ERC FUNDED PROJECTS

The problem: Cancer metastases are responsible for 90% of cancer-associated deaths. Circulating tumour cells (CTCs) that enter the blood stream on their way to potential metastatic sites are of obvious interest to evaluate correctly patient treatment and therefore influence outcome. CTCs have been identified in bladder, gastric, prostate, lung, breast and colon cancer. The only FDA approved CTCs detection system is Veridex’ CellSearch, which detects only epithelial cancer cells using antibody labelling. Recent evidence showed that non-epithelial cancer cells, which are not detected by CellSearch, are of critical importance in cancer progression. The idea: Our CTC detection method is based, instead of on antibody labelling, on metabolic features of cancer cells, thus providing potential for detecting both epithelial and mesenchymal cancer cells. Cancer cells induce environmental changes; e.g. in aerobic conditions most cancer cells display a high rate of glycolysis with lactate production in the cytosol, known as the Warburg effect. By separating cells into micro-droplets of pico-liter volume using micro-fluidic water-in-oil emulsions and by characterising the microenvironment surrounding them, CTCs are detected by probing for environmental changes using pH sensitive dyes or enzymatic lactate assays. Our inexpensive diagnostic method provides a way to count and isolate CTCs without any labelling while maintaining cells alive and intact for further studies. The project: “A CACTUS” is meant to assess the feasibility of commercialising the developed method for counting and sorting CTCs and develop a proper commercialisation strategy. The final goal of this project is to develop a proposition package consisting of technical proof of concept, the business proposition and strategy and an IP portfolio and strategy. This information will be presented in an attractive business plan that will be proposed to potential investors.

149 875 €

Start date: 2015-04-01, End date: 2016-09-30

"Understanding the dawn of the first galaxies and how their light permeated the early Universe is at the very frontier of modern astrophysical cosmology. Generous resources, including ambitions observational programs, are being devoted to studying these epochs of Cosmic Dawn (CD) and Reionization (EoR). In order to interpret these observations, we propose to build on our widely-used, semi-numeric simulation tool, 21cmFAST, and apply it to observations. Using sub-grid, semi-analytic models, we will incorporate additional physical processes governing the evolution of sources and sinks of ionizing photons. The resulting state-of-the-art simulations will be well poised to interpret topical observations of quasar spectra and the cosmic 21cm signal. They would be both physically-motivated and fast, allowing us to rapidly explore astrophysical parameter space. We will statistically quantify the resulting degeneracies and constraints, providing a robust answer to the question, ""What can we learn from EoR/CD observations?"" As an end goal, these investigations will help us understand when the first generations of galaxies formed, how they drove the EoR, and what are the associated large-scale observational signatures."

1 468 750 €

Start date: 2015-05-01, End date: 2021-01-31

Until now the greatest limitation in the application of bioactive compounds has been the inability of confining them specifically to single cells or subcellular components within the organism. Our recently synthesized photoactive forms of bioactive compounds solve this problem. We have developed effective chemical synthesis methods to attach an azide group to small drug-like molecules, which makes them photoactive. As a result, light irradiation can induce the covalent attachment of these molecules to their target enzymes. By controlling the timing and position of light irradiation it is possible to confine the effect of these molecules in time and space. It is important to emphasize that azidation is the smallest possible modification (adding 3 nitrogen atoms) that makes a compound photoactive and based on our experience it does not alter biological activities of most of the original compounds. Azidated inhibitors give unprecedented freedom to researchers because the covalent compound-target formations allow them to address questions which could not have been addressed before. Three major advantages are obtained by using azidated compounds 1: determination of small molecule interactome becomes highly effective, especially, the weak interactions can be determined, which was not possible before 2: it improves the pharmacodynamic and pharmacokinetic properties of biological compounds as the covalent attachment prolongs their effect. 3: Recently, we showed that photoactivation can be initiated by two-photon excitation, thereby confining the effect to femtoliter volumes and well-controlled spatial locations. This feature provides unprecedented spatial and temporal control in localizing the effect of biological compounds in cellular and subcelluler level in in vivo experiments. By realizing the need for photoactive compounds, the PI has established Drugmotif Ltd., a spin-off company, which provides the customers with special azidated chemicals for high-tech research.

150 000 €

Start date: 2013-12-01, End date: 2014-11-30

This project will undertake the first systematic investigation of the various literary documents that circulated simultaneously in more than one language in Tuscany, and especially Florence, between the mid-13th Century and the beginning of 15th Century. During that period, Florence was both a prominent literary centre in the vernacular, and home to a renewal of classical Latin eloquence. While both fields are well studied, their interaction remains largely unexplored. This research, at the convergence of several disciplines (literature, philology, linguistics and medieval history), has a strong pioneering character. It aims at changing the perception of medieval Italian culture and interpretation of the break between medieval Culture and Humanism. For this reason, the project will develop research in varying degrees of depth. First, it will provide the first catalogue of bilingual texts and manuscripts of medieval Tuscany. Organized as a database, this tool of analysis will stir innovative research in this field, some of which will be immediately promoted during the project. Secondly, two case studies, considered as important and methodologically exemplary, will be researched in detail, through the publication of two important set of texts, of secular and religious nature : 1. The vernacular translation of the Latin Epistles of Dante Alighieri; 2. A collection of polemical, historiographical, devotional and prophetical documents produced by the Tuscan dissident Franciscans in last decades of the 14th Century. Finally, the entire team, led by the PI, will be involved in the preparation of a synthesis volume on Tuscan culture in the fourteenth century viewed through bilingualism, entitled Cartography of bilingual culture in Fourteenth-Century Tuscany. From this general map of the Italian culture of the time, no literary genre nor field (be it religious or lay) shall be excluded.

1 480 625 €

Start date: 2015-10-01, End date: 2020-09-30

We and others have recently delineated the molecular architecture of a new feedback pathway in brain synapses, which operates as a synaptic circuit breaker. This pathway is supposed to use a group of lipid messengers as retrograde synaptic signals, the so-called endocannabinoids. Although heterogeneous in their chemical structures, these molecules along with the psychoactive compound in cannabis are thought to target the same effector in the brain, the CB1 receptor. However, the molecular catalog of these bioactive lipids and their metabolic enzymes has been expanding rapidly by recent advances in lipidomics and proteomics raising the possibility that these lipids may also serve novel, yet unidentified physiological functions. Thus, the overall aim of our research program is to define the molecular and anatomical organization of these endocannabinoid-mediated pathways and to determine their functional significance. In the present proposal, we will focus on understanding how these novel pathways regulate synaptic and extrasynaptic signaling in hippocampal neurons. Using combination of lipidomic, genetic and high-resolution anatomical approaches, we will identify distinct chemical species of endocannabinoids and will show how their metabolic enzymes are segregated into different subcellular compartments in cell type- and synapse-specific manner. Subsequently, we will use genetically encoded gain-of-function, loss-of-function and reporter constructs in imaging experiments and electrophysiological recordings to gain insights into the diverse tasks that these new pathways serve in synaptic transmission and extrasynaptic signal processing. Our proposed experiments will reveal fundamental principles of intercellular and intracellular endocannabinoid signaling in the brain.

1 638 000 €

Start date: 2009-11-01, End date: 2014-10-31

"The eruption of volcanoes appears one of the most unpredictable phenomena on Earth. Yet the situation is rapidly changing. Quantification of the eruptive record constrains what is possible in a given volcanic system. Timing is the hardest part to quantify. The main process triggering an eruption is the refilling of a sub-volcanic magma chamber by a new magma coming from depth. This process results in magma mixing and provokes a time-dependent diffusion of chemical elements. Understanding the time elapsed from mixing to eruption is fundamental to discerning pre-eruptive behaviour of volcanoes to mitigate the huge impact of volcanic eruptions on society and the environment. The CHRONOS project proposes a new method that will cut the Gordian knot of the presently intractable problem of volcanic eruption timing using a surgical approach integrating textural, geochemical and experimental data on magma mixing. I will use the compositional heterogeneity frozen in time in the rocks the same way a broken clock at a crime scene is used to determine the time of the incident. CHRONOS will aim to: 1) be the first study to reproduce magma mixing, by performing unique experiments constrained by natural data and using natural melts, under controlled rheological and fluid-dynamics conditions; 2) obtain unprecedented high-quality data on the time dependence of chemical exchanges during magma mixing; 3) derive empirical relationships linking the extent of chemical exchanges and the mixing timescales; 4) determine timescales of volcanic eruptions combining natural and experimental data. CHRONOS will open a new window on the physico-chemical processes occurring in the days preceding volcanic eruptions providing unprecedented information to build the first inventory of eruption timescales for planet Earth. If these timescales can be linked with geophysical signals occurring prior to eruptions, this inventory will have an immense value, enabling precise prediction of volcanic eruptions."

