ERC FUNDED PROJECTS

Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.

1 000 000 €

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

New neurons are continuously generated in certain regions of adult mammalian brain. One of those regions is the dentate gyrus, a subregion of hippocampus, which is essential for memory formation. Although these new neurons in the adult dentate gyrus are thought to have an important role in learning and memory, it is largely unclear how new neurons are involved in information processing and storage underlying memory. Because new neurons constitute a minor portion of intermingled local neuronal population, simple application of conventional techniques such as multi-unit extracellular recording and pharmacological lesion are not suitable for the functional analysis of new neurons. In this proposed research program, I will combine multi-unit recording and behavioral analysis with virus mediated, cell-type-specific genetic manipulation of neuronal activity, to investigate computational roles of new neurons in learning and memory. Specifically, I will determine: 1) specific memory processes that require new neurons, 2) dynamic patterns of activity that new neurons express during memory-related behavior, 3) influence of new neurons on their downstream structure. Further, based on the information obtained by these three lines of studies, we will establish causal relationship between specific memory-related behavior and specific pattern of activity in new neurons. Solving these issues will cooperatively provide important insight into the understanding of computational roles performed by adult neurogenesis. The information on the function of new neurons in normal brain could contribute to future development of efficient therapeutic strategy for a variety of brain disorders.

1 991 743 €

Start date: 2009-01-01, End date: 2013-12-31

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

1 499 948 €

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

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

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

1 250 000 €

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

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

1 497 715 €

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

My objective is to understand the physiologic and medical importance of the posttranslational processing of CAAX proteins (e.g., K-RAS and prelamin A) and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and progeria. CAAX proteins undergo three posttranslational processing steps at a carboxyl-terminal CAAX motif. These processing steps, which are mediated by four different enzymes (FTase, GGTase-I, RCE1, and ICMT), increase the hydrophobicity of the carboxyl terminus of the protein and thereby facilitate interactions with membrane surfaces. Somatic mutations in K-RAS deregulate cell growth and are etiologically involved in the pathogenesis of many forms of cancer. A mutation in prelamin A causes Hutchinson-Gilford progeria syndrome—a pediatric progeroid syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., the plasma membrane and the nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif. My Specific Aims are: (1) To define the suitability of the CAAX processing enzymes as therapeutic targets in the treatment of K-RAS-induced lung cancer and leukemia; and (2) To test the hypothesis that inactivation of FTase or ICMT will ameliorate disease phenotypes of progeria. I have developed genetic strategies to produce lung cancer or leukemia in mice by activating an oncogenic K-RAS and simultaneously inactivating different CAAX processing enzymes. I will also inactivate several CAAX processing enzymes in mice with progeria—both before the emergence of phenotypes and after the development of advanced disease phenotypes. These experiments should reveal whether the absence of the different CAAX processing enzymes affects the onset, progression, or regression of cancer and progeria.

1 689 600 €

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

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

"The theme of the proposal is the mathematical investigation of chaos (in particular ergodic and spectral properties) in parabolic dynamics, via analytic, geometric and probabilistic techniques. Parabolic dynamical systems are mathematical models of the many phenomena which display a ""slow"" form of chaotic evolution, in the sense that nearby trajectories diverge polynomially in time. In contrast with the hyperbolic case and with the elliptic case, there is no general theory which describes parabolic dynamical systems. Only few classical examples are well understood. The research plan aims at bridging this gap, by studying new classes of parabolic systems and unexplored properties of classical ones. More precisely, I propose to study parabolic flows beyond the algebraic set-up and infinite measure-preserving parabolic systems, both of which are very virgin fields of research, and to attack open conjectures and questions on fine chaotic properties, such as spectra and rigidity, for area-preserving flows. Moreover, connections between parabolic dynamics and respectively number theory, mathematical physics and probability will be explored. g New techniques, stemming from some recent breakthroughs in Teichmueller dynamics, spectral theory and infinite ergodic theory, will be developed. The proposed research will bring our knowledge significantly beyond the current state-of-the art, both in breadth and depth and will identify common features and mechanisms for chaos in parabolic systems. Understanding similar features and common geometric mechanisms responsible for mixing, rigidity and spectral properties of parabolic systems will provide important insight towards an universal theory of parabolic dynamics."

