ERC FUNDED PROJECTS

Topological insulators constitute a novel class of materials where the topological details of the bulk band structure induce a robust surface state on the edges of the material. While transport data for 2-dimensional topological insulators have recently become available, experiments on their 3-dimensional counterparts are mainly limited to photoelectron spectroscopy. At the same time, a plethora of interesting novel physical phenomena have been predicted to occur in such systems. In this proposal, we sketch an approach to tackle the transport and magnetic properties of the surface states in these materials. This starts with high quality layer growth, using molecular beam epitaxy, of bulk layers of HgTe, Bi2Se3 and Bi2Te3, which are the prime candidates to show the novel physics expected in this field. The existence of the relevant surface states will be assessed spectroscopically, but from there on research will focus on fabricating and characterizing nanostructures designed to elucidate the transport and magnetic properties of the topological surfaces using electrical, optical and scanning probe techniques. Apart from a general characterization of the Dirac band structure of the surface states, research will focus on the predicted magnetic monopole-like response of the system to an electrical test charge. In addition, much effort will be devoted to contacting the surface state with superconducting and magnetic top layers, with the final aim of demonstrating Majorana fermion behavior. As a final benefit, growth of thin high quality thin Bi2Se3 or Bi2Te3 layers could allow for a demonstration of the (2-dimensional) quantum spin Hall effect at room temperature - offering a road map to dissipation-less transport for the semiconductor industry.

2 419 590 €

Start date: 2011-04-01, End date: 2016-03-31

Extreme astrophysical events such as relativistic flows, cataclysmic explosions and black hole accretion are one of the key areas for astrophysics in the 21st century. The extremes of physics experienced in these environments are beyond anything achievable in any laboratory on Earth, and provide a unique glimpse at the laws of physics operating in extraordinary regimes. All of these events are associated with transient radio emission, a tracer both of the acceleration of particles to relativistic energies, and coherent emitting regions with huge effective temperatures. By studying radio bursts from these phenomena we can pinpoint the sources of explosive events, understand the budget of kinetic feedback by explosive events in the ambient medium, and probe the physical state of the universe back to the epoch of reionisation, less than a billion years after the big bang. In seeking to push back the frontiers of extreme astrophysics, I will use a trio of revolutionary new radio telescopes, LOFAR, ASKAP and MeerKAT, pathfinders for the Square Kilometre Array, and all facilities in which I have a major role in the search for transients. I will build an infrastructure which transforms their combined operations for the discovery, classification and reporting of transient astrophysical events, over the whole sky, making them much more than the sum of their parts. This will include development of environments for the coordinated handling of extreme astrophysical events, in real time, via automated systems, as well as novel techniques for the detection of these events in a sea of noise. I will furthermore augment this program by buying in as a major partner to a rapid-response robotic optical telescope, and by cementing my relationship with an orbiting X-ray facility. This multiwavelength dimension will secure the astrophysical interpretation of our observational results and help to revolutionise high-energy astrophysics via a strong scientific exploitation program.

2 999 847 €

Start date: 2011-07-01, End date: 2017-06-30

Global change involves a large number of complex interactions between various earth system processes. In the atmosphere, one component of the earth system, there are crucial feedbacks between physical, chemical and biological processes. Thus many of the drivers of climate change depend on chemical processes in the atmosphere including, in addition to ozone and water vapour, methane, nitrous oxide, the halocarbons as well as a range of inorganic and organic aerosols. The link between chemistry and climate is two-way and changes in climate can influence atmospheric chemistry processes in a variety of ways. Previous studies have looked at these interactions in isolation but the time is now right for more comprehensive studies. The crucial contribution that will be made here is in improving our understanding of the processes within this complex system. Process understanding has been the hallmark of my previous work. The earth system scope here will be ambitiously wide but with a similar drive to understand fundamental processes. The ambitious programme of research is built around four interrelated questions using new state-of-the-art modelling tools: How will the composition of the stratosphere change in the future, given changes in the concentrations of ozone depleting substances and greenhouse gases? How will these changes in the stratosphere affect tropospheric composition and climate? How will the composition of the troposphere change in the future, given changes in the emissions of ozone precursors and greenhouse gases? How will these changes in the troposphere affect the troposphere-stratosphere climate system? ACCI will break new ground in bringing all of these questions into a single modelling and diagnostic framework, enabling interrelated questions to be answered which should radically improve our overall projections for global change.

