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

The role of the African continent in the global carbon cycle, and therefore in climate change, is increasingly recognised. Despite the increasingly acknowledged importance of Africa in the global carbon cycle and its high vulnerability to climate change there is still a lack of studies on the carbon cycle in representative African ecosystems (in particular tropical forests), and on the effects of climate on ecosystem-atmosphere exchange. In the present proposal we want to focus on these spoecifc objectives : 1. Understand the role of African tropical rainforest on the GHG balance of the atmosphere and revise their role on the global methane and N2O emissions. 2. Determine the carbon source/sink strength of African tropical rainforest in the pre-industrial versus the XXth century by temporal reconstruction of biomass growth with biogeochemical markers 3. Understand and quantify carbon and GHG fluxes variability across African tropical forests (west east equatorial belt) 4.Analyse the impact of forest degradation and deforestation on carbon and other GHG emissions

2 406 950 €

Start date: 2010-04-01, End date: 2014-12-31

"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

From the twelfth to the seventeenth century, Aristotle’s writings lay at the foundation of Western culture, providing a body of knowledge and a set of analytical tools applicable to all areas of human investigation. Scholars of the Renaissance have emphasized the remarkable longevity and versatility of Aristotelianism, but their attention has remained firmly, and almost exclusively, fixed on the transmission of Aristotle’s works in Latin. Scarce attention has gone to works in the vernacular. Nonetheless, several important Renaissance figures wished to make Aristotle’s works accessible and available outside the narrow circle of professional philosophers and university professors. They believed that his works could provide essential knowledge to a broad set of readers, and embarked on an intense programme of translation and commentary to see this happen. It is the argument of this project that vernacular Aristotelianism made fundamental contributions to the thought of the period, anticipating many of the features of early modern philosophy and contributing to a new encyclopaedia of knowledge. Our project aims to offer the first detailed and comprehensive study of the vernacular diffusion of Aristotle through a series of analyses of its main texts. We will thus study works that fall within the two main Renaissance divisions of speculative philosophy (metaphysics, natural philosophy, mathematics, and logic) and civil philosophy (ethics, politics, rhetoric, and poetics). We will give strong attention to the contextualization of the texts they examine, as is standard practice in the best kind of intellectual history, focusing on institutional contexts, reading publics, the value of the vernacular, new visions of knowledge and eclecticism. With the work of the PI, two professors, 5 post-docs and two PhD students we aim to make considerable advances in the understanding of both speculative and civil philosophy within vernacular Aristotelianism.

1 483 180 €

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

Autism spectrum disorders (ASD) affect 1-2% of the population and are a major public health issue. Heterogeneity between affected ASD individuals is substantial both at clinical and etiological levels, thus warranting the idea that we should begin characterizing the ASD population as multiple kinds of ‘autisms’. Without an advanced understanding of how heterogeneity manifests in ASD, it is likely that we will not make pronounced progress towards translational research goals that can have real impact on patient’s lives. This research program is focused on decomposing heterogeneity in ASD at multiple levels of analysis. Using multiple ‘big data’ resources that are both ‘broad’ (large sample size) and ‘deep’ (multiple levels of analysis measured within each individual), I will examine how known variables such as sex, early language development, early social preferences, and early intervention treatment response may be important stratification variables that differentiate ASD subgroups at phenotypic, neural systems/circuits, and genomic levels of analysis. In addition to examining known stratification variables, this research program will engage in data-driven discovery via application of advanced unsupervised computational techniques that can highlight novel multivariate distinctions in the data that signal important ASD subgroups. These data-driven approaches may hold promise for discovering novel ASD subgroups at biological and phenotypic levels of analysis that may be valuable for prioritization in future work developing personalized assessment, monitoring, and treatment strategies for subsets of the ASD population. By enhancing the precision of our understanding about multiple subtypes of ASD this work will help accelerate progress towards the ideals of personalized medicine and help to reduce the burden of ASD on individuals, families, and society.