1 193 534 €

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

In the biomedical sciences, where endless combinatorial diversity of genes, proteins and synthetic molecules is involved, miniaturisation has not simply allowed an increase in the speed at which experiment can be performed: it has given birth to new areas such as combinatorial chemistry and biology, proteomics, genomics, and more recently, systems and synthetic biology. In all these areas, the synthesis, assay and analysis of large molecular ensembles has become the essence of experimental progress. However, it is the systematic analysis of the enormous amounts of data generated that will ultimately lead to an understanding of fundamental chemical and biological problems. This proposal deals with approaches in which libraries of molecules are employed to give such mechanistic insight – into how enzyme catalysis is brought about in proteins and polymeric enzyme models and into the molecular recognition and cell biology of drug delivery reagents. In each case considerable technical challenges are involved in the way diversity is brought about and probed: ranging from either using the tools of synthetic chemistry to using gene repertoires in emulsion microdroplet reactors with femtolitre volumes, handled in microfluidic devices.

563 848 €

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

The aim of the project is to develop chemical processing systems based on the principle of swarm robotics. The inspiration for swarm robotics comes from the behaviour of collective organisms – such as bees or ants – that can perform complex tasks by the combined actions of a large number of relatively simple, identical agents. The main scientific challenge of the project will be the design and synthesis of chemical swarm robots (“chobots”), which we envisage as internally structured particulate entities in the 10-100 µm size range that can move in their environment, selectively exchange molecules with their surrounding in response to a local change in temperature or concentration, chemically process those molecules and either accumulate or release the product. Such chemically active autonomous entities can be viewed as very simple pre-biotic life forms, although without the ability to self-replicate or evolve. In the course of the project, the following topics will be explored in detail: (i) the synthesis of suitable shells for chemically active swarm robots, both soft (with a flexible membrane) and hard (porous solid shells); (ii) the mechanisms of molecular transport into and out of such shells and means of its active control; (iii) chemical reaction kinetics in spatially complex compartmental structures within the shells; (iv) collective behaviour of chemical swarm robots and their response to external stimuli. The project will be carried out by a multi-disciplinary team of enthusiastic young researchers and the concepts and technologies developed in course of the project, as well as the advancements in the fundamental understanding of the behaviour of “chemical robots” and their functional sub-systems, will open up new opportunities in diverse areas including next-generation distributed chemical processing, synthesis and delivery of personalised medicines, recovery of valuable chemicals from dilute resources, environmental clean-up, and others.

1 644 000 €

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

The ubiquity of arsenic resistant genes across all of life’s variety suggests a close intimacy between arsenic biogeochemistry and evolution, over geological time scales. However, the behaviour of arsenic in past environments where life originated and its impact on our evolution is essentially unknown. Arsenic is of particular importance because of its toxic properties, prevalence in tight association with ubiquitous iron and sulfide minerals and as a major component of sulfide-rich waters, all common features of Precambrian oceans. Arsenic obstructs the synthesis of the building blocks of life, exhibiting both chronic and acute toxicity at very low concentrations. These properties make arsenic an agent capable of exerting strong selective pressure on the distribution, success and diversity of life. This is exemplified by when the release of arsenic into groundwater following rock-weathering processes results in widespread poisoning. Using the state of the art stable isotopes tools, coupled to biomass production, bacterial iron, arsenic and sulfur cycling under ancient oceanic conditions, this project will open a new discussion on the much debated relationship between ocean chemistry and evolution, by introducing a new arsenic framework. This will be achieved under three majors themes: 1) Does there exist a biogeochemical connection between arsenic and the timing and transition from the iron-rich to the hypothesized sulfide-rich oceans that are linked to the rise of atmospheric oxygen? 2) Does arsenic and sulfide show concomitant cyclicity during the Precambrian? 3) Could arsenic thus serve as a proxy for the calibration of key transitional steps in the timing of biological innovation?

