle detection technologies employed. The collection of the LF violating decay candidates will take place in ""parasitic"" mode alongside main NA62 data taking, which guarantees the feasibility, high data quality and cost-effectiveness. The project will bridge a significant research gap that has developed due to the absence of dedicated LF projects in the kaon sector, in sharp contrast with B-meson, lepton and neutrinoless double beta decay experiments. Any observed LF violating process will unambiguously point to physical phenomena beyond the Standard Model description, and will thus represent a major discovery. The Standard Model extensions that will be probed include those involving heavy Majorana neutrinos and R-parity breaking supersymmetry. Entire classes of new physics models will be confirmed, rigorously constrained or eliminated."

1 617 546 €

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

Contemporary cryptography, with security relying on the factorisation and discrete logarithm problems, is ill-prepared for the future: It will collapse with the rise of quantum computers, its costly algorithms require growing resources, and it is utterly ill-fitted for the fast-developing trend of externalising computations to the cloud. The emerging field of *lattice-based cryptography* (LBC) addresses these concerns: it resists would-be quantum computers, trades memory for drastic run-time savings, and enables computations on encrypted data, leading to the prospect of a privacy-preserving cloud economy. LBC could supersede contemporary cryptography within a decade. A major goal of this project is to enable this technology switch. I will strengthen the security foundations, improve its performance, and extend the range of its functionalities. A lattice is the set of integer linear combinations of linearly independent real vectors, called lattice basis. The core computational problem on lattices is the Shortest Vector Problem (SVP): Given a basis, find a shortest non-zero point in the spanned lattice. The hardness of SVP is the security foundation of LBC. In fact, SVP and its variants arise in a great variety of areas, including computer algebra, communications (coding and cryptography), computer arithmetic and algorithmic number theory, further motivating the study of lattice algorithms. In the matter of *algorithm design*, the community is quickly nearing the limits of the classical paradigms. The usual approach, lattice reduction, consists in representing a lattice by a basis and steadily improving its quality. I will assess the full potential of this framework and, in the longer term, develop alternative approaches to go beyond the current limitations. This project aims at studying all computational aspects of lattices, with cryptography as the driving motive. The strength of LattAC lies in its theory-to-practice and interdisciplinary methodological approach

1 414 402 €

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

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

Limb defects, which are amongst the most frequent congenital malformations in humans, are the result of deviation in normal developmental program deployment affecting limb specification, initiation or patterning. In most cases the mechanisms underlying limb abnormalities are, at the best, poorly defined. This is in part due because despite considerable advances in our understanding of normal limb morphogenesis, on a molecular level, fundamental aspects of limb formation are not understood at a cellular level. Thus, we still have a very incomplete picture of limb formation that prevents further progress in our understanding of this process. Here, we propose to elucidate the role of dynamic cell behavior in the consecutive steps of limb specification, initiation and patterning. More specifically, we will first generate transgenic quail lines expressing various fluorescent proteins as unique tools to investigate the cellular and molecular dynamics underlying the vertebrate limb formation. Using these transgenic quail lines in combination with state-of-the-art live imaging, biophysical, cellular, molecular and classical developmental biology approaches we will (1) elucidate how early cellular and molecular events taking place during gastrulation specify the position of the limbs; (2) decipher how positional information and molecular signaling are then integrated by limb precursors cells to initiate the formation of the limb; (3) investigate how cellular behavior at the onset of limb formation affects its patterning into different skeletal elements. The elucidation of the cellular events underlying the different steps of limb development, together with their molecular regulation, represents crucial missing information, which will undoubtedly push forward the frontier of our current knowledge of normal limb formation. Importantly, these studies will provide an integrated and comprehensive framework for understanding the mechanisms underlying congenital limb malformations.

1 665 862 €

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

"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