1 499 444 €

Start date: 2018-01-01, End date: 2022-12-31

I will address the fundamental question of which is the role of neuron activity and plasticity in information elaboration and storage in the brain. I, together with an interdisciplinary team, will develop a hybrid neuro-morphic computing platform. Integrated photonic circuits will be interfaced to both electronic circuits and neuronal circuits (in vitro experiments) to emulate brain functions and develop schemes able to supplement (backup) neuronal functions. The photonic network is based on massive reconfigurable matrices of nonlinear nodes formed by microring resonators, which enter in regime of self-pulsing and chaos by positive optical feedback. These networks resemble human brain. I will push this analogy further by interfacing the photonic network with neurons making hybrid network. By using optogenetics, I will control the synaptic strengthen-ing and the neuron activity. Deep learning algorithms will model the biological network functionality, initial-ly within a separate artificial network and, then, in an integrated hybrid artificial-biological network. My project aims at: 1. Developing a photonic integrated reservoir-computing network (RCN); 2. Developing dynamic memories in photonic integrated circuits using RCN; 3. Developing hybrid interfaces between a neuronal network and a photonic integrated circuit; 4. Developing a hybrid electronic, photonic and biological network that computes jointly; 5. Addressing neuronal network activity by photonic RCN to simulate in vitro memory storage and retrieval; 6. Elaborating the signal from RCN and neuronal circuits in order to cope with plastic changes in pathologi-cal brain conditions such as amnesia and epilepsy. The long-term vision is that hybrid neuromorphic photonic networks will (a) clarify the way brain thinks, (b) compute beyond von Neumann, and (c) control and supplement specific neuronal functions.

2 499 825 €

Start date: 2018-11-01, End date: 2023-10-31

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

In BIORECAR I will develop a new breakthrough multifunctional biomaterial-based platform for myocardial regeneration after myocardial infarction, provided with biochemical cues able to enhance the direct reprogramming of human cardiac fibroblasts into functional cardiomyocytes. My expertise in bioartificial materials and biomimetic scaffolds and the versatile chemistry of polyurethanes will be the key elements to achieve a significant knowledge and technological advancement in cell reprogramming therapy, opening the way to the future translation of the therapy into the clinics. I will implement this advanced approach through the design of a novel 3D in vitro tissue-engineered model of human cardiac fibrotic tissue, as a tool for testing and validation, to maximise research efforts and reduce animal tests. I will adapt novel nanomedicine approaches I have recently developed for drug release to design innovative cell-friendly and efficient polyurethane nanoparticles for targeted reprogramming of cardiac fibroblasts. I will design an injectable bioartificial hydrogel based on a blend of a thermosensitive polyurethane and a natural component selected among a novel cell-secreted natural polymer mixture (“biomatrix”) recapitulating the complexity of cardiac extracellular matrix or one of its main protein constituents. Such multifunctional hydrogel will deliver in situ agents stimulating recruitment of cardiac fibroblasts together with the nanoparticles loaded with reprogramming therapeutics, and will provide biochemical signalling to stimulate efficient conversion of fibroblasts into mature cardiomyocytes. First-in-field biomaterials-based innovations introduced by BIORECAR will enable more effective regeneration of functional myocardial tissue respect to state-of-the art approaches. BIORECAR innovation is multidisciplinary in nature and will be accelerated towards future clinical translation through my clinical, scientific and industrial collaborations.

2 000 000 €

Start date: 2018-07-01, End date: 2023-06-30

"In the comprehension of fundamental laws of nature, particle physics is now facing two important questions: 1) What is the nature of the neutrino, is it a standard (Dirac) particle or a Majorana particle? The nature of the neutrino plays a crucial role in the global framework of particle interactions and in cosmology. The only practicable way to answer this question is to search for a nuclear process called ""neutrinoless double beta decay"" (0nuDBD). 2) What is the so called ""dark matter"" made of? Astrophysical observations suggest that the largest part of the mass of the Universe is composed by a form of matter other than atoms and known matter constituents. We still do not know what dark matter is made of because its rate of interaction with ordinary matter is really low, thus making the direct experimental detection extremely difficult. Both 0nuDBD and dark matter interactions are rare processes and can be detected using the same experimental technique. Bolometers are promising devices and their combination with light detectors provides the identification of interacting particles, a powerful tool to reduce the background. 
 The goal of CALDER is to realize a new type of light detectors to improve the upcoming generation of bolometric experiments. The detectors will be designed to feature unprecedented energy resolution and reliability, to ensure an almost complete particle identification. In case of success, CUORE, a 0nuDBD experiment in construction, would gain in sensitivity by up to a factor 6. LUCIFER, a 0nuDBD experiment already implementing the light detection, could be sensitive also to dark matter interactions, thus increasing its research potential. The light detectors will be based on Kinetic Inductance Detectors (KIDs), a new technology that proved its potential in astrophysical applications but that is still new in the field of particle physics and rare event searches."