1 486 374 €

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

"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

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

1 080 000 €

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

"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

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

960 000 €

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

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

1 499 571 €

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

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

1 376 704 €

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

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

1 954 565 €

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

Recent development of atmospheric pressure desorption ionization methods has opened a unique area of application for analytical mass spectrometry. Most of these methods do not require any modification of samples, and this feature, together with the minimal invasiveness of these methods allows direct analytical interrogation of biological tissues, even the real-time, in-vivo observation of biochemical processes. The proposed research focuses on the development of atmospheric pressure desorption ionization mass spectrometric methods for the characterization of biological tissues. The first question to answer is aimed at the nature of information which can be obtained, using a variety of desorption ionization methods including desorption electrospray ionization and jet desorption ionization methods. Preliminary results show, that APDI-MS methods provide information on lipids, metabolic compounds, drugs and certain proteins. First task of the proposed research is to implement a chemical imaging system, which is capable of producing 3D concentration distribution functions for various constituents of tissue samples. The developed methodology will be used to tackle fundamental pathophysiological problems including development of various malignant tumors. A database will be created for the unequivocal identification of various tissues including healthy and malignant tissue samples. In-vivo applications of MS will also be developed. JeDI-MS,similarly to water jet surgery, also utilizes high velocity water jet can directly be used as an intelligent scalpel. Real-time in-situ tissue identification has the potential of revolutionizing cancer surgery, since this way the amount of removed tissue can be minimized, while the tumor removal efficiency is maximized. The identical experimental platform can also be used to gather real-time in-situ metabolic information, which can help to understand pathophysiological changes.

1 750 000 €

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

One of the most profound trends in global governance over the past two decades is the growing extent to which international institutions offer mechanisms for the participation of transnational actors. This project will explore two central research questions, pertaining to the causes and effects of this shift in the design of international institutions: (1) Why have international institutions increasingly opened up to transnational actor involvement? (2) What are the consequences of involving transnational actors for the democratic legitimacy, problem-solving effectiveness, and distributional effects of international institutions? These are research questions that previously have not been explored systematically in existing literatures on international institutional design, transnational actors in global governance, and democracy beyond the nation-state. This project opens up a new research agenda on the design of international institutions through an ambitious combination of novel theory development and comparative empirical research. Theoretically, the project develops and tests alternative hypotheses about the causes and effects of transnational participation in international policy-making. Empirically, the project explores the dynamics of transnational participation through comparative case studies of five major international institutions, supplemented with a large-n mapping of formal mechanisms of transnational access in a broader sample of institutions. The project will help to establish an internationally competitive research group of post-doc researchers and Ph.D. students devoted to international institutional design, and consolidate the position of the principal investigator as a leading researcher in this field.

1 651 200 €

Start date: 2009-01-01, End date: 2014-12-31

"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

We are building a parallel and independent (orthogonal) translational machinery for the encoded biosynthesis of unnatural polymers in living cells. The orthogonal translation system has many potential applications beyond those possible with the natural translation system: I propose to use it: 1) To expand the chemical scope of monomers that can be polymerized by the ribosome in living cells, allowing the incorporation of monomers with unnatural backbones into proteins; 2) To increase the efficiency of in vivo unnatural amino acid mutagenesis via amber suppression, so that no truncated protein is produced and multi-site incorporation of unnatural amino acids is possible; 3) To create probes of protein function for use in vivo; 4) To free numerous codons for simultaneous encoding of multiple distinct unnatural monomers, and to experimentally explore alternate genetic codes; 5) To explore the evolution of encoded unnatural polymers toward new cellular functions.

