ERC FUNDED PROJECTS

The applicant will collaborate with Irish, European and U.S.-based colleagues to develop a sustainable biorefinery and bioenergy industry in Ireland and Europe. The focus of this ERC Starting Grant will be the application of classical microbiological, physiological and real-time polymerase chain reaction (PCR)-based assays, to qualitatively and quantitatively characterize microbial communities underpinning novel and innovative, low-temperature, anaerobic waste (and other biomass) conversion technologies, including municipal wastewater treatment and, demonstration- and full-scale biorefinery applications. Anaerobic digestion (AD) is a naturally-occurring process, which is widely applied for the conversion of waste to methane-containing biogas. Low-temperature (<20 degrees C) AD has been applied by the applicant as a cost-effective alternative to mesophilic (c. 35C) AD for the treatment of several waste categories. However, the microbiology of low-temperature AD is poorly understood. The applicant will work with microbial consortia isolated from anaerobic bioreactors, which have been operated for long-term experiments (>3.5 years), and include organic acid-oxidizing, hydrogen-producing syntrophic microbes and hydrogen-consuming methanogens. A major focus of the project will be the ecophysiology of psychrotolerant and psychrophilic methanogens already identified and cultivated by the applicant. The project will also investigate the role(s) of poorly-understood Crenarchaeota populations and homoacetogenic bacteria, in complex consortia. The host organization is a leading player in the microbiology of waste-to-energy applications. The applicant will train a team of scientists in all aspects of the microbiology and bioengineering of biomass conversion systems.

1 499 797 €

Start date: 2011-05-01, End date: 2016-04-30

Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations: - First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37); - Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells (Turk et al.,Cancer Res, 2009. 69(21)); - Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15); - Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204). I propose a comprehensive series of studies that will address thefollowing critical questions: - First, what is the scope of MDR-selective compounds? - Second, what is their mechanism of action? - Third, what is the optimal therapeutic modality? Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.

1 499 640 €

Start date: 2012-01-01, End date: 2016-12-31

This project aims at designing novel hybrid nanophotonic devices comprising metallic nanostructures and active elements such as dye molecules or colloidal quantum dots. Three core objectives, each going far beyond the state of the art, shall be tackled: (i) Metamaterials containing gain materials: Metamaterials introduce magnetism to the optical frequency range and hold promise to create entirely novel devices for light manipulation. Since present day metamaterials are extremely absorptive, it is of utmost importance to fight losses. The ground-breaking approach of this proposal is to incorporate fluorescing species into the nanoscale metallic metastructures in order to compensate losses by stimulated emission. (ii) The second objective exceeds the ansatz of compensating losses and will reach out for lasing action. Individual metallic nanostructures such as pairs of nanoparticles will form novel and unusual nanometre sized resonators for laser action. State of the art microresonators still have a volume of at least half of the wavelength cubed. Noble metal nanoparticle resonators scale down this volume by a factor of thousand allowing for truly nanoscale coherent light sources. (iii) A third objective concerns a substantial improvement of nonlinear effects. This will be accomplished by drastically sharpened resonances of nanoplasmonic devices surrounded by active gain materials. An interdisciplinary team of PhD students and a PostDoc will be assembled, each scientist being uniquely qualified to cover one of the expertise fields: Design, spectroscopy, and simulation. The project s outcome is twofold: A substantial expansion of fundamental understanding of nanophotonics and practical devices such as nanoscopic lasers and low loss metamaterials.

1 494 756 €

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

The colonisation of Europe by anatomically modern humans (AMHs) ca. 45,000 years before present (BP) and the transition to farming ca. 8,000 BP are two major events in human prehistory. Both events involved certain cultural and biological adaptations, technological innovations, and behavioural plasticity which are unique to our species. The reconstruction of these processes and the causality between them has so far remained elusive due to technological, methodological and logistical complexities. Major developments in our understanding of the anthropology of the Upper Palaeolithic, Mesolithic and Neolithic, and advances in ancient DNA (aDNA) technology and chronometric methods now allow us to assess in sufficient resolution the interface between these evolutionary processes, and changes in human culture and behaviour. The proposed research will investigate the complex interface between the morphological, genetic, behavioural, and cultural factors that shaped the population history of European AMHs. The PI s interdisciplinary expertise in these areas, his access to and experience of relevant skeletal collections, and his ongoing European collaborations will allow significant progress in addressing these fundamental questions. The approach taken will include (a) the collection of bioarchaeological, aDNA, stable isotope (for the analysis of ancient diet) and radiometric data on 500 skeletons from key sites/phases in Europe and western Anatolia, and (b) the application of existing and novel aDNA, bioarchaeological and simulation methodologies. This research will yield results that transform our current understanding of major demographic and evolutionary processes and will place Europe at the forefront of anthropological biological and genetic research.

1 088 386 €

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

Interferometers are fundamental tools for the study of nature laws and for the precise measurement and control of the physical world. In the last century, the scientific and technological progress has proceeded in parallel with a constant improvement of interferometric performances. For this reason, the challenge of conceiving and realizing new generations of interferometers with broader ranges of operation and with higher sensitivities is always open and actual. Despite the introduction of laser devices has deeply improved the way of developing and performing interferometric measurements with light, the atomic matter wave analogous, i.e. the Bose-Einstein condensate (BEC), has not yet triggered any revolution in precision interferometry. However, thanks to recent improvements on the control of the quantum properties of ultra-cold atomic gases, and new original ideas on the creation and manipulation of quantum entangled particles, the field of atom interferometry is now mature to experience a big step forward. The system I want to realize is a Mach-Zehnder spatial interferometer operating with trapped BECs. Undesired decoherence sources will be suppressed by implementing BECs with tunable interactions in ultra-stable optical potentials. Entangled states will be used to improve the sensitivity of the sensor beyond the standard quantum limit to ideally reach the ultimate, Heisenberg, limit set by quantum mechanics. The resulting apparatus will show unprecedented spatial resolution and will overcome state-of-the-art interferometers with cold (non condensed) atomic gases. A successful completion of this project will lead to a new generation of interferometers for the immediate application to local inertial measurements with unprecedented resolution. In addition, we expect to develop experimental capabilities which might find application well beyond quantum interferometry and crucially contribute to the broader emerging field of quantum-enhanced technologies.

1 068 000 €

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

The field of disordered quantum gases is developing rapidly. Dramatic progress has been achieved recently and first experimental observation of one-dimensional Anderson localization (AL) of matterwaves has been reported using Bose-Einstein condensates in controlled disorder (in our group at Institut d'Optique and at LENS; Nature, 2008). This dramatic success results from joint theoretical and experimental efforts, we have contributed to. Most importantly, it opens unprecedented routes to pursue several outstanding challenges in the multidisciplinary field of disordered systems, which, after fifty years of Anderson localization, is more active than ever. This theoretical project aims at further developing the emerging field of disordered quantum gases towards novel challenges. Our aim is twofold. First, we will propose and analyze schemes where experiments on ultracold atoms can address unsolved issues: AL in dimensions higher than one, effects of inter-atomic interactions on AL, strongly-correlated disordered gases and quantum simulators for spin systems (spin glasses). Second, by taking into account specific features of ultracold atoms, beyond standard toy-models, we will raise and study new questions which have not been addressed before (eg long-range correlations of speckle potentials, finite-size effects, controlled interactions). Both aspects would open new frontiers to disordered quantum gases and offer new possibilities to shed new light on highly debated issues. Our main concerns are thus to (i) study situations relevant to experiments, (ii) develop new approaches, applicable to ultracold atoms, (iii) identify key observables, and (iv) propose new challenging experiments. In this project, we will benefit from the original situation of our theory team: It is independent but forms part of a larger group (lead by A. Aspect), which is a world-leader in experiments on disordered quantum gases, we have already developed close collaborative relationship with.