1 993 813 €

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

The objective of this project is to quantify the role of consumers’ behaviour on the design and assessment of policies aimed at enhancing energy efficiency and conservation and at promoting climate change mitigation. The project brings together different disciplines –namely energy policy, environmental and ecological economics, behavioral public finance, experimental economics, and technology policy- in an integrated fashion. COBHAM is designed to go beyond the standard analysis of energy and climate policies in the presence of environmental externalities, by accounting for the heterogeneity in consumers’ preferences, the role of social interactions, and the presence of behavioral tendencies and biases. The project seeks to: i) carry out innovative research in the theoretical understanding of the interplay between behavioral tendencies and environmental externalities; ii) generate new empirical data and research on individual preferences by means of original surveys and controlled experiments; iii) enhance integrated assessment models (IAMs) of economy, energy and climate with an advanced representation of consumers’ behavior. In doing so, the project will be able to provide a richer characterization of energy demand and of greenhouse gas emission scenarios, to better estimate consumers’ responsiveness to energy and climate policies, and to provide input to the design of new policy instruments aimed at influencing energy and environmental sustainable behavior. COBHAM is of high public policy relevance given Europe’s legislation on energy efficiency and CO2 emissions, and can provide important insights also outside the sphere of energy and climate policymaking.

1 451 840 €

Start date: 2014-08-01, End date: 2019-07-31

"Electronic nanodevices have demonstrated to be versatile and effective tools for the investigation of exotic quantum phenomena under controlled and adjustable conditions. Yet, these have enabled to give access to the manipulation of charge flow with unprecedented precision. On the other hand, the wisdom dealing with control, measurements, storage, and conversion of heat in nanoscale devices, the so-called “caloritronics” (from the Latin word “calor”, i.e., heat), despite a number of recent advances is still at its infancy. Although coherence often plays a crucial role in determining the functionalities of nanoelectronic devices very little is known of its role in caloritronics. In such a context, coherent control of heat seems at present still very far from reach, and devising methods to phase-coherently manipulate the thermal current would represent a crucial breakthrough which could open the door to unprecedented possibilities in several fields of science. Here we propose an original approach to set the experimental ground for the investigation and implementation of a new branch of science, the “coherent caloritronics”, which will take advantage of quantum circuits to phase-coherently manipulate and control the heat current in solid-state nanostructures. To tackle this challenging task our approach will follow three main separate approaches, i.e., the coherent control of heat transported by electrons in Josephson nanocircuits, the coherent manipulation of heat carried by electrons and exchanged between electrons and lattice phonons in superconducting proximity systems, and finally, the control of the heat exchanged between electrons and photons by coherently tuning the coupling with the electromagnetic environment. We will integrate superconductors with normal-metal or semiconductor electrodes thus exploring new device concepts such as heat transistors, heat diodes, heat splitters, where thermal flux control is achieved thanks to the use of the quantum phase."

1 754 897 €

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

This project focuses on nontrivial solutions of systems of differential equations characterized by strongly nonlinear interactions. We are interested in the effect of the nonlinearities on the emergence of non trivial self-organized structures. Such patterns correspond to selected solutions of the differential system possessing special symmetries or shadowing particular shapes. We want to understand, from the mathematical point of view, what are the main mechanisms involved in the aggregation process in terms of the global variational structure of the problem. Following this common thread, we deal with both with the classical N-body problem of Celestial Mechanics, where interactions feature attractive singularities, and competition-diffusion systems, where pattern formation is driven by strongly repulsive forces. More precisely, we are interested in periodic and bounded solutions, parabolic trajectories with the final intent to build complex motions and possibly obtain the symbolic dynamics for the general N–body problem. On the other hand, we deal with elliptic, parabolic and hyperbolic systems of differential equations with strongly competing interaction terms, modeling both the dynamics of competing populations (Lotka- Volterra systems) and other interesting physical phenomena, among which the phase segregation of solitary waves of Gross-Pitaevskii systems arising in the study of multicomponent Bose-Einstein condensates. In particular, we will study existence, multiplicity and asymptotic expansions of solutions when the competition parameter tends to infinity. We shall be concerned with optimal partition problems related to linear and nonlinear eigenvalues

1 346 145 €

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

The study of semantic memory considers a broad range of knowledge extending from basic elemental concepts that allow us to recognise and understand objects like ‘an apple’, to elaborated semantic information such as knowing when it is appropriate to use a Wilcoxon Rank-Sum test. Such elaborated semantic knowledge is fundamental to our daily lives yet our understanding of the neural substrates is minimal. The objective of CRASK is to advance rapidly beyond the state-of-the-art to address this issue. CRASK will begin by building a fundamental understanding of regional contributions, hierarchical organisation and regional coordination to form a predictive systems model of semantic representation in the brain. This will be accomplished through convergent evidence from an innovative combination of fine cognitive manipulations, multimodal imaging techniques (fMRI, MEG), and advanced analytical approaches (multivariate analysis of response patterns, representational similarity analysis, functional connectivity). Progress will proceed in stages. First the systems-level network underlying our knowledge of other people will be determined. Once this is accomplished CRASK will investigate general semantic knowledge in terms of the relative contribution of canonical, feature-selective and category-selective semantic representations and their respective roles in automatic and effortful semantic access. The systems-level model of semantic representation will be used to predict and test how the brain manifests elaborated semantic knowledge. The resulting understanding of the neural substrates of elaborated semantic knowledge will open up new areas of research. In the final stage of CRASK we chart this territory in terms of human factors: understanding the role of the representational semantic system in transient failures in access, neural factors that lead to optimal encoding and retrieval and the effects of ageing on the system.

1 472 502 €

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

A new generation of parasitic beam extraction of high energy particles from an accelerator is proposed in CRYSBEAM. Instead of massive magnetic kickers, bent thin crystals trapping particles within the crystal lattice planes are used. This type of beam manipulation opens new fields of investigation of fundamental interactions between particles and of coherent interactions between particles and matter. An experiment in connection to Ultra High Energy Cosmic Rays study in Earth’s high atmosphere can be conducted. Several TeV energy protons or ions are deflected towards a chosen target by the bent lattice planes only when the lattice planes are parallel to the incoming particles direction. The three key ingredients of CRYSBEAM are: - a goniometer based on piezoelectric devices that orients a bent finely-polished low-miscut silicon crystal with a high resolution and repeatability, monitoring its position with synthetic diamond sensors. Novel procedures in crystal manufacturing & testing and cutting-edge mechanical solutions for motion technology in vacuum are developed; - a silica screen that measures the deflected particles via Cherenkov radiation emission in micrometric optical waveguides. These are obtained with an ultra-short laser micro-machining technique as for photonic devices used in quantum optics and quantum computing. The screen is a direct beam-imaging detector for a high radiation dose environment; - a smart absorber, which simulates the Earth’s atmosphere, where particles are smashed and secondary showers are initiated. This sets the path to measure hadronic cross sections at an energy relevant for cosmic rays investigation. The R&D for the various components of such a system are carried out within this project and direct tests at CERN Super Proton Synchrotron to be performed prior to the final installation in the Large Hadron Collider at CERN are proposed. A new concept of particle accelerator operations will be finally set in place.

1 989 746 €

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

The so-called “DNA damage response” (DDR) is a coordinated set of evolutionary-conserved events that, triggered upon DNA damage detection, arrests the cell-cycle and attempts DNA repair. Recently, we have unveiled and reported that DDR activation depends on RNA. We observed that DNA double-strand breaks (DSBs) trigger the local generation of small non-coding RNAs at the site of DNA damage carrying the sequence surrounding the damaged site. These DDR RNAs (DDRNAs) are essential for DDR activation: removal of DDRNAs by RNAse A treatment of permeabilized cells inhibits DDR activation and DDR can be fully restored by the addition of chemically-synthesized DDRNA carrying the sequence surrounding the damaged site but not other sequences (Francia, Nature 2012). Cancer cells must preserve unlimited proliferative potential. We have previously shown that oncogene activation (and therefore cell transformation) is associated with DDR activation at fragile sites (Di Micco, Nature 2006). Several studies have shown that RNA functions can be inhibited by antisense oligonucleotides (ASO) that act by pairing with target RNAs. We propose scientific development and commercialization activities to bring to a clinical application a therapeutic approach for tumors based on DDRNA inhibition by ASO. Analysis of prior art indicate that there is no overlapping IP protection. Based on our solid IPR, we trust we have an excellent candidate for a first-in-class tool to block proliferation in a subtype of tumors.