1 176 758 €

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

"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

In recent years, our theoretical understanding of the strong-field regime of gravity has grown in parallel with the observational confirmations that culminated in the landmark detection of gravitational waves (GWs). This synergy of breakthroughs at the observational, technical, and conceptual level offers the unprecedented opportunity to merge traditionally disjoint areas, and to make strong gravity a precision tool to probe fundamental physics. The aim of the DarkGRA project is to investigate novel effects related to strong gravitational sources -such as black holes (BHs) and compact stars- that can be used to turn these objects into cosmic labs, where matter in extreme conditions, particle physics, and the very foundations of Einstein's theory of gravity can be put to the test. In this context, we propose to explore some outstanding, cross-cutting problems in fundamental physics: the existence of extra light fields, the limits of classical gravity, the nature of BHs and of spacetime singularities, and the effects of dark matter near compact objects. Our ultimate goal is to probe fundamental physics in the most extreme gravitational settings and to devise new approaches for detection, complementary to laboratory searches. This groundbreaking research program -located at the interface between particle physics, astrophysics and gravitation- is now made possible by novel techniques to scrutinize astrophysical compact objects, by current and future GW and X-ray detectors, and by the astonishing precision of pulsar timing. If supported by a solid theoretical framework, these new observations can potentially lead to surprising discoveries and paradigm shifts in our understanding of the fundamental laws of nature at all scales.

1 337 481 €

Start date: 2017-10-01, End date: 2022-09-30

The hippocampus is essential for building episodic memories. Coding of locations, contexts or events in the hippocampus is based on the correlated activity of neuronal ensembles; however, the mechanisms promoting the recruitment of individual neurons into information-coding ensembles are poorly understood. In particular, the recurrent synaptic network of pyramidal cells (PCs) in the hippocampal CA3 area, receiving external inputs from the entorhinal cortex and the dentate gyrus, is thought to be essential for associative memory. Current models of the associative functions of CA3 are mainly based on plasticity of these synaptic connections. Recent work by us and others however suggests that active, voltage-dependent properties of CA3PC dendrites may also promote ensemble functions. Dendritic voltage-dependent ion channels allow nonlinear amplification of spatiotemporally correlated synaptic inputs (such as those produced by ensemble activity) and can even generate local dendritic spikes, which may elicit specific action potential patterns and induce synaptic plasticity. Furthermore, dendritic processing may be modulated by activity-dependent regulation of dendritic ion channels. However, still little is known about the active properties of CA3PC dendrites and their functions during spatial coding or memory tasks. The general aim of my research program is to understand the cellular mechanisms that underlie the formation of hippocampal memory-coding neuronal ensembles. Specifically, we will test the hypothesis that active input integration by dendrites of individual CA3PCs plays an important role in their recruitment into specific context-coding ensembles. By combining in vitro (patch-clamp electrophysiology and two-photon (2P) microscopy in slices) and in vivo (2P imaging and activity-dependent labelling in behaving rodents) approaches, we will provide an in-depth understanding of the dendritic components contributing to the generation of the CA3 ensemble code.