985 200 €

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

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

The overall goal of this project is to develop new concepts and techniques in geometric and asymptotic group theory for a systematic study of the analytic properties of discrete groups. These are properties depending on the unitary representation theory of the group. The fundamental examples are amenability, discovered by von Neumann in 1929, and property (T), introduced by Kazhdan in 1967. My main objective is to establish the precise relations between groups recently appeared in K-theory and topology such as C*-exact groups and groups coarsely embeddable into a Hilbert space, versus those discovered in ergodic theory and operator algebra, for example, sofic and hyperlinear groups. This is a first ever attempt to confront the analytic behavior of so different nature. I plan to work on crucial open questions: Is every coarsely embeddable group C*-exact? Is every group sofic? Is every hyperlinear group sofic? My motivation is two-fold: - Many outstanding conjectures were recently solved for these groups, e.g. the Novikov conjecture (1965) for coarsely embeddable groups by Yu in 2000 and the Gottschalk surjunctivity conjecture (1973) for sofic groups by Gromov in 1999. However, their group-theoretical structure remains mysterious. - In recent years, geometric group theory has undergone significant changes, mainly due to the growing impact of this theory on other branches of mathematics. However, the interplay between geometric, asymptotic, and analytic group properties has not yet been fully understood. The main innovative contribution of this proposal lies in the interaction between 3 axes: (i) limits of groups, in the space of marked groups or metric ultralimits; (ii) analytic properties of groups with curvature, of lacunary or relatively hyperbolic groups; (iii) random groups, in a topological or statistical meaning. As a result, I will describe the above apparently unrelated classes of groups in a unified way and will detail their algebraic behavior.

1 065 500 €

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

The analysis of geometric and functional inequalities naturally leads to consider the extremal cases, thus looking for optimal sets, or optimal functions, or optimal constants. The most classical examples are the (different versions of the) isoperimetric inequality and the Sobolev-like inequalities. Much is known about equality cases and best constants, but there are still many questions which seem quite natural but yet have no answer. For instance, it is not known, even in the 2-dimensional space, the answer of a question by Brezis: which set, among those with a given volume, has the biggest Sobolev-Poincaré constant for p=1? This is a very natural problem, and it appears reasonable that the optimal set should be the ball, but this has never been proved. The interest in problems like this relies not only in the extreme simplicity of the questions and in their classical flavour, but also in the new ideas and techniques which are needed to provide the answers. The main techniques that we aim to use are fine arguments of symmetrization, geometric constructions and tools from mass transportation (which is well known to be deeply connected with functional inequalities). These are the basic tools that we already used to reach, in last years, many results in a specific direction, namely the search of sharp quantitative inequalities. Our first result, together with Fusco and Maggi, showed what follows. Everybody knows that the set which minimizes the perimeter with given volume is the ball. But is it true that a set which almost minimizes the perimeter must be close to a ball? The question had been posed in the 1920's and many partial result appeared in the years. In our paper (Ann. of Math., 2007) we proved the sharp result. Many other results of this kind were obtained in last two years.

540 000 €

Start date: 2010-08-01, End date: 2015-07-31

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 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

How can we create molecular life in the lab? That is, can we drive evolvable DNA/RNA-machines under a simple nonequilibrium setting? We will trigger basic forms of autonomous Darwinian evolution by implementing replication, mutation and selection on the molecular level in a single micro-chamber? We will explore protein-free replication schemes to tackle the Eigen-Paradox of replication and translation under archaic nonequilibrium settings. The conditions mimic thermal gradients in porous rock near hydrothermal vents on the early earth. We are in a unique position to pursue these questions due to our previous inventions of convective replication, optothermal molecule traps and light driven microfluidics. Four interconnected strategies are pursued ranging from basic replication using tRNA-like hairpins, entropic cooling or UV degradation down to protein-based DNA evolution in a trap, all with biotechnological applications. The approach is risky, however very interesting physics and biology on the way. We will: (i) Replicate DNA with continuous, convective PCR in the selection of a thermal molecule trap (ii) Replicate sequences with metastable, tRNA-like hairpins exponentially (iii) Build DNA complexes by structure-selective trapping to replicate by entropic decay (iv) Drive replication by Laser-based UV degradation Both replication and trapping are exponential processes, yielding in combination a highly nonlinear dynamics. We proceed along publishable steps and implement highly efficient modes of continuous molecular evolution. As shown in the past, we will create biotechnological applications from basic scientific questions (see our NanoTemper Startup). The starting grant will allow us to compete with Jack Szostak who very recently picked up our approach [JACS 131, 9628 (2009)].

1 487 827 €

Start date: 2010-08-01, End date: 2015-07-31

A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size. A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size.

1 445 000 €

Start date: 2010-09-01, End date: 2015-08-31

The use of renewable feedstocks by the chemical industry is fundamental due to both the depletion of fossil resources and the increasing pressure of environmental concerns. Biomass can act as a sustainable source of organic industrial chemicals; however, the establishment of a renewable chemical industry that is economically competitive with the present oil-based one requires the development of new processes to convert biomass-derived compounds into useful industrial materials following the principles of green chemistry. To achieve these goals, developments in several fields including heterogeneous catalysis are needed. One of the ways to accelerate the discovery of new potentially active, selective and stable catalysts is the massive use of computational chemistry. Recent advances have demonstrated that Density Functional Theory coupled to ab initio thermodynamics, transition state theory and microkinetic analysis can provide a full view of the catalytic phenomena. The aim of the present project is thus to employ these well-tested computational techniques to the development of a theoretical framework that can accelerate the identification of new catalysts for the conversion of biomass derived target compounds into useful chemicals. Since compared to petroleum-based materials-biomass derived ones are multifuncionalized, the search for new catalytic materials and processes has a strong requirement in the selectivity of the chemical transformations. The main challenges in the project are related to the high functionalization of the molecules, their liquid nature and the large number of potentially competitive reaction paths. The requirements of specificity and selectivity in the chemical transformations while keeping a reasonably flexible framework constitute a major objective. The work will be divided in three main work packages, one devoted to the properties of small molecules or fragments containing a single functional group; the second addresses competition in multiple functionalized molecules; and third is dedicated to the specific transformations of two molecules that have already been identified as potential platform generators. The goal is to identify suitable candidates that could be synthetized and tested in the Institute facilities.

1 496 200 €

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

This ERC-StG proposal, BIOMOF, outlines a dual strategy for the growth and processing of porous metal-organic framework (MOF) materials, inspired by the interfacial interactions that characterise highly controlled biomineralisation processes. The aim is to prepare MOF (bio)-composite materials of hierarchical structure and multi-modal functionality to address key societal challenges in healthcare, catalysis and energy. In order for MOFs to reach their full potential, a transformative approach to their growth, and in particular their processability, is required since the insoluble macroscopic micron-sized crystals resulting from conventional syntheses are unsuitable for many applications. The BIOMOF project defines chemically flexible routes to MOFs under mild conditions, where the added value with respect to wide-ranging experimental procedures for the growth and processing of crystalline controllably nanoscale MOF materials with tunable structure and functionality that display significant porosity for wide-ranging applications is extremely high. Theme 1 exploits protein vesicles and abundant biopolymer matrices for the confined growth of soluble nanoscale MOFs for high-end biomedical applications such as cell imaging and targeted drug delivery, whereas theme 2 focuses on the cost-effective preparation of hierarchically porous MOF composites over several length scales, of relevance to bulk industrial applications such as sustainable catalysis, separations and gas-storage. This diverse yet complementary range of applications arising simply from the way the MOF is processed, coupled with the versatile structural and physical properties of MOFs themselves indicates strongly that the BIOMOF concept is a powerful convergent new approach to applied materials chemistry.