149 425 €

Start date: 2015-06-01, End date: 2016-11-30

"Catabolism of amino acids is an ancient survival strategy that also controls immune responses in mammals. Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions, including autoimmune diseases, in which it is often defective, and neoplasia, in which it promotes immune unresponsiveness. The PI’s group recently revealed that IDO does not merely degrade tryptophan and produce immunoregulatory kynurenines but also acts as a signal-transducing molecule independently of its enzyme activity. IDO’s signaling function relies on the presence of phosphorylable motifs in a region (small IDO domain) distant from the catalytic site (large IDO domain). Preliminary data indicate that IDO, depending on microenvironmental conditions, can move among distinct cellular compartments. Thus IDO may be considered a ‘moonligthing’ protein, i.e., an ancestral metabolic molecule that, during evolution, has acquired the DYNAMIC feature of moving intracellularly and switching among distinct functions by changing its conformational state. By means of computational studies, Macchiarulo’s group (team member) has identified distinct conformations of IDO, some of which are associated with optimal catalytic activity of the enzyme whereas others may favor tyrosine phosphorylation of IDO’s small domain. A switch between distinct conformations can be induced by the use of ligands that bind either the catalytic site or an accessory pocket outside the IDO catalytic site. The first aim of DIDO is to decipher the relationships between IDO conformations and multiple functions of the enzyme. A second aim is to identify small molecules with drug-like properties capable of modulating distinct IDO’s molecular conformations in order to either potentiate (a new therapeutic approach in autoimmune diseases) or inhibit (more efficient anti-tumor therapeutic strategy) immunoregulatory signaling ability of IDO."

2 442 078 €

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

The fundamental limitation in our ability to dissect human diseases is the scarce availability of human tissues at relevant disease stages, which is particularly salient for neural disorders. Somatic cell reprogramming is overcoming this limitation through the derivation of patient-specific induced pluripotent stem cells (iPSC) that can be differentiated into disease-relevant cell-types. Despite these tantalizing possibilities, there are critical issues to be addressed in order to secure iPSC-modeling as a robust platform for the interrogation of disease aetiology and the development of new therapies. These concern the taming of human genetic variation, the identification of differentiation stages in which to uncover and validate phenotypes, and finally their translational into drug discovery assays. This project confronts these challenges focusing on the paradigmatic case of two rare but uniquely informative disorders caused by symmetric gene dosage imbalances at 7q11.23: Williams Beuren Syndrome and the subset of autism spectrum disorders associated to 7q11.23 microduplication. The hallmark of WBS is a unique behavioral-cognitive profile characterized by hypersociability and intellectual disability in the face of comparatively well-preserved language abilities. Hence, the striking symmetry in genotype and phenotype between WBS and 7dupASD points to the 7q11.23 cluster as a surprisingly small subset of dosage-sensitive genes affecting social behaviour and cognition. We build on a large panel of iPSC lines that we already reprogrammed from a unique cohort of WBS and 7dupASD patients and whose characterization points to specific derangements at the level of transcriptional/epigenetic control, protein synthesis and synaptic dysfunction. Through the integration of transcriptomic and epigenomic profiling with targeted mass spectrometry and gene network prediction we propose an innovative drug discovery pipeline for the identification of new therapeutic leads.

1 997 804 €

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

"Faithful chromosomal DNA replication is essential to maintain genome stability. A number of DNA metabolism genes are involved at different levels in DNA replication. These factors are thought to facilitate the establishment of replication origins, assist the replication of chromatin regions with repetitive DNA, coordinate the repair of DNA molecules resulting from aberrant DNA replication events or protect replication forks in the presence of DNA lesions that impair their progression. Some DNA metabolism genes are present mainly in higher eukaryotes, suggesting the existence of more complex repair and replication mechanisms in organisms with complex genomes. The impact on cell survival of many DNA metabolism genes has so far precluded in depth molecular analysis. The use of cell free extracts able to recapitulate cell cycle events might help overcoming survival issues and facilitate these studies. The Xenopus laevis egg cell free extract represents an ideal system to study replication-associated functions of essential genes in vertebrate organisms. We will take advantage of this system together with innovative imaging and proteomic based experimental approaches that we are currently developing to characterize the molecular function of some essential DNA metabolism genes. In particular, we will characterize DNA metabolism genes involved in the assembly and distribution of replication origins in vertebrate cells, elucidate molecular mechanisms underlying the role of essential homologous recombination and fork protection proteins in chromosomal DNA replication, and finally identify and characterize factors required for faithful replication of specific vertebrate genomic regions. The results of these studies will provide groundbreaking information on several aspects of vertebrate genome metabolism and will allow long-awaited understanding of the function of a number of vertebrate essential DNA metabolism genes involved in the duplication of large and complex genomes."

1 999 800 €

Start date: 2014-06-01, End date: 2019-05-31

The case of Ebla in northern Syria is certainly the most favourable one for enhancing our understanding of mechanisms of functioning of the early state. The discovery in 1975 of royal archives consisting of 17.000 cuneiform tablets dating to c. 2300 BC has supplied the scientific community with an invaluable mass of documents dealing with all aspects of state organization. These tablets inform us about the political, diplomatic and military affairs of the Eblaite state, as well as on the economic and social fabric of this early state formation. Further, considerable progresses during the past decade have been made at Ebla in seriating material culture assemblages, in interpreting the rich evidence for ancient visual communication and in exposing the urban structure. We now foresee a unique opportunity to test theories and models about the rise and structure of the early state by expanding the level of analysis to the landscape around Ebla: archaeological surface surveys, remote sensing, geomorphological studies will be evaluated together with the results of archaeological and geophysic investigations on village sites. Our research group has already considerable experience in developing calculation programs that employ along with traditional statistic and quantitative methods within a web GIS environment, including all the cuneiform tablets models of modern dynamic mathematics: the massive amount of data obtained from excavations, surveys, epigraphic studies, archeometric and archeobiological analyses will be combined and analyzed by means of mathematical, economical and computer science concepts and models, in order to build a multi-tier explanatory pattern which can be applied also to other early foci of urbanization in the Near East and elsewhere. We thus hope to gain a much richer historical framework and a sophisticated predictive model of general validity: until now no studies have ever focused on explanations of these phenomena on such an integrated scale

1 105 240 €

Start date: 2010-04-01, End date: 2014-03-31

With the ENSURE project I aim at attaining ground-breaking results in the field of superintense laser-driven ion acceleration, proposing a multidisciplinary research program in which theoretical, numerical and experimental research will be coherently developed in a team integrating in an unprecedented way advanced expertise from materials engineering and nanotechnology, laser-plasma physics, computational science. The aim will be to bring this topic from the realm of fundamental basic science into a subject having realistic engineering applications. The discovery in 2000 of brilliant, multi-MeV, collimated ion sources from targets irradiated by intense laser pulses stimulated great interest worldwide, due to the ultra-compact spatial scale of the accelerator and ion beam properties. The laser-target system provides unique appealing features to fundamental physics which can be studied in a small lab. At the same time, laser-ion beams could have future potential in many technological areas. This is boosting the development of new labs and facilities all over Europe, but to support these efforts, crucial challenges need to be faced to make these applications a reality. The goals of ENSURE are: i) design and production of nanoengineered targets, with properties tailored to achieve optimized ion acceleration regimes. This will be pursued exploiting advanced techniques of material science & nanotechnology ii) design of laser-ion beams for novel, key applications in nuclear and materials engineering iii) realization of engineering-oriented ion acceleration experiments, in advanced facilities iv) synergic development of all the required theoretical support for i,ii,iii). The results of the project can determine a unique impact in the research on laser-driven ion acceleration in Europe, providing new directions to support the attainment, in the next future, of concrete applications of great societal relevance, in medical, energy and materials areas.

1 887 500 €

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

EU Border Care is a comparative study of the politics of maternity care among undocumented migrants on the EU’s peripheries. Empirical analysis of personal and institutional relations of care and control in the context of pregnancy and childbirth will support an innovative critique of the moral rationale underpinning healthcare delivery and migration governance in some of Europe’s most densely crossed borderlands in France, Greece, Italy and Spain. Unlike other categories of migrants, undocumented pregnant women are a growing phenomenon, yet few social science or public health studies address EU migrant maternity care. This subject has urgent implications: whilst recent geopolitical events in North Africa and the Middle East have triggered a quantifiable increase in pregnant women entering the EU in an irregular situation, poor maternal health indicators among such women represent ethical and medical challenges to which frontline maternity services located in EU borderlands have to respond, often with little preparation or support from national and European central authorities. Grounded in long-term ethnographic fieldwork in maternity wards located in French Guiana and Mayotte (Overseas France), the North Aegean and Attica (Greece), Sicily (Italy), and Ceuta and Melilla (Spain), my project will trace the networks of maternity care delivery in peripheries facing an increase of immigration flows, and characterised by structural social and economic underinvestment. My team will investigate migrant maternity from three interlinked research perspectives: migrant women, healthcare delivery staff, and regional institutional agencies. Empirical and desk research, combined with creative audio-visual methods, will document migrant maternity on EU borderlands to address wider questions about identity and belonging, citizenship and sovereignty, and humanitarianism and universalism in Europe today.