1 782 918 €

Start date: 2009-01-01, End date: 2014-12-31

The purpose of the project is to develop methods for computing with the rigid and crystalline cohomology of varieties over finite fields. The project will focus on two main problems. First, the fast computation of the Galois action. Second, the effective computation of the cycle class map, and the inverse problem of explicitly recovering algebraic cycles from Galois-invariant cohomology classes (c.f. the Tate conjecture). Research on the first problem would be a natural extension of on-going work of the Prinicipal Investigator and others. By contrast the second problem is entirely new, at least in the context of computational number theory. The overall goal of the project is to provide methods and software which will extend the range of application of computational number theory within the mathematical sciences.

750 000 €

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

The understanding of quantum matter in and out of equilibrium is among the biggest challenges of modern physics. Despite decades of research fundamental questions, such as the precise workings behind rather ubiquitous materials such as high temperature superconductors are still unresolved. At the same time there is a new generation of experiments approaching which realises and probes quantum matter with novel and exotic interactions at an unprecedented level of precision. This has already highlighted new avenues of research but also demands for radically new theoretical approaches which lie outside the scope of just a single traditional physical discipline. Novel and in particular multidisciplinary lines of thinking are required to tackle this immense challenge. Such new research will not solely be delivering invaluable insights into currently unresolved problems but rather form a new basis for the understanding of quantum matter from a multidisciplinary perspective. This will open up new horizons for fundamental research and at the same time will pave the way for future technologies and materials which rely on non-equilibrium phenomena or quantum matter. This research proposal takes on this challenge by setting up a broad theoretical research programme which is multipronged and multidisciplinary and which directly connects to the most recent research efforts in ultra cold atomic physics. Here currently a step change is taking place where new experiments explore strongly correlated quantum physics within gases of excited atoms – so-called Rydberg atoms. Exploiting this unique moment we will develop a framework for the description of the equilibrium and non-equilibrium properties of these complex and very versatile quantum systems. This system-specific research approach has the advantage that theoretical predictions can be verified experimentally and applied in practice almost immediately, leading to research attacking the frontiers of current knowledge.

1 492 000 €

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

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

What impact do forecasts have on political action? How are they communicated, perceived and used in order to prevent harmful events in the future? There are few policy areas as dependent on good forecasts as efforts aimed at preventing intra-state violent conflicts. Both practitioners and scholars agree that early, appropriate and sustained action on the part of various international players can help to avoid or at least alleviate many of the harmful consequences. Preventing the outbreak of such conflicts has increasingly become a priority objective of the European Union and its most influential member states. But there is a curious gap in the literature with respect to the exact linkage between early warning and political response: under what conditions do forecasts of impending conflicts lead to political action? The first objective of the project is to better understand the interplay of communication and political perception of early warnings about impending intra-state armed conflict. In a second step, the project will compare the findings about early warnings regarding armed conflict to insights about the impact of forecasts in other policy-areas such as adjusting to impending environmental and economic crises. Thus, the project aims to contribute to improving public policy by analysing the interplay of forecasting, advocacy and preventive decision-making.

754 077 €

Start date: 2008-09-01, End date: 2011-10-31

The eukaryotic genome combines a highly dynamic nature with stable transmission of genetic information from mother to daughter cells. This is achieved by a plethora of protein networks regulating processes such as chromosome duplication, segregation and repair. The principal aim of our research is to determine the molecular interplay between chromosome segregation and repair. Accurate execution of these two events is crucial for the maintenance of genome stability, which in turn is essential for life. Additionally, erroneous segregation or repair leads to chromosomal aberrations that are linked to tumor formation and human developmental syndromes. Thus, our investigations are not only crucial in a basic research perspective, but important also for the understanding of the causes of human disease. The research is based on the budding yeast model system, and combines genome-wide analysis of protein-chromosome interactions with cell-based experimental systems. Our investigations have until now revealed that chromosome segregation and repair are directly linked through two evolutionary conserved SMC (Structural Maintenance of Chromosomes) protein complexes, Cohesin and the Smc5/6 complex. The project now further explores the molecular details of this connection, bringing light into this unexplored area of research, and deciphering the cellular defense against genomic alterations connected to cancer and developmental diseases.