2 496 926 €

Start date: 2011-05-01, End date: 2017-04-30

Increasing crop yield to feed the world is a grand challenge of the 21st century but it is hampered by diseases caused by filamentous plant pathogens. The arms race between pathogen and plant demands constant adjustment of crop germplasm to tackle emerging pathogen races with new virulence features. To date, most crop disease resistance has relied on specific resistance genes that are effective only against a subset of races. We cannot solely rely on classical resistance genes to keep ahead of the pathogens. There is an urgent need to develop approaches based on knowledge of the pathogen’s Achilles heel: core plant processes that are required for pathogen colonization. Our hypothesis is that disease resistance based on manipulation of host accessibility processes has a higher probability for durability, and is best identified using a broad host-range pathogen. I will employ the filamentous pathogen Phytophthora palmivora to mine plant alleles and unravel host processes providing microbial access in roots and leaves of monocot and dicot plants. In Aim 1 I will utilize plant symbiosis mutants and allelic variation to elucidate general mechanisms of colonization by filamentous microbes. Importantly, allelic variation will be studied in economically relevant barley and wheat to allow immediate translation into breeding programs. In Aim 2 I will perform a comparative study of microbial colonization in monocot and dicot roots and leaves. Transcriptional profiling of pathogen and plant will highlight common and contrasting principles and illustrate the impact of differential plant anatomies. We will challenge our findings by testing beneficial fungi to assess commonalities and differences between mutualist and pathogen colonization. We will use genetics, cell biology and genomics to find suitable resistance alleles highly relevant to crop production and global food security. At the completion of the project, I expect to have a set of genes for resistance breeding.

1 991 054 €

Start date: 2015-09-01, End date: 2021-08-31

MAL: an actin-regulated SRF transcriptional coactivator Recent years have seen a revitalised interest in the role of actin in nuclear processes, but the molecular mechanisms involved remain largely unexplored. We will elucidate the molecular basis for the actin-based control of the SRF transcriptional coactivator, MAL. SRF controls transcription through two families of coactivators, the actin-binding MRTFs (MAL, Mkl2), which couple its activity to cytoskeletal dynamics, and the ERK-regulated TCFs (Elk-1, SAP-1, Net). MAL subcellular localisation and transcriptional activity responds to signal-induced changes in G-actin concentration, which are sensed by its actin-binding N-terminal RPEL domain. Members of a second family of RPEL proteins, the Phactrs, also exhibit actin-regulated nucleocytoplasmic shuttling. The proposal addresses the following novel features of actin biology: ¿ Actin as a transcriptional regulator ¿ Actin as a signalling molecule ¿ Actin-binding proteins as targets for regulation by actin, rather than regulators of actin function We will analyse the sequences and proteins involved in actin-regulated nucleocytoplasmic shuttling, using structural biology and biochemistry to analyse its control by changes in actin-RPEL domain interactions. We will characterise the dynamics of shuttling, and develop reporters for changes in actin-MAL interaction for analysis of pathway activation in vivo. We will identify genes controlling MAL itself, and the balance between the nuclear and cytoplasmic actin pools. The mechanism by which actin represses transcriptional activation by MAL in the nucleus, and its relation to MAL phosphorylation, will be elucidated. Finally, we will map MRTF and TCF cofactor recruitment to SRF targets on a genome-wide scale, and identify the steps in transcription controlled by actin-MAL interaction.

1 889 995 €

Start date: 2011-10-01, End date: 2017-09-30

The mechanism of cell division is conserved in many eukaryotes, from yeast to man. A contractile ring of filamentous actin and myosin II motors generates the force to bisect a mother cell into two daughters. The actomyosin ring is among the most complex cellular machines, comprising over 150 proteins. Understanding how these proteins organize themselves into a functional ring with appropriate contractile properties remains one of the great challenges in cell biology. Efforts to generate a comprehensive understanding of the mechanism of actomyosin ring assembly have been hampered by the lack of structural information on the arrangement of actin, myosin II, and actin modulators in the ring in its native state. Fundamental questions such as how actin filaments are assembled and organized into a ring remain actively debated. This project will investigate key issues pertaining to cytokinesis in the fission yeast Schizosaccharomyces pombe, which divides employing an actomyosin based contractile ring, using the methods of genetics, biochemistry, cellular imaging, DNA origami, genetic code expansion, and click chemistry. Specifically, we will (1) attempt to visualize actin filament assembly in live cells expressing fluorescent actin generated through synthetic biological approaches, including genetic code expansion and click chemistry (2) decipher actin filament polarity in the actomyosin ring using total internal reflection fluorescence microscopy of labelled dimeric and multimeric myosins V and VI generated through DNA origami approaches (3) address when, where, and how actin filaments for cytokinesis are assembled and organized into a ring and (4) reconstitute actin filament and functional actomyosin ring assembly in permeabilized spheroplasts and in supported bilayers. Success in the project will provide major insight into the mechanism of actomyosin ring assembly and illuminate principles behind cytoskeletal self-organization.