1 498 463 €

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

Collisions of ultra relativistic nuclei are a tool to reach huge energy densities and to form a new state of matter called Quark-Gluon Plasma (QGP), where quarks and gluons can move freely. A number of experiments have studied the possible formation of QGP, but the behaviour of heavy particles such as charm (c) and beauty (b) quarks when they traverse this medium is largely unknown and is the most powerful tool to prove the creation of the QGP and to characterise it. I will perform novel measurements using the LHCb detector at CERN, which covers an unique kinematic region, essential for a full understanding of QGP and nuclear matter in general. LHCb has been optimised to perform c and b quark physics measurements in proton-proton collisions. In EXPLORINGMATTER I propose to extend the LHCb programme to collect for the first time data in heavy ion collisions. Three experimental scenarios are foreseen: (1) Collisions of protons, benchmark to understand the behaviour of the c and b particles in other more complicated environments, as well as providing the final answers to the mechanism of heavy quarkonium production; (2) Collisions of protons with heavy nuclei, where cold nuclear matter effects in high-energy collisions can be studied in detail to understand lead nuclei collisions, where QGP is expected to be formed. (3) Collisions of heavy nuclei, pursued (a) by analysing heavy nuclei interactions through a dedicated setup in which gas will be injected in the LHCb interaction region, reaching energy densities typical of dedicated fixed target experiments; (b) by collecting heavy ion collision data at the LHC. This second setup, which has not been envisaged by LHCb up to now will revolutionise the measurements in this area thanks to the LHCb coverage and precision not achievable by any other experiment. My measurements will furthermore indicate the route to new experiments that could be designed on the basis of these findings.

1 849 957 €

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

A foremost health problem stems from the burden of degenerative diseases, including heart failure, neurodegeneration, retinal degeneration and diabetes, essentially linked to the aging of the human population and the incapacity of post-mitotic tissues to undergo efficient repair. This is an ambitious, highly innovative project aimed at developing an in vivo selection procedure, based on gene transfer of two genetic libraries cloned into Adeno-Associated Virus (AAV)-based vectors, for the identification of novel secreted factors or microRNAs providing benefit against various degenerative diseases. Two arrayed libraries will be generated, one coding for ~1,300 cDNAs from the mouse secretome, the other for all known microRNAs (~800 genes). Pools of vectors from each library will be obtained with serotypes suitable for in vivo transduction of different organs. The vectors will be injected in a series of mouse models of degenerative disorders involving damage to cardiomyocytes,, neurodegeneration, retinal degeneration and loss of beta-cells in the pancreas. The degenerative conditions will drive the selection for secreted factors or miRNA putatively preventing cell apoptosis, enhancing residual cell function or, in the best possible scenario, promoting tissue regeneration. This in vivo selection approach, which is supported by very encouraging preliminary results, has never been attempted before and is rendered possible by the property of AAV vectors to be produced at high titers, infect tissues at high multiplicity, persist in the transduced cells for prolonged period of times and efficiently express their transgenes in vivo. In addition to its final goal of identifying novel biotherapeutics, the project entails the successful achievement of several intermediate objectives and is expected to extend both technology and knowledge beyond the state-of-the art.

1 824 000 €

Start date: 2010-04-01, End date: 2015-03-31

Geometric Measure Theory and, in particular, the theory of currents, is one of the most basic tools in problems in Geometric Analysis, providing a parametric-free description of geometric objects which is very efficient in the study of convergence, analysis of concentration and cancellation effects, chenges of topology, existence of solutions to Plateu's problem, etc. In the last years the PI and collaborators obtained ground-breaking results on the theory of currents in metric spaces and on the theory of surface measures in Carnot-Caratheodory spaces. The goal of the project is a wide range analysis of Geometric Measure Theory in spaces with a non-Euclidean structure, including infinite-dimensional spaces.

749 800 €

Start date: 2010-06-01, End date: 2015-05-31

Hairy Cell Leukemia (HCL), a chronic B-cell neoplasm, is initially sensitive to chemotherapy with purine analogs, but ~40% of patients eventually relapses and becomes less responsive to these drugs. Furthermore, purine analogs may cause myelotoxicity, immune-suppression and severe opportunistic infections. Therefore, molecularly-targeted less toxic drugs are highly desirable in HCL. However, its low incidence and the initial efficacy of purine analogs has made HCL an orphan in the world of cancer research and has spoiled the academic and industrial interest in developing better treatments for this disease. But recently we identified the V600E activating mutation in the BRAF kinase as the key genetic lesion of HCL (similar to BCR-ABL1 in chronic myeloid leukemia). Orally available specific BRAF inhibitors (e.g., Vemurafenib) have in the meantime showed remarkable efficacy in melanoma patients harboring the BRAF-V600E mutation, although resistance to such drugs eventually develops in this malignancy through reactivation of MEK (the downstream target of BRAF). The ground-breaking objective of this project is to introduce for the first time in HCL, by means of phase-2 investigator-driven pilot clinical trials, the concept of BRAF and/or MEK inhibition as an oral, non chemotherapy-based, entirely out-patient, genetics-driven and rationally designed treatment strategy, first in patients with active disease despite (or severe toxicity from) previous chemotherapy with purine analogs, and then, potentially, in the frontline setting. In comparison to melanoma, deeper and longer effect of BRAF inhibition may be expected in HCL, due to its much lower genetic complexity and proliferation rate. Anyway, potential mechanisms of resistance will be searched for to identify other genes recurrently mutated or aberrantly expressed in HCL patients developing resistance to BRAF inhibition (if any), and the clinical feasibility of combined BRAF and MEK inhibition will be addressed.

2 000 000 €

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

The HEROIC project aims at filling the gap between the currently low operation frequencies of printed, organic flexible electronics and the high-frequency regime, by demonstrating polymer-based field-effect transistors with maximum operation frequencies of 1 GHz and complementary integrated logic circuits switching in the 10-100 MHz range, fabricated by means of printing and direct-writing scalable processes in order to retain low temperature manufacturability of cost-effective large area electronics on plastic. The recent development of semiconducting polymers with mobilities in the range of 1 to 10 cm^2/Vs, and even higher in the case of aligned films, suggests that suitably downscaled printed polymer transistors with operation frequencies in the GHz regime, at least three orders of magnitude higher than current printed polymer devices, are achievable, by addressing in a holistic approach the specific challenges set in the HEROIC trans-disciplinary research programme: (i)development of scalable high resolution processes for the patterning of functional inks, where printing will be combined with direct-writing techniques such as fs-laser machining, both in an additive and subtractive approach; (ii)development of printable nanoscale hybrid dielectrics with high specific capacitance, where low-k polymer buffer materials will be combined with solution processable high-k dielectrics, such as insulating metal oxides; (iii)improvement of the control of charge injection and transport in printed polymer and hybrid semiconductors, where high-mobility 1-D and 2-D structures are included in polymer films; (iv)development of advanced printed and direct-written transistors architectures with low parasitic capacitances for high-speed operation. HEROIC will radically advance and expand the applicability of polymer-based printed electronics, thus making it suitable for next generation portable and wearable short-range wireless communicating devices with low power consumption.

1 608 125 €

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

"Partial Differential Equations (PDEs) are widely used in science and engineering simulations, often in tight connection with Computer Aided Design (CAD). The Finite Element Method (FEM) is one of the most popular technique for the discretization of PDEs. The IsoGeometric Method (IGM), proposed in 2005 by T.J.R. Hughes et al., aims at improving the interoperability between CAD and FEMs. This is achieved by adopting the CAD mathematical primitives, i.e. Splines and Non-Uniform Rational B-Splines (NURBS), both for geometry and unknown fields representation. The IGM has gained an incredible momentum especially in the engineering community. The use of high-degree, highly smooth NURBS is extremely successful and the IGM outperforms the FEM in most academic benchmarks. However, we are far from having a satisfactory mathematical understanding of the IGM and, even more importantly, from exploiting its full potential. Until now, the IGM theory and practice have been deeply influenced by finite element analysis. For example, the IGM is implemented resorting to a FEM code design, which is very inefficient for high-degree and high-smoothness NURBS. This has made possible a fast spreading of the IGM, but also limited it to quadratic or cubic NURBS in complex simulations. The use of higher degree IGM for real-world applications asks for new tools allowing for the efficient construction and solution of the linear system, time integration, flexible local mesh refinement, and so on. These questions need to be approached beyond the FEM framework. This is possible only on solid mathematical grounds, on a new theory of splines and NURBS able to comply with the needs of the IGM. This project will provide the crucial knowledge and will re-design the IGM to make it a superior, highly accurate and stable methodology, having a significant impact in the field of numerical simulation of PDEs, particularly when accuracy is essential both in geometry and fields representation."