1 492 970 €

Start date: 2010-11-01, End date: 2015-10-31

This research project investigates the dynamics of private and public property in contemporary biomedical research. It will develop an analytical framework combining insights from science and technology studies, economic sociology, and legal and political philosophy, and pursues a social scientific investigation of the evolution of intellectual property rights in three fields of bioscientific research: 1) the use of transgenic research mice; 2) the legal status of totipotent and pluripotent stem cell lines; and 3) modes of collaboration for research and development on neglected diseases. These three domains, and their attendant modes of appropriation, will be compared across three general research themes: a) the production of public scientific goods; b) categories of appropriation; and c) the moral economy of research. The project rests on close observation of research practices in these three domains. The BioProperty research programme will track the trajectories of property rights and property objects in each of the three fields of biomedical research.

887 602 €

Start date: 2011-03-01, End date: 2014-12-31

A fundamental feature of language is that it allows us to reproduce what others have said. It is traditionally assumed that there are two ways of doing this: direct discourse, where you preserve the original speech act verbatim, and indirect discourse, where you paraphrase it in your own words. In accordance with this dichotomy, linguists have posited a number of universal characteristics to distinguish the two modes. At the same time, we are seeing more and more examples that seem to fall somewhere in between. I reject the direct indirect distinction and replace it with a new paradigm of blended discourse. Combining insights from philosophy and linguistics, my framework has only one kind of speech reporting, in which a speaker always attempts to convey the content of the reported words from her own perspective, but can quote certain parts verbatim, thereby effectively switching to the reported perspective. To explain why some languages are shiftier than others, I hypothesize that a greater distance from face-to-face communication, with the possibility of extra- and paralinguistic perspective marking, necessitated the introduction of an artificial direct indirect separation. I test this hypothesis by investigating languages that are closely tied to direct communication: Dutch child language, as recent studies hint at a very late acquisition of the direct indirect distinction; Dutch Sign Language, which has a special role shift marker that bears a striking resemblance to the quotational shift of blended discourse; and Ancient Greek, where philologists have long been observing perspective shifts. In sum, my research combines a new philosophical insight on the nature of reported speech with formal semantic rigor and linguistic data from child language experiments, native signers, and Greek philology.

677 254 €

Start date: 2011-03-01, End date: 2016-08-31

While previous studies have investigated cell-signalling pathways that facilitate mechanotransduction and have provided a wealth of data, to date, in vivo mechanobiology is not fully understood. In the research study proposed the applicant will embark upon frontier research to delineate these specific aspects of bone mechanotransduction during normal physiology, disease and for tissue regeneration purposes. If these quantities were better understood the proposed research program will deliver significant advances in the understanding of the mechanical regulation of bone remodelling during normal physiology and osteoporosis, and will enhance approaches for regeneration of bone tissue for treatment of bone pathologies. The primary objective is to delineate the normal mechanosensory and signalling mechanisms of bone cells. The secondary objective is to determine whether the regulatory role of bone cells is inhibited or impaired during bone diseases such as osteoporosis. The final objective of this project is to develop an in vitro mechanical loading device that can enhance bone tissue regeneration and thereby advance current treatment approaches for bone pathologies. To address these objectives, five hypotheses have been defined, each of which will underpin the research of five work packages. A combination of experimental studies, using animal models and in vitro cell culture, and computational modelling will be taken to test each of these hypotheses. Answering these hypotheses will bring us closer to an understanding of the origins of bone mechanobiology and diseases such as osteoporosis. Furthermore, the results of these studies will facilitate development of novel approaches to enhance bone regeneration in vitro.

1 499 911 €

Start date: 2011-02-01, End date: 2016-01-31

The study of synthetic molecular networks is of fundamental importance for understanding the organizational principles of biological systems and may well be the key to unraveling the origins of life. In addition, such systems may be useful for parallel synthesis of molecules, implementation of catalysis via multi-step pathways, and as media for various applications in nano-medicine and nano-electronics. We have been involved recently in developing peptide-based replicating networks and revealed their dynamic characteristics. We argue here that the structural information embedded in the polypeptide chains is sufficiently rich to allow the construction of peptide 'Systems Chemistry', namely, to facilitate the use of replicating networks as cell-mimetics, featuring complex dynamic behavior. To bring this novel idea to reality, we plan to take a unique holistic approach by studying such networks both experimentally and via simulations, for elucidating basic-principles and towards applications in adjacent fields, such as molecular electronics. Towards realizing these aims, we will study three separate but inter-related objectives: (i) design and characterization of networks that react and rewire in response to external triggers, such as light, (ii) design of networks that operate via new dynamic rules of product formation that lead to oscillations, and (iii) exploitation of the molecular information gathered from the networks as means to control switching and gating in molecular electronic devices. We believe that achieving the project's objectives will be highly significant for the development of the arising field of Systems Chemistry, and in addition will provide valuable tools for studying related scientific fields, such as systems biology and molecular electronics.

1 500 000 €

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

Thanks to the recent advances in mapping brain activation during task performance using functional Magnetic Resonance Imaging (i.e., studying the brain in action), it is now possible to study one of the oldest questions in psychology: how the development of neural circuitry underlies the development of cognition and emotion. The ‘Storm and Stress’ of adolescence, a period during which adolescents develop cognitively with great speed but are also risk-takers and sensitive to opinions of their peer group, has puzzled scientists for centuries. New technologies of brain mapping have the potential to shed new light on the mystery of adolescence. The approach proposed here concerns the investigation of brain regions which underlie developmental changes in cognitive, emotional and social-emotional functions over the course of child and adolescent development. For this purpose I will measure functional brain development longitudinally across the age range 8-20 years by using a combined cross-sectional longitudinal design including 240 participants. Participants will take part in two testing sessions over a four-year-period in order to track the within-subject time courses of functional brain development for cognitive, emotional and social-emotional functions and to understand how these functions develop relative to each other in the same individuals, using multilevel models for change. The cross-sectional longitudinal assessment of cognitive, emotional and social-emotional functional brain development in relation to brain structure and hormone levels is unique in the international field and has the potential to provide new explanations for old questions. The application of brain mapping combined with multilevel models for change is original, and allows for the examination of developmental trajectories rather than age comparisons. An integrative mapping (i.e., combined with task performance and with biological markers) of functional brain development is important not only for theory development, but also for understanding how children learn new tasks and participate in a complex social world, and eventually to tailor educational programs to the needs of children.

1 500 000 €

Start date: 2011-02-01, End date: 2016-01-31

Global changes in patterns of neuronal activity or brain state are the first phenomenon recorded in the awake human brain (1). Changes in brain state are present in recordings of neocortical activity from mouse to man. It is now thought that changes in brain state are fundamental to normal brain function and neuronal computation. Despite their importance, we have very little idea about the underlying neuronal mechanisms that generate them or their precise impact on neuronal processing and behaviour. In previous work we have characterised brain state changes in a well characterised model for neuroscience research the mouse whisker system. We have recorded changes in the brain state in mouse cortex during whisker movements (2). In this proposal, we aim to use the mouse whisker system further to investigate the mechanisms and functions of changes in brain state. First we will use state of the art techniques to record and manipulate neuronal activity in the awake, behaving mouse to investigate the network and cellular mechanisms involved in generating brain state. Second we will use 2-photon microscopy to investigate the impact of brain state on excitatory and inhibitory synaptic integration in vivo. Finally we will use behaviourally trained mice to measure the impact of brain state changes on sensory perception and behaviour. This proposal will therefore provide fundamental insights into brain function at every step: mechanisms of changes in brain state, how neurons communicate with eachother and how the brain controls sensory perception and behaviour. References 1 Berger H (1929) Archiv für Psychiatrie und Nervenkrankheiten 87:527-570. 2 Poulet JFA, Petersen CC (2008) Nature 454:881-885.