900 000 €

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

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

Two key variables, temperature and atmospheric carbon dioxide (pCO2), define the sensitivity of the Earth’s climate system. The geological record provides our only evidence of the past climate sensitivity of the Earth system, but there is no direct quantitative measure of pCO2 or temperature beyond the 650 kyr extent of the Antarctic ice cores. The reconstruction of past climate, on timescales of millions of years, relies on the analysis of chemical or isotopic proxies in preserved shells or organic matter. Such indirect approaches depend upon empirical calibration in modern species, without understanding the biological mechanisms that underpin the incorporation of the climate signal. The intention of this ERC grant proposal is to establish a research team to investigate the “living geological record” to address this major gap in climate research. I hypothesise that direct climate signals of the past are harboured within, and can ultimately be deciphered from, the genetic make up of extant organisms. Specifically, I propose an innovative approach to the constraint of the evolution of atmospheric pCO2 during the Cenozoic. The approach is based on the statistical signal of positive selection of adaptation within the genetic sequences of marine algal Rubisco, the notoriously inefficient enzyme responsible for photosynthetic carbon fixation, but supplemented by analysis of allied carbon concentrating mechanisms. As a calibration, I will characterise the biochemical properties of Rubisco in terms of specificity for pCO2, isotopic fractionation and kinetics, from a range of marine phytoplankton. The prime motivation is a history of pCO2, but the project will yield additional insight into the feedback between phytoplankton and climate, the carbon isotopic signatures of the geological record and the mechanistic link between genetic encoding and specific

1 652 907 €

Start date: 2008-09-01, End date: 2015-08-31

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

I propose a novel evolutionary approach for studying ecological and demographic factors that affect senescence and lifespan in humans. Women are unique among animals due to menopause and a prolonged lifespan after last birth. Evolutionarily, the quest of everyone is to maximise grandchildren numbers. Hence, human women life-history is enigmatic. One possibility is that older women increase their fitness by directing resources to already produced offspring rather than having more. Thus, although women gain most grandchildren from own reproduction, they also gain more by helping offspring. This has fascinating implications. All animals must split their energy between reproduction vs. self-maintenance. Most continue to reproduce until death and produce maximum grandchildren by optimising investment between current vs. future reproduction. Human women must also optimise investment between mothering and grandmothering. How this is done and affected by ecological, social and demographic factors is unknown, but is essential to understanding the ecological and genetic basis of reproduction, senescence and lifespan. My project has 5 aims: 1. How does reproductive effort affect reproductive and post-reproductive senescence? 2. What proportion of grandchildren is gained post-menopause and how is this modified? 3. Is there heritable variation in life-history traits and their senescence, and how do genetic correlations affect evolution? 4. How do patterns of fitness acquisition account for menopause, prolonged post-reproductive lifespan and age of death in humans? 5. How does fitness maximization differ between men and women and affect their lifespans? The questions will be answered using unique data on three generations of individuals that lived before healthcare and modern contraceptives in Finland. The results will have important implications for predicting demographic structure and will appeal to a wide range of people within and outwith the scientific community.