2 863 705 €

Start date: 2015-11-01, End date: 2020-10-31

What processes shape vertebrate diversity through deep time? Approaches to this question can focus on many different factors, from life history and ecology to large-scale environmental change and extinction. To date, the majority of studies on the evolution of vertebrate diversity have focused on relatively simple metrics, specifically taxon counts or univariate measures, such as body size. However, multivariate morphological data provides a more complete picture of evolutionary and palaeoecological change. Morphological data can also bridge deep-time palaeobiological analyses with studies of the genetic and developmental factors that shape variation and must also influence large-scale patterns of evolutionary change. Thus, accurately reconstructing the patterns and processes underlying evolution requires an approach that can fully represent an organism’s phenome, the sum total of their observable traits. Recent advances in imaging and data analysis allow large-scale study of phenomic evolution. In this project, I propose to quantitatively analyse the deep-time evolutionary diversity of tetrapods (amphibians, reptiles, birds, and mammals). Specifically, I will apply and extend new imaging, morphometric, and analytical tools to construct a multivariate phenomic dataset for living and extinct tetrapods from 3-D scans. I will use these data to rigorously compare extinction selectivity, timing, pace, and shape of adaptive radiations, and ecomorphological response to large-scale climatic shifts across all tetrapod clades. To do so, I will quantify morphological diversity (disparity) and rates of evolution spanning over 300 million years of tetrapod history. I will further analyse the evolution of phenotypic integration by quantifying not just the traits themselves, but changes in the relationships among traits, which reflect the genetic, developmental, and functional interactions that shape variation, the raw material for natural selection.

1 482 818 €

Start date: 2015-06-01, End date: 2020-05-31

Advanced insight into ever smaller structures of matter and their ever faster dynamics hold promise for pushing the frontiers of many fields in science and technology. Time-domain investigations of ultrafast microscopic processes are most successfully carried out by pump/probe experiments. Intense waveform-controlled few-cycle near-infrared laser pulses combined with isolated sub-femtosecond XUV (extreme UV) pulses have made possible direct access to electron motion on the atomic scale. These tools along with the techniques of laser-field-controlled XUV photoemission (“attosecond streaking”) and ultrafast UV-pump/XUV-probe spectroscopy have permitted real-time observation of electronic motion in experiments performed on atoms in the gas phase and of electronic transport processes in solids. The purpose of this project is to to get insight into intra- and inter-molecular electron dynamics by extending attosecond spectroscopy to these processes. AEDMOS will allow control and real-time observation of a wide range of hyperfast fundamental processes directly on their natural, i.e. attosecond (1 as = EXP-18 s) time scale in molecules and molecular structures. In previous work we have successfully developed attosecond tools and techniques. By combining them with our experience in UHV technology and target preparation in a new beamline to be created in the framework of this project, we aim at investigating charge migration and transport in supramolecular assemblies, ultrafast electron dynamics in photocatalysis and dynamics of electron correlation in high-TC superconductors. These dynamics – of electronic excitation, exciton formation, relaxation, electron correlation and wave packet motion – are of broad scientific interest reaching from biomedicine to chemistry and physics and are pertinent to the development of many modern technologies including molecular electronics, optoelectronics, photovoltaics, light-to-chemical energy conversion and lossless energy transfer.

1 999 375 €

Start date: 2015-05-01, End date: 2020-04-30

Alkenones are algal lipids that have been used for decades to reconstruct quantitative past sea surface temperature. Although alkenones are being discovered in an increasing number of lake sites worldwide, only two terrestrial temperature records have been reconstructed so far. The development of this research field is limited by the lack of interdisciplinary research that combines modern biological and ecological algal research with the organic geochemical techniques needed to develop a quantitative biomarker (or molecular fossil) for past lake temperatures. More research is needed for alkenones to become a widely used tool for reconstructing past terrestrial temperature change. The early career Principal Investigator has discovered a new lake alkenone-producing species of haptophyte algae that produces alkenones in high abundances both in the environment and in laboratory cultures. This makes the new species an ideal organism for developing a culture-based temperature calibration and exploring other potential environmental controls. In this project, alkenone production will be manipulated, and monitored using state-of-the-art photobioreactors with real-time detectors for cell density, light, and temperature. The latest algal culture and isolation techniques that are used in microalgal biofuel development will be applied to developing the lake temperature proxy. The objectives will be achieved through the analysis of 90 new Canadian lakes to develop a core-top temperature calibration across a large latitudinal and temperature gradient (Δ latitude = 5°, Δ spring surface temperature = 9°C). The results will be used to assess how regional palaeo-temperature (Uk37), palaeo-moisture (δDwax) and palaeo-evaporation (δDalgal) respond during times of past global warmth (e.g., Medieval Warm Period, 900-1200 AD) to find an accurate analogue for assessing future drought risk in the interior of Canada.