1 463 125 €

Start date: 2011-02-01, End date: 2016-01-31

Combinatorial Computational Chemistry is developed as a standard tool to tackle complex problems in chemistry and materials science. The method employs a series of state-of-the-art methods, ranging from empirical molecular mechanics to first principles calculations, as well as of mathematical (graph theoretical and combinatorial) methods. The process is similar as in experimental combinatorial chemistry: First, a large set of candidate structures is generated which is complete in the sense that the best possible structure for a particular purpose must be found among the set. This structure is then identified using computational chemistry. We will apply methodologies at different stages in hierarchical order and successively screen the set of candidate structures. Screening criteria are based on the computer simulations and include geometry, stability and properties of the candidate structures. Detailed characteristics of the final materials will be simulated, including the X-ray diffraction pattern, the electronic structure, and the target properties. We will apply C3 to two important problems of environmental science. (i) We will optimise nanoporous materials to act as molecular sieves to separate water from ethanol, an important task for the production of biofuels. Here, materials are optimised to transport ethanol, but not water (or vice versa). The tuning parameters are the channel size of the material and its polarity. (ii) We will optimise nanoporous materials to transport protons, an important task for the design of energy-efficient fuel cells, by distributing flexible functional groups, acting as hopping sites for the protons, in the framework.

1 500 000 €

Start date: 2011-02-01, End date: 2016-04-30

This project will be aimed at obtaining a deeper insight into the physical processes taking place in astrophysical magnetized plasmas. To study these scenarios I will employ different numerical codes as virtual tools that enable me to experiment on computers (virtual labs) with distinct initial and boundary conditions. Among the kind of sources I am interested to consider, I outline the following: Gamma-Ray Bursts (GRBs), extragalactic jets from Active Galactic Nuclei (AGN), magnetars and collapsing stellar cores. A number of important questions are still open regarding the fundamental properties of these astrophysical sources (e.g., collimation, acceleration mechanism, composition, high-energy emission, gravitational wave signature). Additionally, there are analytical issues on the formalism in relativistic dynamics not resolved yet, e.g., the covariant extension of resistive magnetohydrodynamics (MHD). All these problems are so complex that only a computational approach is feasible. I plan to study them by means of relativistic and Newtonian MHD numerical simulations. A principal focus of the project will be to assess the relevance of magnetic fields in the generation, collimation and ulterior propagation of relativistic jets from the GRB progenitors and from AGNs. More generally, I will pursue the goal of understanding the process of amplification of seed magnetic fields until they become dynamically relevant, e.g., using semi-global and local simulations of representative boxes of collapsed stellar cores. A big emphasis will be put on including all the relevant microphysics (e.g. neutrino physics), non-ideal effects (particularly, reconnection physics) and energy transport due to neutrinos and photons to account for the relevant processes in the former systems. A milestone of this project will be to end up with a numerical tool that enables us to deal with General Relativistic Radiation Magnetohydrodynamics problems in Astrophysics.

1 497 000 €

Start date: 2011-03-01, End date: 2017-02-28

The study of several genetic disorders is hampered by the lack of suitable in vitro human models. We hypothesize that the generation of patient-specific induced pluripotent stem cells (iPSCs) will allow the development of disease-specific in vitro models; yielding new pathophysiologic insights into several genetic disorders and offering a unique platform to test novel therapeutic strategies. In the current proposal we plan utilize this novel approach to establish human iPSC (hiPSC) lines for the study of a variety of inherited cardiac disorders. The specific disease states that will be studied were chosen to reflect abnormalities in a wide-array of different cardiomyocyte cellular processes. These include mutations leading to: (1) abnormal ion channel function (“channelopathies”), such as the long QT and Brugada syndromes; (2) abnormal intracellular storage of unnecessary material, such as in the glycogen storage disease type IIb (Pompe’s disease); and (3) abnormalities in cell-to-cell contacts, such as in the case of arrhythmogenic right ventricular cardiomyopathy-dysplasia (ARVC-D). The different hiPSC lines generated will be coaxed to differentiate into the cardiac lineage. Detailed molecular, structural, functional, and pharmacological studies will then be performed to characterize the phenotypic properties of the generated hiPSC-derived cardiomyocytes, with specific emphasis on their molecular, ultrastructural, electrophysiological, and Ca2+ handling properties. These studies should provide new insights into the pathophysiological mechanisms underlying the different familial arrhythmogenic and cardiomyopathy disorders studied, may allow optimization of patient-specific therapies (personalized medicine), and may facilitate the development of novel therapeutic strategies. Moreover, the concepts and methodological knowhow developed in the current project could be extended, in the future, to derive human disease-specific cell culture models for a plurality of genetic disorders; enabling translational research ranging from investigation of the most fundamental cellular mechanisms involved in human tissue formation and physiology through disease investigation and the development and testing of novel therapies that could potentially find their way to the bedside

1 500 000 €

Start date: 2011-03-01, End date: 2016-02-29

Cerebellar and brainstem congenital defects (CBCDs) are heterogeneous disorders with high pre-and post-natal mortality and morbidity. Their genetic basis and pathogenetic mechanisms are largely unknown, hampering patients’ diagnosis and management and family counselling. This project aims at improve current understanding of primary CBCDs through a multidisciplinary approach combining innovative clinical, neuroimaging, molecular and functional studies, that will be articulated in four workpackages: WP1- Clinical and neuroimaging studies: collection of detailed data and biological samples from a large cohort of patients covering a broad spectrum of CBCDs, neuroimaging classification based on magnetic resonance imaging and tractography, genotype-phenotype correlates and follow-up studies. WP2 - Molecular studies on mendelian CBCDs: high-throughput resequencing of ciliary genes to identify pathogenic mutations and genetic modifiers in patients with ciliopathies, identification of novel disease genes, mutation analysis of genes causative of other mendelian CBCDs. WP3 - Molecular studies on sporadic CBCDs: identification of cryptic chromosomal rearrangements by high resolution SNP-array analysis, selection and mutation analysis of candidate genes mapping to the rearranged regions. WP4 - Functional studies: optimisation of a novel neuroembryonic in vitro model derived from mouse embryonic stem cells, to test the role of known and candidate disease genes (from WP2 and 3) on cerebellar and brainstem development, define the pathways in which they are involved and the effect of disease-causative mutations. This project is expected to improve the current CBCD nosology, identify novel genes and mechanisms involved in cerebellar and brainstem development that are responsible for mendelian or sporadic defects, expand the available tools for pre- and post-natal diagnosis and identify clinical-genetic correlates and prognostic indexes.

1 367 960 €

Start date: 2011-08-01, End date: 2018-03-31

The aim of this project is to understand and control the fundamental physical properties of novel carbon nanomaterials: carbon nanotubes and graphene. By a combination of complementary methods, i.e. vibrational spectroscopy, scanning probe microscopy, and theoretical modelling, a comprehensive understanding of the electronic, vibrational, optical properties, and their connection with the material’s structure will be obtained. A diagnostics “toolbox” will be established on the materials in their most unperturbed, ideal states. Taking the results as reference, the materials will be studied under conditions relevant when incorporated into devices. These include imperfections of the materials and interaction with different environments, with other carbon nanotubes/graphene, and with extrinsic materials introduced during device processing. The gained insight and understanding on a fundamental level will also advance technological routes for scaling up carbon-nanomaterial electronic device fabrication, which is still lacking sufficient control over selectivity towards the desired physical properties. Control over the electronic and optical properties will be sought through deliberately induced interactions and chemical functionalization of the materials. The project benefits from close collaborations between experimental and theoretical physics, chemistry, and materials science.