1 143 824 €

Start date: 2008-07-01, End date: 2014-06-30

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 develops new theories and constructs new datasets to understand the determinants of net and gross foreign assets, the trade balance and the exchange rate. It also quantifies their respective roles in the dynamics of countries’ external deficits. In previous work, I constructed a database of US foreign assets and liabilities to analyse the sustainability of US current account deficits. I propose to build on this work along four related lines. First, I will generalize the analysis to other countries, contrasting the external balance sheets of large financially developed economies (US, UK) with those of small open economies (Canada, Australia). I will compare the historical role of the UK as a world banker to the current position of the US in the international monetary system. I will construct disaggregated databases of foreign assets at market value for these countries. Second, I will develop new theories of portfolio investment where international wealth transfers and predictable excess returns play a key role. These elements are rarely incorporated in open economy models but are essential for realism. I will develop and calibrate a new class of portfolio balance models compatible with the macroeconomic stylized facts on capital flows to study how countries’ capacity to accumulate foreign debt depends on changes in portfolio preferences (e.g. erosion of home bias). Third, I will use a disaggregated database of international investment positions of institutional investors to test for portfolio rebalancing at the microeconomic level. This exceptional database should also provide insights on the international propagation of financial crises. I will link the magnitude of price drops of given equities in crisis times to the institutional and geographical characteristics of their holders. Fourth, I will extend the methodology developed to analyze external adjustment to the issue of fiscal adjustment and twin deficits.

1 340 000 €

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

A major goal of 21st century science is to protect human health from the growing mismatch between ancient behavioural instincts and modern socio-economic reality. This is especially vital for basic instinctive drives such as appetite, which lead to overeating when food is readily available. The resulting obesity is responsible for 100,000s of premature deaths per year in Europe and North America, and this number is rapidly rising. Sleep is another powerful instinct which substantially contributes to premature human death, for example from car accidents caused by tiredness. Thus “self-destructive” behaviours caused by inappropriate activation of feeding and sleep drives take a devastating social and economic toll in developed countries, and there is a huge unmet need for effective therapies in this area. To design these therapies, we need to understand the brain mechanisms of instinctive drives. However, brain circuits regulating appetite and sleep have only been delineated in the past few years, and their principles of operation are poorly understood at present. The broad aim of my newly-established laboratory is to fill this gap in knowledge. To understand neural signals controlling instinctive drives, and their relationship to well-being and disease, the following questions must be answered: 1) how do neurons that control appetite and sleep generate their electrical and chemical signals? ) how do these neurons interact with each other? 3) how are these neurons altered in disorders of energy balance and sleep? Our objective for the next five years is to address these key unknowns by focusing on neurons known to be unequivocally important for normal sleep and appetite, the orexin and MCH neurons of the lateral hypothalamus.

1 299 999 €

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

Inhibitory interneurons function as modulators of local circuit excitability. Their properties are of fundamental importance for normal brain function therefore understanding how these cells are generated during development may provide insight into neurodevelopmental disorders such as epilepsy and schizophrenia, in which interneuron defects have been implicated. Inhibitory GABAergic interneurons of the cerebral cortex (pallium) are generated from proliferating subpallial precursors during development and migrate extensively to populate the cortex. The aim of this proposal is to identify genetic pathways and signalling systems that underlie cortical interneuron migration and integration into functional neuronal circuits. Distinct interneuron subtypes are generated from the two most prominent neuroepithelial stem cell pools in the subpallium: the medial ganglionic eminence (MGE) and the lateral/caudal ganglionic eminence (LGE/CGE). We will genetically tag and purify interneurons originating from these precursors in order to examine their transcriptomes and identify factors involved in specification and migration. We will use Cre-lox fate mapping in transgenic mice to label specific sub-populations of neural stem cells and their differentiated progeny in the embryonic telencephalon. This will allow us to determine whether subdomains of the MGE or LGE/CGE neuroepithelium generate interneurons with distinct neurochemical phenotypes and/or characteristic migratory properties. Electrical activity and/or neurotransmitter receptor activation can act in concert with genetic programs to promote precursor proliferation, neuronal differentiation as well as neuronal migration. We will use gain-of-function and loss-of-function approaches to examine the role of neurotransmitters and neuropeptides at early stages of interneuron migration to the cortex.