940 883 €

Start date: 2015-04-01, End date: 2020-03-31

Methane, a key greenhouse gas, is cycled by microorganisms via two pathways, aerobically and anaerobically. Research on the marine methane cycle has mainly concentrated on anaerobic processes. Recent biomarker work has provided compelling evidence that aerobic methane oxidation (AMO) can play a more significant role in cycling methane emitted from sediments than previously considered. AMO, however, is not well studied requiring novel proxies that can be applied to the sedimentary record. A group of complex lipids biosynthesised by aerobic methanotrophs known as aminobacteriohopanepolyols represent an ideal target for developing such poxies. Recently BHPs have been identified in a wide range of modern and recent environments including a continuous record from the Congo deep sea fan spanning the last 1.2 million years. In this integrated study, the regulation and expression of BHP will be investigated and calibrated against environmental variables including temperature, pH, salinity and, most importantly, methane concentrations. The work program has three complementary strands. (1) Pure culture and sedimentary microcosm experiments providing an approximation to natural conditions. (2) Calibration of BHP signatures in natural marine settings (e.g. cold seeps, mud volcanoes, pockmarks) against measured methane gradients. (3) Application of this novel approach to the marine sedimentary record to approximate methane fluxes in the past, explore the age and bathymetric limits of this novel molecular proxy, and identify and potentially 14C date palaeo-pockmarks structures. Crucial to the success is also the refinement of the analytical protocols to improve both accuracy and sensitivity, using a more sensitive analytical instrument (triple-quadrupole mass spectrometer).

1 496 392 €

Start date: 2010-11-01, End date: 2016-04-30

Allocation Made PracticaL The AMPLify project will lay the foundations of a new field, computational behavioural game theory that brings a computational perspective, computational implementation, and behavioural insights to game theory. These foundations will be laid by tackling a pressing problem facing society today: the efficient and fair allocation of resources and costs. Research in allocation has previously considered simple, abstract models like cake cutting. We propose to develop richer models that capture important new features like asynchronicity which occur in many markets being developed in our highly connected and online world. The mechanisms currently used to allocate resources and costs are limited to these simple, abstract models and also do not take into account how people actually behave in practice. We will therefore design new mechanisms for these richer allocation problems that exploit insights gained from behavioural game theory like loss aversion. We will also tackle the complexity of these rich models and mechanisms with computational tools. Finally, we will use computation to increase both the efficiency and fairness of allocations. As a result, we will be able to do more with fewer resources and greater fairness. Our initial case studies in resource and cost allocation demonstrate that we can improve efficiency greatly, offering one company alone savings of up to 10% (which is worth tens of millions of dollars every year). We predict even greater impact with the more sophisticated mechanisms to be developed during the course of this project.

2 499 681 €

Start date: 2016-06-01, End date: 2021-05-31

This project is a comparative anthropology of conscience, ethics and human rights. Numerous international human rights documents formally declare their commitment to protect freedom of conscience. But, what is conscience and how do we know it when we see it? How do we distinguish it from self-interest or fanaticism? And what happens when the concept, often associated with a distinct Christian or liberal history, travels across cultural boundaries? The project will examine the cultural conditions under which claims to conscience are made possible, and the types of claims that are most persuasive when doing so. The project addresses these issues through the comparative analysis of three case studies: British pacifists, Sri Lankan activists, and Soviet dissidents. These case studies have been carefully chosen to provide globally significant, but contrasting examples of contests over the implications of claims to conscience. If claims of conscience are often associated with a specifically liberal and Christian tradition, mid-twentieth century Britain can be said to stand at the centre of that tradition. Sri Lanka represents a particularly fraught post-colonial South Asian counterpoint, wracked by nationalist violence, and influenced by ethical traditions associated with forms of Hinduism and Buddhism. Soviet Russia represents a further contrast, a totalitarian regime, where atheism was the dominant ethical language. Finally, the project will return specifically to international human rights institutions, examining the history of the category of conscience in the UN human rights system. This project will be ground breaking, employing novel methods and analytical insights, in order to producing the first comparative analysis of the cultural and political salience of claims of conscience. In doing so, the research aims to transform our understandings of the limits and potentials of attempts to protect freedom of conscience.