1 468 960 €

Start date: 2010-12-01, End date: 2015-11-30

The mammalian brain is assembled from thousands of neuronal cell types that are organized into distinct circuits to perform behaviourally relevant computations. To gain mechanistic insights about brain function and to treat specific diseases of the nervous system it is crucial to understand what these local circuits are computing and how they achieve these computations. By examining the structure and function of a few genetically identified and experimentally accessible neural circuits we plan to address fundamental questions about the functional architecture of neural circuits. First, are cell types assigned to a unique functional circuit with a well-defined function or do they participate in multiple circuits (“multitasking cell types”), adjusting their role depending on the state of these circuits? Second, does a neural circuit perform “a single computation” or depending on the information content of its inputs can it carry out radically different functions? Third, how, among the large number of other cell types, do the cells belonging to the same functional circuit connect together during development? We use the mouse retina as a model system to address these questions. Finally, we will study the structure and function of a specialised neural circuit in the human fovea that enables humans to read. We predict that our insights into the mechanism of multitasking, network switches and the development of selective connectivity will be instructive to study similar phenomena in other brain circuits. Knowledge of the structure and function of the human fovea will open up new opportunities to correlate human retinal function with human visual behaviour and our genetic technologies to study human foveal function will allow us and others to design better strategies for restoring vision for the blind.

1 499 000 €

Start date: 2010-11-01, End date: 2015-10-31

Currently, haemophilia A cannot be cured. To prevent major bleeding episodes in haemophilia, human Factor VIII (FVIII) protein must be frequently administered as prophylaxis or on demand. This treatment is complicated by its high cost and development of antibodies that neutralize FVIII activity in 20 to 30% of the patients. Therefore, permanent solutions in the form of cell and gene therapy are very attractive for haemophilia A. Recently, we demonstrated in a murine model that liver sinusoidal endothelial cells (LSEC) produce and secrete FVIII, although not exclusively. We have also found that these mice can be treated by reconstitution with wild-type bone marrow, indicating that bone marrow-derived cells, of hematopoietic, mesenchymal or even endothelial origin, can produce and secrete FVIII. Based on these findings in mice, I propose that human LSEC, umbilical cord blood cells, and bone marrow cells might be suitable sources of FVIII to be used for cell replacement therapy for haemophilia A. To advance opportunities for cell and gene therapies in haemophilia A and for identifying additional cell sources of FVIII, I intend to explore whether replacement of liver endothelium and bone marrow in immnocompromised Haemophilia A mice with healthy human cells will provide therapeutic correction. Recently, the possibility of reprogramming mature somatic cells to generate induced pluripotent stem (iPS) cells has enabled the derivation of disease-specific pluripotent cells, thus providing unprecedented experimental platforms to treat human diseases. Therefore, I intend to study whether the generation of patient-specific iPS cells may be applied to cell and gene therapy of coagulation disorders and in particular for the treatment of Haemophilia A. Studies with these novel target cells may impact significantly the future course of Haemophilia A by providing proof-of feasibility of a novel therapy strategies.

1 123 000 €

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

Tetralogy of Fallot (TOF) is the most common congenital heart disease (CHD) occurring 1 in 3000 births. Genetic studies have identified numerous genes that are responsible for inherited and sporadic forms of TOF, most of which encode key molecules that are part of regulatory networks controlling heart development. The identification of two populations of cardiac precursors, one exclusively forming the left ventricle and the second the outflow tract, the right ventricle and the atria, has suggested a new approach to interpret CHDs, in particular in TOF, not as a defect in a specific gene, but rather as a defect in the formation, expansion, and differentiation of defined subsets of embryonic cardiac precursors. The LIM-homeodomain transcription factor ISL1 marks the second population of cardiac progenitors, but little is known about its downstream targets, and how causative genes of CHDs affect cell-fate decisions in the ISL1 lineage. The main goals of this research program are: (1) to decipher the functional role of Isl1 downstream targets identified by a genome-wide ChIP-Seq approach; (2) to generate induced pluripotent stem (iPS) cells from controls and patients affected by severe forms of TOF characterized by defects in heart compartments known to derive from ISL1 cardiac progenitors; (3) to direct these iPS cells to ISL1+ cardiovascular precursors and identify cell-surface makers enabling their antibody-based purification; and (4) to use TOF-iPS-derived ISL1+ progenitors as an unique in vitro model system for deciphering molecular mechanisms that govern the fates and differentiation of this progenitor lineage and determine the pathological phenotype seen in TOF. This work will shed light on the molecular mechanisms of ISL1+ cardiac progenitor lineage specification and will give important new insights into the mechanisms of how alterations in transcriptional and epigenetic programs translate to a distinct structural defect during cardiogenesis.

1 499 996 €

Start date: 2011-03-01, End date: 2017-02-28

Nanoscale systems binding single molecules, or small numbers of molecules, in conducting junctions show considerable promise for a range of technological applications, from photovoltaics to rectifiers to sensors. These environments differ significantly from the traditional domain of chemical studies involving molecules in solution and the gas phase, necessitating renewed efforts to understand the physical properties of these systems. The objective of this proposal concerns one particular class of physical processes: understanding and controlling local heating in molecular junctions in terms of excitation, dissipation and transfer. Local heating and dissipation in molecular junctions has long been a concern due to the possibly detrimental impact on device stability and function. More recently there has been increased interest, as these processes underlie both spectroscopic techniques and potential technological applications. Together these issues make an investigation of ways to chemically control local heating in molecular junctions timely and important. The proposal objective will be addressed through the investigation of three challenges: - Developing chemical control of local heating in molecular junctions. - Developing chemical control of heat dissipation in molecular junctions. - Design of optimal thermoelectric materials. These three challenges constitute distinct, yet complementary, avenues for investigation with progress in each area supporting the other two. All three challenges build on existing theoretical methods, with the important shift of focus to methods to achieve chemical control. The combination of state-of-the-art computational methods with careful chemical studies promises significant new developments for the area.

1 499 999 €

Start date: 2010-12-01, End date: 2015-11-30

Proper and controlled expression of genes is essential for normal cell growth. Chromatin modifying enzymes play a fundamental role in the control of gene expression and their deregulation is often linked to cancer. In recent years chromatin modifiers have been considered key targets for cancer therapy and this demands a full understanding of their biological functions. Previous biochemical and structural studies have focused on the identification of chromatin modifying enzymes and characterization of their substrate specificities and catalytic mechanisms. However, a comprehensive view of the biological processes, signaling pathways and regulatory circuits in which these enzymes participate is missing. Protein arginine methyltransferases (PRMTs), which methylate histones and are evolutionarily conserved from yeast to human, constitute an example of chromatin modifying enzymes whose functional and regulatory networks remain unexplored. I propose to use complementary state-of-the-art genomic and proteomic approaches in order to identify the protein networks and cellular pathways that are linked to PRMTs. In parallel, I will identify novel regulatory circuits and define the molecular mechanisms that control methylation of specific histone arginine residues. I will utilize the yeast S. cerevisiae as a model organism because it allows genetic, biochemical and genomic approaches to be combined. Most importantly, many of the pathways and mechanisms in yeast are highly conserved and therefore, the findings from this study will be pertinent to human and other eukaryotic organisms. Establishing a global cellular wiring diagram of PRMTs will serve as a paradigm for other chromatin modifiers and is imperative for assessing the efficacy of these enzymes as therapeutic targets.