928 188 €

Start date: 2014-06-01, End date: 2019-05-31

"HOLMES is aimed at directly measuring the electron neutrino mass using the electron capture (EC) decay of 163Ho. The measurement of the absolute neutrino mass represents a major breakthrough in particle physics and cosmology. Due to their abundance as big-bang relics, massive neutrinos strongly affect the large-scale structure and dynamics of the universe. In addition, the knowledge of the scale of neutrino masses, together with their hierarchy pattern, is invaluable to clarify the origin of fermion masses beyond the Higgs mechanism. The innovative approach of HOLMES consists in the calorimetric measurement of the energy released in the decay of 163Ho. In this way, all the atomic de-excitation energy is measured, except that carried away by the neutrino. A finite neutrino mass m causes a deformation of the energy spectrum which is truncated at Q-m, where Q is the EC transition energy. The sensitivity depends on Q - the lower the Q, the higher the sensitivity - and 163Ho is an ideal isotope with a Q around 2.5keV. The direct measurement exploits only energy and momentum conservation, and it is therefore completely model-independent. At the same time, the calorimetric measurement eliminates systematic uncertainties arising from the use of external beta sources, as in neutrino mass measurements with beta spectrometers, and minimizes the effect of the atomic de-excitation process uncertainties. HOLMES will deploy a large array of low temperature microcalorimeters with implanted 163Ho nuclei. The resulting mass sensitivity will be as low as 0.4eV. HOLMES will be an important step forward in the direct neutrino mass measurement with a calorimetric approach as an alternative to spectrometry. It will also establish the potential of this approach to extend the sensitivity down to 0.1eV. The detection techniques developed for HOLMES will have an impact in many frontier fields as astrophysics, material analysis, nuclear safety, archeometry, quantum communication."

3 057 067 €

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

The recent hypothesis that postnatal microglia are maintained independently of circulating monocytes by local precursors that colonize the brain before birth has relevant implications for the treatment of various neurological diseases, including lysosomal storage disorders (LSDs). LSDs are fatal diseases of childhood occurring in 1:5000-7000 live births; in >50% of the cases, LSD patients experience a severe neurological deterioration. Most LSDs with central nervous system (CNS) involvement lack a curative treatment. Hematopoietic cell transplantation (HCT) form healthy donors is applied to LSD patients in order to repopulate the recipient myeloid compartment, including CNS microglia, with donor-derived cells expressing the defective functional hydrolase. Over the past three decades, about 1000 HCTs have been performed for patients with LSDs with a variable benefit exerted on the CNS. The positive results obtained in Hurler syndrome and few other LSDs and the benefit observed in our on going Phase I/II clinical trial of HSC gene therapy for the demyelinating LSD metachromatic leukodystrophy indicate that migration of the transplanted Hematopoietic Stem Cells (HSCs)/their progeny into the affected human brain occurs. However, timing of resident CNS macrophages and microglia replacement by the transplanted cell progeny is frequently too slow for clinical benefit due to the rapid progression of the primary neurological disease, particularly in the most aggressive LSD variants. Thus, a deep understanding of the modalities, time course and factors that affect this phenomenon might allow enhancing clinical benefit of HSC-based approaches for treating the LSD brain disease. The proposed work, combining basic and innovative preclinical research with the information derived from a pioneering clinical experience, will generate the basis for designing more efficacious and safer transplant approaches for these fatal diseases.

1 751 147 €

Start date: 2014-06-01, End date: 2020-05-31

Much has been said on how to reduce current anthropogenic emissions with the aid of a portfolio of existing technologies. However, stabilization of atmospheric concentrations of greenhouse gasses to a safe level requires that over time net emissions fall to zero. There is only one way that this can be achieved in a manner that is acceptable to the majority of the world's citizens: through some kind of technological revolution. To bring about such an innovation breakthrough extensive research and development (R&D) investments will be required. This will be specifically important for Europe, given its leading position in climate negotiations and in the light of the Lisbon Agenda. Technological breakthroughs will have an essential role in tackling the competitiveness issue that has gained great relevance lately in the policy debate. On top of this, technological transfers to Developing Countries could be the turning key to solve the logjam affecting international negotiations. The current proposal aims at producing an unprecedented analysis of energy-related innovation mechanisms; understanding the role of R&D investments and of inter countries and inter sector spillovers; disentangling the role of public and private R&D investments; incorporating in the analysis the uncertainty that inevitably affects the successfulness of R&D programs; simulating optimal responses using an integrated assessment model. The analysis will make use of empirical analysis of existing databases and will collect new data. Expert elicitation methods will be used in order to better assess technology-specific uncertain effectiveness of R&D programs. Simulation models will be used to produce quantitative grounded results. Summa of the analyses will be projections for optimal public and private energy R&D and energy technologies investment strategies as a product of a cost effectiveness analysis of a stringent climate stabilization target.

920 000 €

Start date: 2010-01-01, End date: 2013-09-30

The iMPACT project focuses on the realization of a proton Computed Tomography (pCT) scanner capable of acquiring a target full 3D image with 1s exposure, therefore opening the way to the practical application of proton imaging technique in medical radiotherapy treatments. Such cutting-edge particles scanner combines innovative ideas devised for the future High Energy Physics experiments together with original developments in the microelectronic field to enable charged particles imaging at the GHz scale. In recent years the use of hadrons (1H and 12C ions) for cancer radiation treatment has become an established technique and many facilities are currently operational or under construction worldwide. To fully exploit the therapeutic advantages offered by hadron therapy, precise target (body) imaging for accurate beam delivery is decisive. pCT systems, currently in their R&D phase, provide the ultimate in low dose (< 2 mGy), 3D imaging for hadrons treatment guidance. Key components of a pCT system are the detectors used to track the protons and measure their residual energy. The iMPACT scanner, composed by a proprietary monolithic pixels tracking detector and an innovative achromatic calorimeter, will improve current pCT imaging speed by more than a factor 100, leading to potential recording times of about 1 second for a full 3D target image (compared to present ≈ 10 minutes). The iMPACT detector will also have higher spatial resolution (equal or better than 10 µm) and lower material budget (by a factor 10) respect to state of the art systems, further enhancing 3D imaging accuracy. Not least when considering actual industrial application, production costs will be far lower than existent systems, because all sensors will be designed with commercially available technologies, making it possible to move pCT from the academic research realm to that of viable medical equipment.

1 810 000 €

Start date: 2016-01-01, End date: 2019-12-31

The goal of this proposal is to advance the theory of decentralized trade with informational asymmetries and limited commitment. In most trading situations, some of the parties possess superior information about critical aspects of the environment. For example, in financial markets, professional investors are better informed about the quality of the assets that they sell to individuals. Similarly, consumers typically have private information about their willingness to pay for goods and services. It is well understood that informational asymmetries are responsible for one of the most serious forms of market inefficiency. Because of its strong assumptions in term of commitment, the standard theory of mechanism design is unsuitable for the study of many actual trading institutions. On the other hand, the focus of most of the existing literature on trading with limited commitment is the case in which the parties can trade at most once. While satisfactory in situations like the sale of a house, this assumption leaves out many important economic environments where the parties trade repeatedly over time. However, repeated transactions are natural both when the objects of trade are non-durable (e.g., services such as phone or internet plans) and when they are durable but divisible (e.g., financial assets). A crucial difference between these cases and those analyzed in the literature is the fact that the information revealed in early transactions may affect the outcome of future negotiations. We plan to provide a systematic game-theoretic analysis of decentralized markets with repeated trading and informational asymmetries. Our investigation will shed light on the properties of various commonly used trading mechanisms and will inform us about possible remedies to make them more efficient. This will contribute substantially to the design of adequate institutions and to the regulation of markets.

827 410 €

Start date: 2014-03-01, End date: 2018-02-28

Chemicals detection is a crucial problems that Chemistry is addressing since its origin and one of the most important in the everyday life (diagnosis, environment analysis). The most common analytical techniques (chromatography, mass spectrometry, Elisa assays) are able to efficiently separate and detect the target compound but provide only indirect information on its identity and may fail in the identification of new compounds. On the other hand, Nuclear Magnetic Resonance (NMR) spectrometry is probably the most powerful technique in identifying organic compounds. Unfortunately, even if highly desired, a robust method that may allow the use of NMR for analysing mixtures of compounds does not exist. The research activity carried out by Fabrizio Mancin as PI of the ERC project MOSAIC has recently led to the invention of “NMR sensing”, a new method that allow both the detection and identification of organic molecules, based on the use of NMR spectrometry and nanoparticles. In a simplified picture, the nanoparticles added to the sample are able to “capture” and “label” the target molecule in such a way that the NMR experiment sees only the target and is not disturbed by the other compounds present in the sample. In this way, detection, unambiguous identification and quantification of the analyte are simultaneously possible in a single experiment. This method, already covered by a Patent, showed excellent preliminary results and could find several application in the chemical analysis and diagnostic fields. The goal of this Proof of Concept application is to bring the “NMR sensing” method at the level of an attractive commercial proposal. In particular, the plan include technical testing and preliminary product realization, recruitment of financial and management competencies, collection of information and data capable to indicate the best strategy to create of a start-up company to be presented to venture capitalists/industrial partners to raise further funding.