1 457 869 €

Start date: 2015-08-01, End date: 2020-07-31

This project will engineer an injectable biomaterial that forms an anisotropic microheterogeneous structure in vivo. Injectable hydrogels enable a minimal invasive in situ generation of matrices for the regeneration of tissues and organs, but currently lack structural organization and unidirectional orientation. The anisotropic, injectable hydrogels to be developed will mimic local extracellular matrix architectures that cells encounter in complex tissues (e.g. nerves, muscles). This project aims for the development of a biomimetic scaffold for spinal cord regeneration. To realize such a major breakthrough, my group will focus on three research objectives. i) Poly(ethylene glycol) microgel-in-hydrogel matrices will be fabricated with the ability to create macroscopic order due to microgel shape anisotropy and magnetic alignment. Barrel-like microgels will be prepared using an in-mold polymerization technique. Their ability to self-assemble will be investigated in function of their dimensions, aspect ratio, crosslinking density, and volume fraction. Superparamagnetic nanoparticles will be included into the microgels to enable unidirectional orientation by means of a magnetic field. Subsequently, the oriented microgels will be interlocked within a master hydrogel. ii) The microgel-in-hydrogel matrices will be equipped with (bio)functional properties for spinal cord regeneration, i.e., to control and optimize mechanical anisotropy and biological signaling by in vitro cell growth experiments. iii) Selected hydrogel composites will be injected after rat spinal cord injury and directional tissue growth and animal functional behavior will be analyzed. Succesful fabrication of the proposed microgel-in-hydrogel matrix will provide a new type of biomaterial, which enables investigating the effect of an anisotropic structure on physiological and pathological processes in vivo. This is a decisive step towards creating a clinical healing matrix for anisotropic tissue repair.

1 435 396 €

Start date: 2015-03-01, End date: 2020-02-29

This is a proposal for research at the interface of analytic number theory, automorphic forms and algebraic geometry. Motivated by fundamental conjectures in number theory, classical problems will be investigated in higher order situations: general number fields, automorphic forms on higher rank groups, the arithmetic of algebraic varieties of higher degree. In particular, I want to focus on - computation of moments of L-function of degree 3 and higher with applications to subconvexity and/or non-vanishing, as well as subconvexity for multiple L-functions; - bounds for sup-norms of cusp forms on various spaces and equidistribution of Hecke correspondences; - automorphic forms on higher rank groups and general number fields, in particular new bounds towards the Ramanujan conjecture; - a proof of Manin's conjecture for a certain class of singular algebraic varieties. The underlying methods are closely related; for example, rational points on algebraic varieties will be counted by a multiple L-series technique.

1 004 000 €

Start date: 2010-10-01, End date: 2015-09-30

Within a 12 month period, 20% of adults will meet criteria for one or more clinical anxiety disorders (ADs). These disorders are hugely disruptive, placing an emotional burden on individuals and their families. While both cognitive behavioural therapy and pharmacological treatment are widely viewed as effective strategies for managing ADs, systematic review of the literature reveals that only 30–45% of patients demonstrate a marked response to treatment (anxiety levels being reduced into the nonaffected range). In addition, a significant proportion of initial responders relapse after treatment is discontinued. There is hence a real and marked need to improve upon current approaches to AD treatment. One possible avenue for improving response rates is through optimizing initial treatment selection. Specifically, it is possible that certain individuals might respond better to cognitive interventions while others might respond better to pharmacological treatment. Recently it has been suggested that there may be two or more distinct biological pathways disrupted in anxiety. If this is the case, then specification of these pathways may be an important step in predicting which individuals are likely to respond to which treatment. Few studies have focused upon this issue and, in particular, upon identifying neural markers that might predict response to cognitive (as opposed to pharmacological) intervention. The proposed research aims to address this. Specifically, it tests the hypothesis that there are at least two mechanisms disrupted in ADs, one entailing amygdala hyper-responsivity to cues that signal threat, the other impoverished recruitment of frontal regions that support cognitive and emotional regulation. Two series of functional magnetic resonance imaging experiments will be conducted. These will investigate differences in amygdala and frontal function during (a) attentional processing and (b) fear conditioning. Initial clinical experiments will investigate whether Generalised Anxiety Disorder and Specific Phobia involve differing degrees of disruption to frontal versus amygdala function during these tasks. This work will feed into training studies, the goal being to characterize AD patient subgroups that benefit from cognitive training.