1 250 000 €

Start date: 2008-07-01, End date: 2014-08-31

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

1 407 037 €

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

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

1 999 859 €

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

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

940 200 €

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

Existing tools for human interactive behaviour analysis typically handle only deliberately displayed, exaggerated expressions. As they are usually trained only on series of such exaggerated expressions, they lack models of human expressive behaviour found in real-world settings and cannot handle subtle changes in audiovisual expressions typical for such spontaneous behaviour. The main aim of MAHNOB project is to address this problem and to attempt to build automated tools for machine understanding of human interactive behaviour in naturalistic contexts. MAHNOB technology will represent a set of audiovisual spatiotemporal methods for automatic analysis of human spontaneous (as opposed to posed and exaggerated) patterns of behavioural cues including head pose, facial expression, visual focus of attention, hands and body movements, and vocal outbursts like laughter and yawns. As a proof of concept, MAHNOB technology will be developed for two specific application areas: automatic analysis of mental states like fatigue and confusion in Human-Computer Interaction contexts and non-obtrusive deception detection in standard interview settings. A team of 5 Research Assistants (RAs), led by the PI and having the background in signal processing and machine learning will develop MAHNOB technology. The expected result after 5 years is MAHNOB technology with the following capabilities: - analysis of human behaviour from facial expressions, hand and body movements, gaze, and non-linguistic vocalizations like speech rate and laughter; - interpretation of user behaviour with respect to mental states, social signals, dialogue dynamics, and deceit/veracity; - near real-time, robust, and adaptive processing by means of incremental processing, robust observation models, and learning person-specific behavioural patterns; - provision of a large, annotated, online dataset of audiovisual recordings providing a basis for benchmarks for efforts in machine analysis of human behaviour.

1 736 800 €

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

Most joints start off the same during embryonic development, as two opposing cartilage surfaces, and are moulded into the diverse range of shapes seen in the adult in a process known as morphogenesis. While we understand very little of the biological or mechanobiological processes driving joint morphogenesis, there is evidence to suggest that fetal movements play a critical role in joint shape development. Developmental Dysplasia of the Hip (DDH), where the hip is partly or fully dislocated, is much more common when the baby’s movement is restricted or prevented. This proposal will determine how mechanical forces influence joint shape morphogenesis, which is of key relevance to neonatal joint conditions such as DDH, to adult joint health and disease, and to tissue engineering of cartilage. A mouse line in which mutant embryos have no skeletal muscle will be studied, providing the first in depth analysis of mammalian joint shape development for normal and abnormal mechanical environments. The mouse line could provide the first mammalian model system for prenatal onset DDH. ‘Passive’ movements of these mutant embryos will then be induced by massage of the mother, and the effects on the joints measured. If the effects on joint shape of absent spontaneous movement are mitigated by the treatment, this technique could eventually be used as a preventative treatment for DDH. Next, an in vitro approach will be used to quantify how much movement is needed for joint shape development. This research will provide an optimised protocol for applying biophysical stimuli to promote cartilage growth and morphogenesis in culture, providing valuable cues to cartilage tissue engineers. Finally, a computational simulation of joint shape morphogenesis will be created, which will integrate the new understanding gained from the experimental research in order to predict how different joints shapes develop in normal and abnormal mechanical environments.

1 499 501 €

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

The overall aim of this project is to identify key biophysical mechanisms that control the spatial arrangement of signalling proteins and membrane lipids in the regulation of T cell activation. During an immune response, T cells are activated in response to antigenic peptides in a process that requires the formation of multi-molecular signalling complexes. It is known that many T cell signalling proteins (such as the kinase Lck and the scaffold protein LAT) are not randomly distributed within the plasma membrane thus giving rise to lateral organization which affects signalling efficiency. However, the biophysical mechanism(s) that control protein distributions and hence the rate of molecular interactions remains poorly understood. Two of the principal mechanisms are compartmentalisation of the membrane by lipid microdomains (the ‘lipid raft’ hypothesis) and by the cortical actin meshwork (the ‘picket-fence’ model). The two key technologies needed to unravel how protein clustering and the biophysical properties of the lipid bilayer regulate specific interactions at the molecular level have now been developed. These are single-molecule, super-resolution localisation microscopy and quantification of membrane biophysical properties using new-generation environmentally sensitive fluorescent probes. Using these methods, the proposed project will generate unique insights into the biophysical mechanisms that govern the formation of the protein clusters and complexes during early T cell signalling events. This knowledge is critical to our understanding of the molecular basis of T cell activation during the immune response and has potential applications in the development of therapeutic treatments for a range of conditions.