150 000 €

Start date: 2015-01-01, End date: 2016-06-30

"Failure in ductile materials results from a multiscale interaction of discrete microstructures hierarchically emerging through subsequent material instabilities and self-organizing into regular patterns (shear band clusters, for instance). The targets of the project are: (i.) to disclose the failure mechanisms of materials through analysis of material instabilities and (ii.) to develop innovative microstructures to be embedded in solids, in order to open new possibilities in the design of ultra-resistant materials and structures. The link between the two targets is that micromechanisms developing during failure inspire the way of enhancing the mechanical properties of materials by embedding microstructures. The aim is to provide design tools to obtain groundbreaking and unchallenged mechanical properties employing discrete microstructures, for instance to design a microstructure defining a material working under flutter condition. The design of these microstructures will permit the achievement of innovative dynamical properties, defining elastic metamaterials, for instance, permitting the fabrication of flat lenses for elastic waves, evidencing negative refraction and superlensing effects. The objective is the discovery of these effects in mechanics, thus disclosing new horizons in the dynamics of materials. Microstructures introduce length scales and nonlocal effects in the mechanical modelling, which involve the use of higher-order theories. The analysis of these effects, usually developed within a phenomenological approach, will be attacked from the fundamental and almost unexplored point of view: the explicit evaluation of nonlocality, related to the microstructure via homogenisation theory."

2 379 359 €

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

This proposal addresses the design, manufacturing and control of interfaces in thermally conductive polymer/graphene nanocomposites. In particular, the strong reduction of thermal resistance associated to the contacts between conductive particles in a percolating network throughout the polymer matrix is targeted, to overcome the present bottleneck for heat transfer in nanocomposites. The project includes the investigation of novel chemical modifications of nanoparticles to behave as thermal bridges between adjacent particles, advanced characterization methods for particle/particle interfaces and controlled processing methods for the preparations of nanocomposites with superior thermal conductivity. The results of this project will contribute to the fundamental understanding of heat transfer in complex solids, while success in mastering interfacial properties would open the way to a new generation of advanced materials coupling high thermal conductivity with low density, ease of processing, toughness and corrosion resistance.

1 404 132 €

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

"This path-breaking interdisciplinary project critically analyses the impact of the increased prominence of the individual in the theory and practice of armed conflict. The ‘individualisation of war’, while based on powerful normative and technological developments, places enormous strain on the actors most actively engaged in contexts of conflict: the governments and armed forces of states, international security organisations, and humanitarian agencies. Individualisation has generated new kinds of ‘humanitarian’ wars and peacekeeping missions, as well as precision weapons which enable both the targeted killing of those individuals deemed most liable for acts of war or terror, and the protection of innocent civilians caught up in armed conflict or acts of state suppression. It has also facilitated the injection of human rights law into the law of armed conflict, and a new class of international crimes for which individuals can be held accountable. We hypothesise that efforts to operationalise protection, liability, and accountability are all underpinned by a tension between the newly privileged moral and legal claims of individuals and the more traditional ones of sovereign states. The ethical, legal, and political dilemmas raised by these efforts demonstrate just how contested the process of individualisation remains, and how uncertain is its eventual endpoint. The research of our distinguished inter-disciplinary team will produce two main outcomes: the first integrated conceptual framework for explaining and resolving the dilemmas raised by the individualisation of war; and concrete recommendations for policy actors - both on how to respond to particular ethical, legal, or political challenges and on how to shape the longer term trajectory of individualisation."

2 397 577 €

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

"This project is intended to lead to the identification, design and development of a novel, economically viable pre-industrial process, to make the world's toughest synthetic fibres. Our new concept to obtain fibers with unconventional toughness is indeed very simple and robust: the introduction in high-strength fibers of a smart frictional element, in the form of a large slip loop in a slider, that in its simplest configuration is a knot. A preliminary proof of concept implementation has already been performed, realizing the highest toughness value for a fiber to date, using commercial Zylon® and reaching 1400 J/g, surpassing for the first time 1000 J/g. This knot-based manufacturing strategy is already a milestone of the ERC Starting Grant ""Bio-inspired Hierarchical Super Nanomaterials"" (BIHSNAM), and it has proven to be an extremely simple yet efficient way for the production of ultra-tough materials. Instead of pursuing the synthesis of new materials, we fully exploit the potential of already existing ones, with an evident improvement in the potential quality of current industrial production, exploiting a relatively uncomplicated and economical, and therefore industrially attractive method. The aim of KNOTOUGH is therefore to optimize (identifying the proper slider element, e.g. knot topology, for maximizing toughness), consolidate and develop this manufacturing procedure, taking it to a pre-commercial stage, with potential applications in all those industrial manufacturing sectors where energy absorption is important (e.g., sporting goods, automotive, aerospace, protective devices)."

149 490 €

Start date: 2015-03-01, End date: 2016-02-29

Our visual system can effortlessly recognize hundreds of thousands of objects in spite of tremendous variation in their appearance, resulting, for instance, from changes in object position and pose. Achieving such an invariant representation of the visual world is an extremely challenging computational problem that even the most advanced artificial vision systems are not fully able to solve. This is why understanding the neuronal mechanisms underlying object vision is one of the major challenges of systems neuroscience and a crucial step towards developing artificial vision systems and visual prostheses. Little is known yet about how the brain develops and maintains invariant object representations. The leading theory is that visual neurons exploit the spatiotemporal continuity of visual experience (i.e., the natural tendency of different object views to occur nearby in time) to learn to produce similar responses for temporally contiguous stimuli, so as to factorize object identity from other variables (such as position, size, etc.). This Unsupervised Temporal Learning (UTL) strategy has been instantiated in a number of computational frameworks, but its empirical investigation has received little attention. My proposal will use the visual system of the rat to address key questions about the nature of UTL and other learning theories, such as their impact on recognition behavior and object representations at both single-neuron and population level, and their role during early postnatal development. This will be achieved through a highly multidisciplinary approach, including high-throughput behavioral testing, in vivo neuronal recordings, immediate-early gene labeling, controlled-rearing in virtual visual environments, and computational modeling. This will lead to ground-breaking insights into the learning principles that sculpt the cortical representations of visual objects through unsupervised exposure to the spatiotemporal statistics of visual experience.

2 000 000 €

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

In the field of fundamental particle physics the neutrino has become more and more important in the last few years, since the discovery of its mass. In particular, the ultimate nature of the neutrino (if it is a Dirac or a Majorana particle) plays a crucial role not only in neutrino physics, but in the overall framework of fundamental particle interactions and in cosmology. The only way to disentangle its ultimate nature is to search for the so-called Neutrinoless Double Beta Decay (0½DBD). The goal of LUCIFER is to build a background-free 0½DBD experiment with a discovery potential better than the future, already approved, funded experiments. Although aiming at a discover, in the case of insufficient sensitivity the LUCIFER technique will be the demonstrator for a higher mass experiment able to probe the entire inverted hierarchy region of the neutrino mass and to start approaching the direct one. The idea of LUCIFER is to join the bolometric technique proposed for the CUORE experiment (one of the few 0½DBD experiments in construction world-wide) with the bolometric light detection technique used in cryogenic dark matter experiments. The bolometric technique allows an extremely good energy resolution while its combination with the scintillation detection offers an ultimate tool for background rejection. Preliminary tests on several 0½DBD detectors have clearly demonstrated the excellent background rejection capabilities that arise from the simultaneous, independent, double readout (heat + scintillation).

3 294 400 €

Start date: 2010-03-01, End date: 2016-02-29

This project aims at providing novel foundations for the aggregate supply and demand blocks of current macro models, which are extensively used for policy evaluation. On the aggregate-supply side, the first part of the proposal is motivated by recent extensive and consistent empirical evidence on the presence of downward nominal and real rigidities in developed economies. The objective is to investigate the theoretical and empirical implications of including these rigidities in current macro models for: 1) the long-run relationships between inflation, unemployment and productivity growth; 2) the joint dynamics of inflation and unemployment; 3) the role of macroeconomic volatility in influencing these relationships; 4) the distribution of wages. From the policy perspective, several key implications would be examined in terms of the optimal inflation rate and the appropriate degree of stabilization policies. The second part of the proposal deals with the aggregate-demand side of current models and particularly with the specification of the stochastic discount factor. It is a well-known fact that macro models are unable to match the asset-price implications of the data. These shortcomings are more pronounced in open-economy models since the stochastic discount factors also determine the cross-country distribution of wealth and the portfolio allocations. The project will: 1) document the failures of standard preferences in accounting for several puzzles; 2) study whether there exists some stochastic discount factor that can be consistent with the data and with no-arbitrage theories; 3) add a macro structure on this stochastic discount factor while maintaining its consistency with data. In reference to the latter point, particular attention will be devoted to near-rational theories of optimizing behaviour in which the distortions in the subjective probability distributions can be related to macro variables through an optimizing model. Finally, the research under this proposal will integrate the findings of part 1) and part 2) of the project to propose more realistic frameworks in which it is possible to investigate how investment and consumption decisions change when agents’ evaluation of future contingencies is distorted or uncertain. In particular, the project aims at investigating how monetary policy should be set when agents fear model misspecification, which manifests itself thorugh considerable and realistic premia in holding risky assets.