1 708 407 €

Start date: 2011-04-01, End date: 2016-08-31

The project is the first comprehensive study to assess contemporary parenting norms and practices and their diffusion. The project develops a comparative framework to study prevalent motherhood and fatherhood norms, images, identities and behaviour in current societies. The project will focus on how parenting roles are constructed by professionals, welfare states, and popular media, and will assess how cultural and institutional norms and images are perceived and realized by expecting and new parents. In 4 subprojects this study investigates 1) How standards of 'good' mothering and fathering are perceived, shaped and disseminated by professionals (gynaecologists, midwives, family councils); 2) How welfare states, labour markets and family policies target at mothers and fathers roles as earners and care givers, and how this has changed in recent decades; 3) How images of mothers and fathers roles have been portrayed in print media from 1980 until 2010; 4) How (expecting) mothers and fathers perceive, embody and represent parenting norms and images in their own work and family roles; 5) How new parents divide paid and unpaid work and how these divisions shape career patterns over the life course; 6) How these patterns differ cross-nationally. The international collaboration includes Sweden, the Netherlands, Germany, Italy, the Czech Republic, and Poland. The aim of this project is to develop a contemporary sociology of adult sex roles and parenting norms: A theory of the social creation of parenting norms and a comprehensive framework to study empirically the change of men's and women's roles, identities and practices as earners and care givers in the early phase of family formation. By combining expert interviews, policy analysis and content analysis of print media with analyses of qualitative and quantitative data on (nascent) parents, the project will address the diverse layers associated with changing gender roles and parenting norms over the adult life course.

1 393 751 €

Start date: 2011-01-01, End date: 2016-12-31

Based on wide-ranging sources, the project studies artistic training in pre-modern Central Europe. Up to the end of the Holy Roman Empire, the study area experienced various sizes with changing borders and different linguistic areas and jurisdictions. The project explores these aspects, referring to current research on culture-historical geography. Moreover, it will examine and, in some cases, revise the one-sided negative image of the guilds, using the example of research into historical networks and components of the dynamism of personal associations developed by neighbouring disciplines: Guild structure is viewed at times as an all-embracing, tightly knit network that permitted artists to exchange ideas and move freely and establish art markets. The cross-border research approach thus complements for the first time the historical idea of the artist as a model in social history. Up to about 1800, the artist was part of the hierarchical European society; except for the court artist, he was an artisan bound to the guilds. Numerous attempts to institutionalise artistic training and transfer it to academies succeeded only when the guilds were dissolved under Napoleon. An edition of all German-language guild and artisan regulations in Central Europe will make a hitherto little noted source type of major relevance accessible to research. One aim is to assemble a critical corpus of historical sources structured according to cities, a second, to analyse the social historical contexts, among them, synergy effects of “artistic knowledge” and training practices, the artist’s social and territorial mobility and the gender-specific inclusions and exclusions in pre-modern workshop operations. In terms of globalisation, the project can overcome topographical, methodological and content-related borders in all directions and lay the foundation for a comprehensive analysis of all of European artistic training.

1 665 117 €

Start date: 2011-06-01, End date: 2016-05-31

Fifteen years ago it was widely believed that asthma was an allergic/atopic disease caused by allergen exposure in infancy; this produced atopic sensitization and continued exposure resulted in eosinophilic airways inflammation, bronchial hyper-responsiveness and reversible airflow obstruction. It is now clear that this model is at best incomplete. Less than one-half of asthma cases involve allergic (atopic) mechanisms, and most asthma in low-and-middle income countries is non-atopic. Westernization may be contributing to the global increases in asthma prevalence, but this process appears to involve changes in asthma susceptibility rather than increased exposure to “established” asthma risk factors. Understanding why these changes are occurring is essential in order to halt the growing global asthma epidemic.This will require a combination of epidemiological, clinical and basic science studies in a variety of environments. A key task is to reclassify asthma phenotypes. These are important to: (i) better understand the aetiological mechanisms of asthma; (ii) identify new causes; and (iii) identify new therapeutic measures. There are major opportunities to address these issues using new techniques for sample collection from the airways (sputum induction, nasal lavage), new methods of analysis (microbiome, epigenetics), and new bioinformatics methods for integrating data from multiple sources and levels. There is an unprecedented potential to go beyond the old atopic/non-atopic categorization of phenotypes. I will therefore conduct analyses to re-examine and reclassify asthma phenotypes. The key features are the inclusion of: (i) both high and low prevalence centres from both high income countries and low-and-middle income countries; (ii) much more detailed biomarker information than has been used for previous studies of asthma phenotypes; and (iii) new bioinformatics methods for integrating data from multiple sources and levels.