1 498 279 €

Start date: 2011-01-01, End date: 2016-06-30

Necrosis triggers an inflammatory response driven by macrophages that normally contributes to tissue repair but, under certain conditions, can induce a state of chronic inflammation that forms the basis of many diseases. In addition, dendritic cell (DC)-mediated presentation of antigens from necrotic cells can trigger adaptive immunity in infection-free situations, such as autoimmunity or therapy-induced tumour rejection. Recently, we and others have identified the myeloid C-type lectin receptors (CLRs) CLEC9A (DNGR-1), in DC, and Mincle, in macrophages, as receptors for necrotic cells that can signal via the Syk kinase. Previous studies on similar Syk-coupled CLRs showed that Dectin-1 and Dectin-2 can induce innate and adaptive immune responses. We thus hypothesise that recognition of cell death by myeloid Syk-coupled CLRs is at the root of immune pathologies associated with accumulation of dead cells. The overall objective of this proposal is to investigate necrosis sensing by myeloid cells as a trigger of immunity and to study the underlying molecular mechanisms. Our first goal is to characterise signalling and gene induction via CLEC9A as a model necrosis receptor in DCs. Second, we will investigate the role of myeloid Syk-coupled necrosis-sensing CLRs in animal models of atherosclerosis, lupus and immunity to chemotherapy-treated tumours. Our preliminary data suggest that additional receptors can couple necrosis recognition to the Syk pathway in DC; thus, our third aim is to identify novel myeloid Syk-coupled receptors for necrotic cells. Characterisation of the outcomes of sensing necrosis by myeloid Syk-coupled receptors and their effect on the proposed pathologies promises to identify new mechanisms and targets for the treatment of these diseases.

1 297 671 €

Start date: 2010-12-01, End date: 2016-08-31

Targeted drug delivery across the blood brain barrier (BBB) to the central nervous system is a large challenge for the treatment of neurological disorders. This 4 year ERC program is aimed towards the evaluating the BBB penetration capacity and toxicological potential of novel carbon nanotube (CNT) carriers using an integrated multidisciplinary approach. State-of-art characterisation techniques developed by the PI will be applied and further developed to detect the interaction of carbon nanotubes with in vitro BBB model and neuronal cells. Specific aims: 1. Identify the mechanisms of translocation of CNT across the endothelial cells which comprise the BBB, as well as uptake by neuronal cells in vitro. 2. To investigate the effect of length, diameter and surface charge of CNTs on the BBB and neuronal cells penetration capacity in vitro. 3. To investigate the toxicological profile of CNT on the BBB and the various neuronal cell types (immortalised and primary neuronal cultures). 4. Develop protocols to assess whether the CNTs degrade inside the cell. The ERC Grant will consolidate the new Research Group in nanomaterials-cell interfaces, and allow them to perform stimulating investigator-initiated frontier research in nanotoxicology and nanomedicine. To this end, a multi-disciplinary laboratory will be realized within the framework of this 4-year the ERC Programme. This will permit the group around the PI, to expand activities, push limits, create new boundaries, and develop new protocols for studying nanoparticle-cell interactions in close collaboration with ICL s Department of medicine and chemistry. Within the proposed program there is an underlying ambition both to gain a fundamental understanding for which parameters of CNTs determine their penetration capacity through the BBB and also to assess their toxicological potential at the BBB two highlighted themes by the ERC.

1 229 998 €

Start date: 2011-02-01, End date: 2017-01-31

Nowadays human intellectual product is increasingly produced and disseminated solely in digital form. The capability of digital data for effortless reproduction and transfer has lead to a true revolution that impacts every aspect of human creativity. Nevertheless, as with every technological revolution, this digital media revolution comes with a dark side that, if left unaddressed, it will limit its impact and may counter its potential advantages. In particular, the way we produce and disseminate digital content today does not lend itself to controlling the way data move and change. It turns out that the power of being digital can be a double-edged sword: the ease of production, dissemination and editing also implies the ease of misappropriation, plagiarism and improper modification. To counter the above problems, the proposed research activity will focus on the development of a new generation of enabling cryptographic technologies that have the power to facilitate the appropriate controls for data movement. Using the techniques developed in this project it will be feasible to build digital content distribution systems where content producers will have the full possible control on the dissemination of their intellectual product, while at the same time the rights of the end-users in terms of privacy and fair use can be preserved. The PI is uniquely qualified to carry out the proposed research activity as he has extensive prior experience in making innovations in the area of digital content distribution as well as in the management of research projects. As part of the project activities, the PI will establish the CODAMODA laboratory in the University of Athens and will seek opportunities for technology transfer and interdisciplinary work with the legal science community.

1 212 960 €

Start date: 2011-04-01, End date: 2017-03-31

Networks have been studied in depth for several decades, but one aspect has received little attention: Interference. Most networks use clever algorithms to avoid interference, and this strategy has proved effective for traditional supply-chain or wired communication networks. However, the emergence of wireless networks revealed that simply avoiding interference leads to significant performance loss. A wealth of cooperative communication strategies have recently been developed to address this issue. Two fundamental roadblocks are emerging: First, it is ultimately unclear how to integrate cooperative techniques into the larger fabric of networks (short of case-by-case redesigns); and second, the lack of source/channel separation in networks (i.e., more bits do not imply better end-to-end signal quality) calls for ever more specialized cooperative techniques. This proposal advocates a new understanding of interference as computation: Interference garbles together inputs to produce an output. This can be thought of as a certain computation, perhaps subject to noise or other stochastic effects. The proposed work will develop strategies that permit to exploit this computational potential. Building on these ``computation codes,'' an enhanced physical layer is proposed: Rather than only forwarding bits, the revised physical layer can also forward functions from several transmitting nodes to a receiver, much more efficiently than the full information. Near-seamless integration into the fabric of existing network architectures is thus possible, providing a solution for the first roadblock. In response to the second roadblock, computation codes suggest new computational primitives as fundamental currencies of information.

1 776 473 €

Start date: 2011-05-01, End date: 2016-04-30

Cell-to-cell communication is a central aspect for understanding how cells form and organize multi-cellular communities involving progressive cell specialization. Multi-cellularity cell specialization cell communication those keywords are frequently used to distinguish metazoans from bacteria. Yet bacteria can form morphologically complex multi-cellular communities, they can non-genetically diversify and they can communicate. This implies that even prokaryotic networks must possess the properties to facilitate these complex functions. Thus basic network features ( motifs ) determining these functions can be discovered and characterized from studying simpler bacterial networks. We want to focus on communication motifs that are present in the gene-regulatory network of Bacillus subtilis. Our proposed methodology involves a combination of quantitative fluorescence microscopy techniques (QFTLM, FRET), developmental assays, signal transduction studies in controlled micro-environments and information theory to quantitatively characterize communication motifs..

1 496 840 €

Start date: 2011-09-01, End date: 2016-08-31

Computational cameras go beyond 2D images and allow the extraction of more dimensions from the visual world such as depth, multiple viewpoints and multiple illumination conditions. They also allow us to overcome some of the traditional photography challenges such as defocus blur, motion blur, noise and resolution. The increasing variety of computational cameras is raising the need for a meaningful comparison across camera types. We would like to understand which cameras are better for specific tasks, which aspects of a camera make it better than others and what is the best performance we can hope to achieve. Our 2008 paper introduced a general framework to address the design and analysis of computational cameras. A camera is modeled as a linear projection in ray space. Decoding the camera data then deals with inverting the linear projection. Since the number of sensor measurements is usually much smaller than the number of rays, the inversion must be treated as a Bayesian inference problem accounting for prior knowledge on the world. Despite significant progress which has been made in the recent years, the space of computational cameras is still far from being understood. Computational camera analysis raises the following research challenges: 1) What is a good way to model prior knowledge on ray space? 2) Seeking efficient inference algorithms and robust ways to decode the world from the camera measurements. 3) Evaluating the expected reconstruction accuracy of a given camera. 4) Using the expected reconstruction performance for evaluating and comparing camera types. 5) What is the best camera? Can we derive upper bounds on the optimal performance? We propose research on all aspects of computational camera design and analysis. We propose new prior models which will significantly simplify the inference and evaluation tasks. We also propose new ways to bound and evaluate computational cameras with existing priors.