648 000 €

Start date: 2009-11-01, End date: 2014-10-31

The project addresses the mechanical bases of cell motility by swimming and crawling, and the possibility of replicating the principles behind them in artificial systems. The goals are to elucidate some key mechanisms governing bio-locomotion. In particular, actin- based motility of crawling cells and motility by swimming of unicellular organisms will be studied both in general and with reference to concrete model systems. The study of biological examples of swimming and crawling motility will be used to produce a prototype of a micron-scale bio-inspired motile micro-robot exploiting the miniaturization that becomes possible from the extensive use of active materials. This is a multi-disciplinary research project. The themes arise from the Mechanics of Soft and Bio- logical Matter. The methods are those of Computational Engineering, and take advantage of innovative techniques from Applied Mathematics. The planned research activities rest on the development of new tools and methods in mathematical modeling, numerical simulation, data acquisition on biological systems, and on the construction of prototype devices. ***

1 302 270 €

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

Subjective everyday experience entails a well-structured and continuous flow of sensory signals, actions, thoughts and emotions. How does the brain build such a coherent representation of space and time despite the vast amount and confusing nature of the input? Furthermore, what are the physiological constraints preventing simultaneous awareness of multiple spatial and temporal instances? Here I propose a novel approach (&quot;brain modes&quot;) to investigate these issues within life-like experimental settings. I will investigate how the brain selects and integrates relevant information using complex dynamic environments that includes space, time and multisensorial inputs. Combining model-free and model-driven analyses of functional imaging data I will examine: 1. How signals in different sensory modalities and same/different locations interact in complex environments; 2. How contextual information influences memory encoding and retrieval and the ability to integrate current sensory signals with events in the past. 3. How prospective goals and expectancies arising from the temporal dynamic of the context influence on-line processing. My expectation is that the results will reveal novel mechanisms underlying the ability to organise information in an orderly manner, on a time-line spanning the past, the present and the future; and how we can direct our thoughts along this time-line. My investigation will provide new evidence on the capacity limitations of this selection process and how integration and competition interact to form a representation of the external world that evolves as a coherent flow through space and time. Potential practical implications are foreseen for the design of brain-machine interfaces and for understanding the abnormal perceptions of mental illness.

1 219 597 €

Start date: 2010-07-01, End date: 2015-06-30

Forecasting and monitoring key economic variables is one of the main activities of financial and government institutions, forecasting agencies, and investment companies. In the ERC-funded starting grant (ERC-2007-StG: Change-Point Tests) we developed novel models and tests for forecasting key economic indicators (such as economic activity, financial volatility and others) as well as evaluating the reliability of model predictions. In many cases our methods improve upon the current-state-of-art. The idea of this ERC Proof of Concept (PoC) grant is to use these novel models and tests to develop a software/toolbox that forecasts and monitors economic indicators. Most available forecasting software lack real-time monitoring and predictive breakdown tests which are important for reliable forecasts especially in periods of instability. Our forecasting and monitoring toolbox can improve the reliability of forecasts as follows: (1) using a novel family of models and high frequency information (2) monitoring forecasts in real-time (3) using new predictive tests of potential breakdowns. Such economic forecasts are at the heart of economic decision making made by governments, Central Banks, and firms that are potential users of our toolbox. In this ERC PoC we will initially work with a forecasting agency and a Central Bank, given contacts have already been established, in order to examine various aspects of the development of this toolbox such as: building a user-friendly software, developing a three-dimensional graphical representation of the monitoring and predictive breakdown tests, and generally making our new methods accessible to decision makers. The overall objective of this ERC PoC grant is to provide a software with innovative techniques that can improve economic forecasts and thereby economic decision making. Reliable economic forecasts can lead to prudent economic policy making and affect the growth, economic and social welfare of countries, firms and individuals.

150 000 €

Start date: 2015-10-01, End date: 2017-03-31

The currently available computational methods have often serious limitations to treat systems where electron correlation plays and important role. Many issues concerning the electronic structure of radicals, photoreceptors near-half-filled transition metals (Cr,Mo,Fe,Ni) are of paramount relevance in basic and applied research in Chemistry and Biochemistry, but still out of the capabilities of standard and conventional tools such as Density Functional Theory. On the other hand, post Hartree-Fock methods computationally more expensive and their application is limited to few atoms. The objective of the present proposal is to overcome these limitations and to develop and apply a multiscale, innovative and unconventional computer simulation technique to unravel the electronic properties of strongly correlated chemical and biochemical systems. The methodology is based on a combined approach between Quantum Monte Carlo (QMC), DFT and Molecular Mechanics. The proposed approach has a faster scaling of the calculation time with the system size N with respect others standard quantum chemistry methods of equivalent level (~ N4 vs ~ N7). es to address challenging open problems in the chemistry and biochemistry of radical compounds, photoreceptors, and transition metal catalysis and enzymatic activity. Application to photoreceptors include the study of the spectral properties of rhodopsin, the integral membrane protein responsible of the light detection in the retina. Applications on transition metal molecules will shed the light on the catalytic strategies of iron-based enzymes and their corresponding biomimetic compounds.

1 200 000 €

Start date: 2009-10-01, End date: 2015-09-30

Nanoscience promises innovative solutions in a large variety of sectors, ranging from cost-effective optoelectronic devices to energy generation, and to highly performing materials and interfaces. Realizing this promise will rely heavily on a bottom-up approach. This can only succeed if self assembly of advanced nanoscale building blocks will be developed intensively, to enable creation of useful macroscopic architectures. The unconventional assembly of nanocrystals towards functional materials is the area where this proposal aims at providing a key contribution. This will be achieved via ground-breaking advances in the fabrication of shape controlled nanocrystals, via solution approaches, in their organization following radically new concepts and in the study of their assembly related properties. The bottom line here is to tune the assembly process of nanocrystals so as to generate a desired functionality or a combination of functionalities. This would represent a dramatic leap forward from the trial-and-error approach to controlling the various properties that is currently prevalent in many of the communities working in the field of nanocrystals. The primary motivation of this proposal is therefore to correlate strongly the structural properties with the behaviour of nanostructured assemblies. This is clearly a cutting edge research program, at the frontier of chemistry, physics, materials science and engineering, and whose successful outcome will be of tremendous benefit in several fields.

1 299 960 €

Start date: 2009-11-01, End date: 2013-10-31

The experimental results of the first run of the Large Hadron Collider lead to the discovery of the Higgs boson but have not confirmed the dominant theoretical paradigm about the naturalness of the electro-weak scale, according to which the Higgs boson should have been accompanied by supersymmetric particles or by some other new physics able of protecting the Higgs boson mass from quadratically divergent quantum corrections. While the second LHC run is going to explore physics at higher energies in the next years, it is now the right moment to explore and develop new non conventional ideas about the origin of mass scales in nature and in particular of the electro-weak scale. Indeed, new theoretical ideas prompted by the fact that the standard paradigm is challenged by experiments, have been emerging in the past 1-2 years and are acquiring interest. Furthermore, in view of the large backgrounds unavoidably present at the Large Hadron Collider, unexpected discoveries could be delayed or even missed if experimentalists are not searching in the right direction. The experimental signatures of the new non-conventional models need to be identified now. Research performed by the PI and by the senior team members shows that concrete progress can be achieved in developing new non-conventional ideas about how the electroweak scale and the gravitational Planck scale can be dynamically generated with a vastly different ratio, as observed in nature. However, dedicated funding is needed for younger researches that want to explore such directions outside the mainstream. The main goal of this project is developing such new ideas and identifying their experimental signals.