2 348 803 €

Start date: 2016-01-01, End date: 2020-12-31

The Large Hadron collider (LHC) at CERN will be a milestone for the understanding of fundamental interactions and for the future of high energy physics. Four large experiments at the LHC are complementarily addressing the question of the origin of our Universe by searching for so-called New Physics. The world of particles and their interactions is nowadays described by the Standard Model. Up to now there is no single measurement from laboratory experiments which contradicts this theory. However, there are still many open questions, thus physicists are convinced that there is a more fundamental theory, which incorporates New Physics. It is expected that at the LHC either New Physics beyond the Standard Model will be discovered or excluded up to very high energies, which would revolutionize the understanding of particle physics and require completely new experimental and theoretical concepts. The LHCb (Large Hadron Collider beauty) experiment is dedicated to precision measurements of B hadrons (B hadrons are all particles containing a beauty quark). The analysis proposed here is the measurement of asymmetries between B_s particles and anti-B_s particles at the LHCb experiment. Any New Physics model will change the rate of observable processes via additional quantum corrections. Particle antiparticle asymmetries are extremely sensitive to these corrections thus a very powerful tool for indirect searches for New Physics contributions. In the past, most of the ground-breaking findings in particle physics, such as the existence of the charm quark and the existence of a third quark family, have first been observed in indirect searches. First - still statistically limited - measurements of the asymmetry in the B_s system indicate a 2 sigma deviation from the Standard Model prediction. A precision measurement of this asymmetry is potentially the first observation for New Physics beyond the Standard Model at the LHC. If no hint for New Physics will be found, this measurement will severely restrict the range of potential New Physics models.

1 059 240 €

Start date: 2011-01-01, End date: 2015-12-31

In order for electronics to meet the ever raising demands for higher speeds of operation, the dimensions of its basic elements drop continuously. This miniaturization, that will soon meet the dimensions of a single molecule or an atom, calls for new approaches in electronics that take advantage, rather than confront the dominant at these scales quantum laws. Electronics on the scale of atoms and molecules require fields that are able to trigger and to steer electrons at speeds comparable to their intrinsic dynamics, determined by the quantum mechanical laws. For the valence electrons of atoms and molecules, this motion is clocked in tens to thousands of attoseconds, (1 as =10-18 sec) implying the potential for executing basic electronic operations in the PHz regime and beyond. This is approximately ~1000000 times faster as compared to any contemporary technology. To meet this challenging goal, this project will utilize conceptual and technological advances of attosecond science as its primary tools. First, pulses of light, the fields of which can be sculpted and characterized with attosecond accuracy, for triggering as well as for terminating the ultrafast electron motion in an atom or a molecule. Second, attosecond pulses in the extreme ultraviolet, which can probe and frame-freeze the created electron motion, with unprecedented resolution, and determine the direction and the magnitude of the created currents. This project will interrogate the limits of the fastest electronic motion that light fields can trigger as well as terminate, a few hundreds of attoseconds later, in an atom or a molecule. In this way it aims to explore new routes of atomic and molecular scale electronic switching at PHz frequencies.

1 262 000 €

Start date: 2010-12-01, End date: 2016-11-30

There is an intense interest in the function of human Myc proteins that stems from their pervasive role in the genesis of human tumors. A large body of evidence has established that expression levels of one of three closely related Myc proteins are enhanced in the majority of all human tumors and that multiple tumor entities depend on elevated Myc function, arguing that targeting Myc will have significant therapeutic efficacy. This hope awaits clinical confirmation, since the strategies that are currently under investigation to target Myc function or expression have yet to enter the clinic. Myc proteins are global regulators of transcription, but their mechanism of action is poorly understood. Myc proteins are highly unstable in normal cells and rapidly turned over by the ubiquitin/proteasome system. In contrast, they are stabilized in tumor cells. Work by us and by others has shown that stabilization of Myc is required for tumorigenesis and has identified strategies to destabilize Myc for tumor therapy. This work has also led to the surprising observation that the N-Myc protein, which drives neuroendocrine tumorigenesis, is stabilized by association with the Aurora-A kinase and that clinically available Aurora-A inhibitors can dissociate the complex and destabilize N-Myc. Aurora-A has not previously been implicated in transcription, prompting us to use protein crystallography, proteomics and shRNA screening to understand its interaction with N-Myc. We have now identified a novel protein complex of N-Myc and Aurora-A that provides an unexpected and potentially groundbreaking insight into Myc function. We have also solved the crystal structure of the N-Myc/Aurora-A complex. Collectively, both findings open new strategies to target Myc function for tumor therapy.