1 402 513 €

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

The proposed project concerns the study of mathematical aspects of the general theory of relativity. Major unsolved problems in the area include the problem of nonlinear stability of black hole spacetimes and the problem of weak and strong cosmic censorship. Mathematically, these problems concern the global dynamics of solutions to the Einstein equations. Resolution of these problems is of fundamental importance both to our understanding of the nature of the theory of relativity and to our assessment of its validity. In previous work, I have addressed these problems either under symmetry reductions or in linearised settings. These studies have revealed much of the mathematical structure of the dynamics of the Einstein equations in the context of black holes. Further progress extending beyond symmetry or linearised theory now appears possible. A research programme with this as a goal will be outlined in the proposal.

500 000 €

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

"The MUSYX project will develop a rigorous numerical analysis framework for assessing the accuracy of multiscale methods for simulating the dynamics of crystalline defects. The core focus of the research will be the analysis of approximation errors of atomistic-to-continuum (a/c) coupling methods and related multiscale schemes. The rigorous mathematical foundations, which will be the outcome of this work, will also lead to the construction of more robust and more efficient numerical algorithms. The research will be undertaken within four distinct but closely related themes: Theme A: quasistatic evolutions up to and including bifurcation points (defect nucleation and evolution); Theme B: Transition paths, saddles, and transition rates between local minima (defect nucleation and diffusion at finite temperature); Theme C: Computation of defect formation energies within the framework of equilibrium statistical mechanics; Theme D: Fully dynamic problems. The four themes are connected through the focus on crystal defects and model interfaces (e.g., atomistic/continuum). Themes A and B build on and significantly extend the theory of a/c coupling pioneered by the PI, which combines classical techniques of numerical analysis (consistency, stability) with modern concepts of multiscale and atomistic modeling. Theme C aims to develop an analogous theory for multiscale free energy calculations (precisely, defect formation energies). Theme D approaches the analysis of a fully dynamic multiscale scheme by analyzing its qualitative statistical properties."

1 111 793 €

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

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

1 498 352 €

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

Materials with nanometre-scale dimensions have unique functional properties that can lead to novel engineering systems with highly useful characteristics. Most traditional approaches to synthesis of nanoscale materials, unlike those in biology, require stringent conditions and often produce toxic byproducts. Within biology itself, biomaterials are highly organized from the molecular to the nanoscale, with intricate architectures that allow for optimum functionality. The focus for this proposal on bio-inspired materials is two-fold. In the first instance I aim to rationally design biologically responsive peptides to control the assembly and dis-assembly of bio-inorganic nanostructures and develop fundamental enabling technologies with applications in bio-sensing. The second focus is on exploiting our understanding of the natural biological nanostructures found in the complex extracellular matrix of tissues in order to engineer synthetic biomimetic nanostructures for improved cell growth and tissue regeneration. Outcomes will include greater fundamental understanding of cell-matrix interactions and cell differentiation as well as longer-term clinical impacts. I have begun to establish a creative research team with many developing international links and a record of timely high quality research. If successful with this proposal I will be able to manage my group to its full potential and to expand its influence and vision. The proposed research involves development of important new international collaborations in the basic sciences and is highly multidisciplinary in nature encompassing elements of engineering, biology, chemistry and physics and ranging from high-resolution techniques of surface analysis to peptide design and cell biology.

1 643 021 €

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