756 845 €

Start date: 2010-12-01, End date: 2015-11-30

Nowadays, ageing is one of the main problems in Western society. The increase in the percentage of elderly people serves to strain the Social Security to the point of bankruptcy. The only way to alleviate the suffering caused by age-related degenerative disease is to fully understand the underlying forces which drive ageing and design strategies to delay it. Mitochondria are considered as central modulators of longevity in different species. It has been proposed that free radicals cause the accumulation of oxidative damage and as a result ageing. In accordance with this, production of Reactive Oxygen Species (ROS) by complex I negatively correlates with longevity. However, the overexpression of antioxidants or the reduction of ROS levels does not increase lifespan. These contradictory data can only be reconciled if complex I is modulating longevity through a ROS independent mechanism. We have expressed the alternative internal NADH dehydrogenase 1 (NDI1) from Saccharomyces cerevisiae in Drosophila melanogaster. The expression of NDI1 does not change the level of ROS but increases both the ratio of NAD+/NADH and Drosophila longevity. The main objective of this proposal is to study the mechanisms by which complex I regulates longevity. My general hypothesis is that complex I regulates longevity through a ROS independent mechanism. I propose that complex I controls the cellular levels of NAD+/NADH, keeping their levels at an equilibrium that favours the optimal functioning of the cell. When the ratio is moved towards NADH ageing is promoted, whereas when it is moved towards NAD+ pro-survival pathways are activated. I proposed two specific mechanisms downstream of complex I that promote cellular longevity or senescence: 1) activation of sirtuins, which would increase genome stability and 2) reduction of methylglyoxal generation, which would decrease the accumulation of cellular garbarge .

1 491 600 €

Start date: 2011-02-01, End date: 2016-09-30

The technology of the 20th century was dominated by a single material class: The semiconductors, whose properties can be tuned between those of metals and insulators all of which describable by single-electron effects. In contrast, quantum magnets and strongly correlated electron systems offer a full palette of quantum mechanical many-electron states. CONQUEST aim to discover, understand and demonstrate control over such quantum states. A new experimental approach, building on established powerful laboratory and neutron scattering techniques combined with dynamical control-perturbations, will be developed to study correlated quantum effects in magnetic materials. The immediate goal is to open a new field of non-equilibrium and time dependent studies in solid state physics. The long-term vision is that the approach might nurture the materials of the 21st century.

1 500 000 €

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

The cosmoIGM proposal aims at investigating the role of the Intergalactic Medium (IGM) as a cosmological probe and at exploiting the many IGM-related sinergies between observational cosmology, galaxy formation and fundamental physics. The IGM is a unique cosmological observable as it probes 3/4 of the present age of the universe, it contains up to 80% of the baryons and is sensitive to scales that are not measured by other data. In the last decade, astronomical data sets have started to be widely used by the scientific community to address important physical issues such as: the nature of the dark matter and dark energy components and their evolution; the physical properties of the baryonic matter; variation of fundamental constants; feedback processes by galaxies, etc. For example, results obtained from astronomical data are nowadays comparable to those obtained by ground based physics laboratories (e.g. neutrino masses). This proposal will rely on observations of the IGM at high and low redshift and will interpret them by means of state-of-the-art computational facilities in order to firmly establish the (yet controversial) role of the IGM as a probe for cosmology and fundamental physics. Moreover, we aim at exploring the galaxy-IGM interplay at a crucial stage of the cosmic history when the universe was few Gyrs old and star forming galaxies were strongly affecting the dynamical, thermal and chemical properties of the IGM. The hosting institution, Trieste Observatory, and the Trieste Area (ICTP, SISSA and Trieste University) have a long-standing expertise on the topics above. We foresee that the present interdisciplinary proposal will have a strong scientific impact and will help the P.I. to consolidate its independence and to create his first research team.

891 400 €

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

The analysis and synthesis of complex 3D geometric data sets is of crucial importance in many scientific disciplines (e.g. bio-medicine, material science, mechanical engineering, physics) and industrial applications (e.g. drug design, entertainment, architecture). We are currently witnessing a tremendous increase in the size and complexity of geometric data, largely fueled by significant advances in 3D acquisition and digital production technology. However, existing computational tools are often not suited to handle this complexity. The goal of this project is to explore a fundamentally different way of processing 3D geometry. We will investigate a new generalized model of geometric symmetry as a unifying concept for studying spatial organization in geometric data. This model allows exposing the inherent redundancies in digital 3D data and will enable truly scalable algorithms for analysis, processing, and design of large-scale geometric data sets. The proposed research will address a number of fundamental questions: What is the information content of 3D geometric models? How can we represent, store, and transmit geometric data most efficiently? Can we we use symmetry to repair deficiencies and reduce noise in acquired data? What is the role of symmetry in the design process and how can it be used to reduce complexity? I will investigate these questions with an integrated approach that combines thorough theoretical studies with practical solutions for real-world applications. The proposed research has a strong interdisciplinary component and will consider the same fundamental questions from different perspectives, closely interacting with scientists of various disciplines, as well artists, architects, and designers.

1 160 302 €

Start date: 2011-02-01, End date: 2016-01-31

Our primary motivation stems from queueing theory, the branch of applied probability that deals with congestion phenomena. Congestion levels are typically nonnegative, which is why reflected stochastic processes arise naturally in queueing theory. Other applications of reflected stochastic processes are in the fields of branching processes and random graphs. We are particularly interested in critically-loaded queueing systems (close to 100% utilization), also referred to as queues in heavy traffic. Heavy-traffic analysis typically reduces complicated queueing processes to much simpler (reflected) limit processes or scaling limits. This makes the analysis of complex systems tractable, and from a mathematical point of view, these results are appealing since they can be made rigorous. Within the large body of literature on heavy-traffic theory and critical stochastic processes, we launch two new research lines: (i) Time-dependent analysis through scaling limits. (ii) Dimensioning stochastic systems via refined scaling limits and optimization. Both research lines involve mathematical techniques that combine stochastic theory with asymptotic theory, complex analysis, functional analysis, and modern probabilistic methods. It will provide a platform enabling collaborations between researchers in pure and applied probability and researchers in performance analysis of queueing systems. This will particularly be the case at TU/e, the host institution, and at the affiliated institution EURANDOM.

970 800 €

Start date: 2010-08-01, End date: 2016-07-31

The field of software security analysis stands at a critical juncture. Applications have become too large for security experts to examine by hand, automated verification tools do not scale, and the risks of deploying insecure software are too great to tolerate anything less than mathematical proof. A radical shift of strategy is needed if programming and analysis techniques are to keep up in a networked world where increasing amounts of governmental and individual information are generated, manipulated, and accessed through web-based software applications. The basic tenet of this proposal is that the main roadblock to the security verification of a large program is not its size, but rather the lack of precise security specifications for the underlying libraries and security-critical application code. Since, large-scale software is often a collaborative effort, no single programmer knows all the design goals. Hence, this proposal advocates a collaborative specification and verification framework that helps teams of programmers write detailed security specifications incrementally and then verify that they are satisfied by the source program. The main scientific challenge is to develop new program verification techniques that can be applied collaboratively, incrementally, and modularly to application and library code written in mainstream programming languages. The validation of this approach will be through substantial case studies. Our aim is to produce the first verified open source cryptographic protocol library and the first web applications with formal proofs of security. The proposed project is bold and ambitious, but it is certainly feasible, and has the potential to change how software security is analyzed for years to come.