1 876 215 €

Start date: 2015-12-01, End date: 2021-11-30

When we see an object, hear a sound or smell an odor, precise spatial and temporal patterns of electrical activity are generated within neuronal networks located in specialized brain areas. This electrical representation of the external stimulus mediates perception and sensory experience. However, this process is highly variable, and repetition of the very same sensory experience results in distinct network activity patterns. What does this variability mean for perception? Do distinct activity patterns carry different information about the stimulus? Or rather, does the brain code the same information coming from the outside world in multiple and equivalent ways? Answering these questions and determining how patterns of activity in neuronal populations are used for behavior has not been possible because of the inability to change the activity of neurons with single cell precision over large networks in an intact mammalian brain. In this ambitious proposal we will take a multidisciplinary approach to causally address these questions and decipher the computational principles of brain networks. To achieve this goal we will develop innovative optical technologies for manipulating and monitoring brain circuits with single cell resolution in the intact mouse brain. We will combine these new techniques with novel genetic manipulations and psychophysical behavioral methods that allow precise quantification of animals’ perceptual performance. Using this unique set of tools, we will unravel how the spatial (across neurons) and temporal (across time) aspects of neuronal electrical activity patterns encode information that guides behavior. In achieving our goals we will produce a new technology for stimulating and monitoring neurons in the brains of behaving animals with single-cell specificity that can be adapted to explore cellular dynamics in highly scattering biological media.

1 974 000 €

Start date: 2015-10-01, End date: 2020-09-30

"Neurons and blood vessels rely on common guidance signals to wire into elaborate neural and vascular networks that are closely juxtaposed and interdependent: vascular supply of oxygen and nutrients is essential to sustain the high metabolic rate of the nervous system, and conversely neural control of vascular tone is crucial for circulatory homeostasis. However, it remains unclear how the nervous and vascular systems establish an intimate physical and functional relationship. This proposal seeks to reveal the developmental mechanisms that link neuronal connectivity and vascularization of the nervous system, focusing on the interactions between vascular endothelial cells and spinal motor neurons that control locomotion, respiration and autonomic responses. Motor neuron diseases and a variety of other neurodegenerative conditions are precipitated by vascular abnormalities. Thus, understanding the molecular basis of neurovascular crosstalk may offer novel therapeutic opportunities. My group will use mutagenesis-based forward genetics in reporter mice combined with gene profiling of motor neurons and endothelial cells to screen for novel regulators of neurovascular interactions and pathfinding. Candidate genes will be further characterized using in vivo mouse and chick models, in addition to in vitro studies to uncover the mechanisms of action. Through this multi-disciplinary approach, the proposal will address these fundamental questions: (i) Do neurovascular interactions instruct the assembly of neural and vascular networks? (ii) What signaling pathways connect region-specific vascularization of the CNS to the local metabolic and functional demand of neuronal tissues? (iii) What mechanisms account for specificity, spatiotemporal control and integration of guidance signaling? In addition, this research plan will generate comprehensive transcriptional/proteomic datasets and novel mouse mutants for future studies of neurovascular communication and patterning."

1 653 000 €

Start date: 2015-01-01, End date: 2019-12-31

Many therapeutic applications of stem cells require accurate control of their differentiation. To this purpose there is a major ongoing effort in the development of advanced culture substrates to be used as “synthetic niches” for the cells, mimicking the native ones. The goal of this project is to use a synthetic niche cell culture model to test my revolutionary hypothesis that in stem cell differentiation, nuclear import of gene-regulating transcription factors is controlled by the stretch of the nuclear pore complexes. If verified, this idea could lead to a breakthrough in biomimetic approaches to engineering stem cell differentiation. I investigate this question specifically in mesenchymal stem cells (MSC), because they are adherent and highly mechano-sensitive to architectural cues of the microenvironment. To verify my hypothesis I will use a combined experimental-computational model of mechanotransduction. I will a) scale-up an existing three-dimensional synthetic niche culture substrate, fabricated by two-photon laser polymerization, b) characterize the effect of tridimensionality on the differentiation fate of MSC cultured in the niches, c) develop a multiphysics/multiscale computational model of nuclear import of transcription factors within differentially-spread cultured cells, and d) integrate the numerical predictions with experimentally-measured import of fluorescently-labelled transcription factors. This project requires the synergic combination of several advanced bioengineering technologies, including micro/nano fabrication and biomimetics. The use of two-photon laser polymerization for controlling the geometry of the synthetic cell niches is very innovative and will highly impact the fields of bioengineering and biomaterial technology. A successful outcome will lead to a deeper understanding of bioengineering methods to direct stem cell fate and have therefore a significant impact in tissue repair technologies and regenerative medicine.

1 903 330 €

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

The expansion of a dilute gas through a gasdynamics convergent-divergent nozzle can occur in three different regimes, depending on the inlet and discharge conditions and on the gas: via a fully subsonic expansion, via a subsonic-supersonic or via a subsonic-supersonic-subsonic expansion embedding a compression shock wave within the divergent portion of the nozzle. I devised an exact solution procedure for computing nozzle flows of real gases, which allowed me to discover that in molecularly complex fluids eighteen additional different flow configurations are possible, each including multiple compression classical shocks as well as non classical rarefaction ones. Modern thermodynamic models indicate that these exotic regimes can possibly occur in nozzle flows of molecularly complex fluids such as hydrocarbons, siloxanes or perfluorocarbons operating close to the liquid-vapour saturation curve and critical point. The experimental observation of one only of these eighteen flow configurations would be sufficient to prove for the first time that non classical gasdynamics phenomena are indeed possible in the vapour region of a fluid with high molecular complexity To this purpose, a modification to the blow-down wind tunnel for dense gases at Politecnico di Milano is proposed to use mixtures of siloxane fluids. Measurements are complemented by numerical simulations of the expected flow field and by state-of-the-art uncertainty quantification techniques. The distinctive feature of the proposed experiment is the adoption of mixture of siloxanes as working fluids. Mixtures of siloxanes are well known to exhibit an higher stability limit than their pure components, due to the redistribution process occurring at high temperature. The increased understanding of real-gas dynamics will enable to improve the design of Organic Rankine Cycle Engines, to be used in small scale energy production from biomasses, binary geothermal systems and concentrating solar thermal power plants.

1 485 600 €

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

Evidence demonstrating the presence of mirror neurons in the adult human brain has led many researchers to suggest a fundamental role for the mirror neuron system (MNS) in human mentalizing behavior and social cognition. Recent findings have also suggested strong relationships between MNS impairments and neurodevelopmental disorders in which mentalizing behavior is impaired. In light of this evidence, it has become of paramount importance to understand whether or not the MNS is present at birth and how its functional properties develop throughout infancy. The current project will address these questions within the context of a neuroconstructivist framework, according to which a basic perception-action coupling mechanism would be present from birth, and undergoes a series of refinements through experience and visuomotor learning. Using behavioral, electromyographic and electrophysiological measures, the project aims to investigate action understanding and emotion recognition in newborns and infants. Behavioral looking time and eye-movement paradigms will be used to test infants ability to visually anticipate the action s goal. Electromyographic paradigms will allow for testing of when and how the activation of infants muscles is affected by the goal of the observed action or the emotion expressed by the observed face. Electrophysiological paradigms will be used to investigate modulations of infants EEG activity during the execution and observation of grasping actions.

1 208 400 €

Start date: 2009-12-01, End date: 2015-05-31

Cancer remains a major health burden worldwide. The aggressive targeting of metabolic pathways shared by normal and cancer cells results in prolonged survival and cures, but at a tremendous cost to patient life quality. What is missing is a therapeutic agent that clearly differentiates normal and cancer cells. This proposal delineates a process for killing exclusively cancer cells with no interference with normal cells. In the past two decades there has been considerable effort to develop attenuated viruses for killing cancer cells. Of the oncolytic viruses in clinical trials, attenuated herpes simplex viruses (HSV) are among the most promising because of safety, affinity for cancer cells, ability to treat patients multiple times without block by adaptive immunity. The shortcoming is that they do not discriminate between normal and cancer cells, are effective in a limited number of patients. The remarkable accomplishment by my laboratory at the basis of the proposal is the genetic engineering of HSVs that specifically infect and kill cancer cells and cannot infect normal cells. The prototype retargeted HSV targets HER2, a receptor in breast, ovary and other tumors. HER2-HSV ablates human breast and ovary cancers, and glioblastoma after intratumoral or intraperitoneal administration. This proposal addresses basic research issues for the advancement of retargeted oncolytic HSVs. It is organized in 5 AIMS • Engineer a non-cancer cell line for virus production acceptable to Health Authorities and re-engineer the retargeted-HSV accordingly. This will enable production of clinical grade retargeted-HSVs for clinical tests (AIM1) • Engineer retargeted-HSVs suitable for systemic delivery and for boosting anti-tumor immunity (AIM2-3) • Apply our platform to expand the repertoire of oncolytic HSVs that target glioblastomas, prostate, head-and-neck, colon carcinomas (AIM4) • Determine the tumorigenic potential of cancer cells that escape killing by retargeted HSVs (AIM5)

2 477 346 €

Start date: 2014-03-01, End date: 2020-02-29