2 455 180 €

Start date: 2015-08-01, End date: 2020-07-31

It has long been understood that genes contribute to phenotypes that are then the basis of selection. However, the nature and process of this relationship remains largely theoretical, and the relative contribution of change in gene expression and coding sequence to phenotypic diversification is unclear. The aim of this proposal is to fuse information about sexually dimorphic phenotypes, the mating systems and sexually antagonistic selective agents that shape sexual dimorphism, and the sex-biased gene expression patterns that encode sexual dimorphisms, in order to create a cohesive integrated understanding of the relationship between evolution, the genome, and the animal form. The primary approach of this project is to harnesses emergent DNA sequencing technologies in order to measure evolutionary change in gene expression and coding sequence in response to different sex-specific selection regimes in a clade of birds with divergent mating systems. Sex-specific selection pressures arise in large part as a consequence of mating system, however males and females share nearly identical genomes, especially in the vertebrates where the sex chromosomes house very small proportions of the overall transcriptome. This single shared genome creates sex-specific phenotypes via different gene expression levels in females and males, and these sex-biased genes connect sexual dimorphisms, and the sexually antagonistic selection pressures that shape them, with the regions of the genome that encode them. The Galloanserae (fowl and waterfowl) will be used to in the proposed project, as this clade combines the necessary requirements of both variation in mating systems and a well-conserved reference genome (chicken). The study species selected from within the Galloanserae for the proposal exhibit a range of sexual dimorphism and sperm competition, and this will be exploited with next generation (454 and Illumina) genomic and transcriptomic data to study the gene expression patterns that underlie sexual dimorphisms, and the evolutionary pressures acting on them. This work will be complemented by the development of mathematical models of sex-specific evolution that will be tested against the gene expression and gene sequence data in order to understand the mechanisms by which sex-specific selection regimes, arising largely from mating systems, shape the phenotype via the genome.

1 350 804 €

Start date: 2011-01-01, End date: 2016-07-31

In the human brain, the 'bottleneck' of neuronal integrity are long axonal projections, which are often the first to degenerate in neuro-psychiatric diseases. We have discovered in mice that oligodendrocytes and Schwann cells are not only essential for the formation of myelin, but also for the functional integrity of axons and their long-term survival. However, the underlying molecular mechanisms have remained obscure. We propose to use experimental mouse genetics to study neuron-glia interactions and to identify axonal signals that control the normal behaviour of myelinating oligodendrocytes. We will then test our hypothesis that axons require oligodendrocytes not only for myelination, but also for the metabolic support of impulse propagation and fast axonal transport. Based on striking pilot observations, we will analyze the mechanisms by which ensheathing glial cells respond to axonal distress and ask in vivo whether they provide glycolysis end products to axonal mitochondria for energy production ('lactate shuttle'). We will also investigate whether myelin lipids are a readily accessible energy store in glia and explore a speculative hypothesis that N-acetyl aspartate is an aspartate-based shuttle of acetyl-CoA residues. If this proposal is successful, we will begin to understand the true function of oligodendrocytes in endogenous neuroprotection and as bystanders of neuronal disease and normal brain aging. This would initiate a paradigm shift for the role of myelinating glial cells, and could open the door for novel therapeutic strategies in a broad range of neurodegenerative diseases, which pose a major burden on the EC health care system.

2 477 800 €

Start date: 2011-04-01, End date: 2016-03-31

The production of antibodies against pathogens is an effective mechanism of protection against a wide range of infections. However, some pathogens evade antibody responses by rapidly changing their composition. Designing vaccines that elicit antibody responses against invariant parts of the pathogen is a rational strategy to combat existing and emerging pathogens. Production of antibodies is initiated by binding of B cell receptors (BCRs) to foreign antigens presented on the surfaces of antigen presenting cells. This binding induces B cell signalling and internalisation of the antigens for presentation to helper T cells. Although it is known that T cell help controls B cell expansion and differentiation into antibody-secreting and memory B cells, how the strength of antigen binding to the BCR regulates antigen internalisation remains poorly understood. As a result, the response and the affinity maturation of individual B cell clones are difficult to predict, posing a problem for the design of next-generation vaccines. My aim is to develop an understanding of the cellular mechanisms that underlie critical B cell activation steps. My laboratory has recently described that B cells use mechanical forces to extract antigens from antigen presenting cells. We hypothesise that application of mechanical forces tests BCR binding strength and thereby regulates B cell clonal selection during antibody affinity maturation and responses to pathogen evasion. We propose to test this hypothesis by (1) determining the magnitude and timing of the forces generated by B cells, and (2) determining the role of the mechanical properties of BCR-antigen bonds in affinity maturation and (3) in the development of broadly neutralising antibodies. We expect that the results of these studies will contribute to our understanding of the mechanisms that regulate the antibody repertoire in response to infections and have practical implications for the development of vaccines.

1 999 386 €

Start date: 2015-09-01, End date: 2020-08-31