1 406 726 €

Start date: 2010-11-01, End date: 2015-10-31

Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells release granzyme and perforin from cytotoxic granules into the immune synapse to induce apoptosis of target cells that are either virus-infected or cancerous. Granzyme A activates a caspase-independent apoptotic pathway and induces mitochondrial damage characterized by superoxide anion production and loss of the mitochondrial transmembrane potential, without disrupting the integrity of the mitochondrial outer membrane; while causing single-stranded DNA damage. GzmB induces both caspase-dependent and caspase-independent cell death. In the caspase-dependent pathway, mitochondrial functions are altered as evidenced by the loss of mitochondrial transmembrane potential and the generation of reactive oxygen species (ROS). The mitochondrial outer membrane (MOM) is disrupted, resulting in the release of apoptogenic factors. To date, research on mitochondrial-dependent apoptosis has focused on mitochondrial outer membrane permeabilization (MOMP) however whether the generation of ROS is incidental or essential to the execution of apoptosis remains unclear. Like human GzmA, human GzmB promotes cell death in a ROS-dependent manner. Preliminary data suggest that human GzmB can induce ROS in a MOMP-independent manner as Bax and Bak double knockout MEF cells treated with human GzmB and perforin still display a robust ROS production and dye in an ROS-dependent manner. Since GzmA and GzmB induce cell death in a ROS-dependent manner, we hypothesize that oxygen free radicals are central to the execution of programmed cell death induced by the cytotoxic granules. Therefore, the goal of this proposal is to dissect the key molecular events triggered by ROS that lead to Citotoxic Tcell-induced target cell death. A combination of biochemical, genetic and proteomic approaches in association with Electron Spin Resonance (ESR) spectroscopy methodology will be used to unravel the essential role ROS play in CTL-mediated killing.

1 500 000 €

Start date: 2011-05-01, End date: 2016-04-30

Von Neumann's concept of quantization goes back to the foundations of quantum mechanics and provides a noncommutative model of integration. Over the years, von Neumann algebras have shown a profound structure and set the right framework for quantizing portions of algebra, analysis, geometry and probability. A fundamental part of my research is devoted to develop a very much expected Calderón-Zygmund theory for von Neumann algebras. The lack of natural metrics partly justifies this long standing gap in the theory. Key new ingredients come from recent results on noncommutative martingale inequalities, operator space theory and quantum probability. This is an ambitious research project and applications include new estimates for noncommutative Riesz transforms, Fourier and Schur multipliers on arbitrary discrete groups or noncommutative ergodic theorems. Other related objectives of this project include Rubio de Francia's conjecture on the almost everywhere convergence of Fourier series for matrix valued functions or a formulation of Fefferman-Stein's maximal inequality for noncommutative martingales. Reciprocally, I will also apply new techniques from quantum probability in noncommutative Lp embedding theory and the local theory of operator spaces. I have already obtained major results in this field, which might be useful towards a noncommutative form of weighted harmonic analysis and new challenging results on quantum information theory.

1 090 925 €

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

This project seeks to recover the processes by which religious beliefs and identities were defined through interreligious interaction and debate in the religious culture of a broader social base in the eastern Mediterranean (6-8th centuries AD) through examination of a neglected, unconventional corpus of medieval Greek, Syriac and Arabic literature of debate and disputation (consisting of collections of questions and answers, dialogues among others), treating authors such as Ps. Kaisarios, Anastasios of Sinai, and Ps. Athanasios. These sources help us to understand the kinds of perplexities that were being raised in Christian communities of the eastern Mediterranean as they negotiated a lively and contentious religious and social landscape, and they highlight the multifarious issues which Christian leaders had to be prepared to deal with in their pastoral, pedagogical, and apologetic work. At the same time these collections must be seen as an attempt by Christian authors to work out how Christianity was to define its position with regard to other religions (Hellenism, Judaism and Islam) in a period still characterized by considerable fluidity and change. As well as writing those doubts, challenges, objections, concerns, issues and anxieties back into the religious history of the eastern Mediterranean, when completed this full-length study of these texts will provide scholars not only with a detailed knowledge of the ways in which religious belief, practice and communities were defined in contrast to other religious systems, and a fuller sense of the religious, social and intellectual history of the eastern Mediterranean but also with a nuanced picture of their self-definition, one which will be more sensitive to the processes that led to its formation.

1 483 119 €

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

I propose to measure the growth of non-linear structure in the dark universe to answer two fundamental questions in cosmology: Is the Cold Dark Matter structure formation theory compatible with the galaxy distribution on group scales? Is the accelerating expansion of the Universe caused by Dark Energy? This frontier research probes two key components of our standard cosmological model. This study is fundamental for understanding structure formation and galaxy evolution, leading to possible ground-breaking changes in our comprehension of gravitational physics. I will tackle this ambitious research plan by exploiting my extensive knowledge of galaxy survey analyses and propose to critically test our standard model by measuring three key properties: the shape and evolution of the Cold Dark Matter halo mass function; the efficiency of galaxy formation in Local Group sized systems; the evolution of the growth of structure. To achieve those decisive goals, I will build the DEGAS Team, an inter-disciplinary unit dedicated to solve photometric and spectroscopic survey systematics, to develop optimal clustering statistics for imaging surveys and to create a large variety of state-of-the-art mock Universes to interpret the statistical analyses. The techniques developed will be applied to two world-leading galaxy surveys: GAMA, a multi-wavelength redshift survey of which I am a founder and co-PI, and Pan-STARRS PS1, a unique 3/4-sky imaging survey. Using innovative clustering statistics accounting for individual photometric redshift distributions and statistically robust methods for halo mass function estimates, my DEGAS Team will provide the ultimate test for structure formation models, gain key insights on galaxy evolution and present novel constraints on the nature of gravity.

1 256 696 €

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

Cancer is rapidly becoming the greatest health hazard of our days. The most widespread cancers, are lung cancer (LC), breast cancer (BC), colorectal cancer (CC), and prostate cancer (PC). The impact of the various techniques used for diagnosis, screening and monitoring these cancers is either uncertain and/or inconvenient for the patients. This proposal aims to create a low-cost, easy-to-use and noninvasive screening method for LC, BC, CC, and PC based on breath testing with a novel nanosensors approach. With this in mind, we propose to: (a) modify an array of nanosensors based on Au nanoparticles for obtaining highly-sensitive detection levels of breath biomarkers of cancer; and (b) investigate the use of the developed array in a clinical study. Towards this end, we will collect suitable breath samples from patients and healthy controls in a clinical trial and test the feasibility of the device to detect LC, BC, CC, and PC, also in the presence of other diseases. We will then investigate possible ways to identify the stage of the disease, monitor the response to cancer treatment, and to identify cancer subtypes. Further, we propose that the device can be used for monitoring of cancer patients during and after treatment. The chemical nature of the cancer biomarkers will be identified through spectrometry techniques. The proposed approach would be used outside specialist settings and could considerably lessen the burden on the health budgets, both through the low cost of the proposed all-inclusive cancer test, and through earlier and, hence, more cost-effective cancer treatment.

1 200 000 €

Start date: 2011-01-01, End date: 2014-12-31