1 990 314 €

Start date: 2018-06-01, End date: 2023-05-31

The possibility to artificially induce and expand in vitro tissue-specific stem cells (SCs) is an important goal for regenerative medicine, to understand organ physiology, for in vitro modeling of human diseases and many other applications. Here we found that this goal can be achieved in the culture dish by transiently inducing expression of YAP or TAZ - nuclear effectors of the Hippo and biomechanical pathways - into primary/terminally differentiated cells of distinct tissue origins. Moreover, YAP/TAZ are essential endogenous factors that preserve ex-vivo naturally arising SCs of distinct tissues. In this grant, we aim to gain insights into YAP/TAZ molecular networks (upstream regulators and downstream targets) involved in somatic SC reprogramming and SC identity. Our studies will entail the identification of the genetic networks and epigenetic changes controlled by YAP/TAZ during cell de-differentiation and the re-acquisition of SC-traits in distinct cell types. We will also investigate upstream inputs establishing YAP/TAZ activity, with particular emphasis on biomechanical and cytoskeletal cues that represent overarching regulators of YAP/TAZ in tissues. For many tumors, it appears that acquisition of an immature, stem-like state is a prerequisite for tumor progression and an early step in oncogene-mediated transformation. YAP/TAZ activation is widespread in human tumors. However, a connection between YAP/TAZ and oncogene-induced cell plasticity has never been investigated. We will also pursue some intriguing preliminary results and investigate how oncogenes and chromatin remodelers may link to cell mechanics, and the plasticity of the differentiated and SC states by controlling YAP/TAZ. In sum, this research should advance our understanding of the cellular and molecular basis underpinning organ growth, tissue regeneration and tumor initiation.

2 498 934 €

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

Multiple sclerosis (MS) is a chronic and progressive neurodegenerative disease that is currently affecting 2.3 million people worldwide. Incidence rates of MS are significantly higher in Europe and in other regions located within the northern hemisphere. In Europe, the number of patients currently afflicted with MS is estimated to be at 700,000, with incidence rates ranging from 2.3-12.2/100,000 per year. GlobalData assessed the market value for MS treatments in 10 major markets (France, Germany, Italy, Spain, UK, US, Canada, Japan, China and India) in 2014 to be at €16.2 billion and predicts it to rise to approximately €18.82 billion by 2024. This increase is attributed to the projected sales of newly-approved drugs. The main shortcoming of current MS treatments ultimately lies in their lack of efficacy, specifically in that they are unable to prevent progressive neurodegeneration in MS patients. MS poses a significant economic burden on society as the disease affects primarily young people who are in their most economically-productive years. Aside from limited efficacies, current treatment options are also associated with severe side-effects (increased risks of infection, cancer), high costs and inconvenient administration routes (e.g. intravenous, intramuscular, subcutaneous). The aim of DIDO-MS is to assess the commercial viability of a newly identified small molecule as a drug in the treatment of MS.

150 000 €

Start date: 2018-02-01, End date: 2019-07-31

The connections between the circulation of news of extreme events, the making of influential narratives of collective traumas and the development of emergency response policies lie at the heart of this research proposal, which focuses on four Southern European areas: Catalonia, Naples, Sicily and Valencia, from the 16th to the 18th century. How did accounts and individual memories of extreme events amount to authoritative interpretations? In which ways, and to what extent, did the latter orient collective behaviours and the recovery process, in both the short and the long term? Starting from the assumption that human relations are enhanced by the increased levels of socialisation that commonly occur in the aftermath of shocking events, which trigger the sharing of information, opinions and memories; and that the emotional impact of such events is likely to create a public opinion that draws attention to government’s action; the research proposal aims to contribute new insights into these issues by adopting an original methodology, developed across a variety of disciplines, including Cultural and Social History, Textual Criticism, Philology and Anthropology. Moreover, it will adopt a transnational perspective: since the selected regions belonged to the Spanish Monarchy, the development of practices and polices aimed to respond to disruption depended not only on the specific social and cultural features of local societies, but also on the circulation of political and technical staff, as well as on the sharing of knowledge, experiences and policy models, among the various areas of the Empire and its colonies. Studying the information exchange in the aftermath of disasters and the formation of an imagery of extraordinary events, will allow a comprehensive perspective on the policies and practices adopted by early modern societies to manage uncertainty, and on the potential impact that such narratives could have on the renegotiation of political and social relations.

1 481 813 €

Start date: 2018-02-01, End date: 2023-01-31

Disorder is ubiquitous in nature and has a strong impact on the behaviour of many physical systems. The most celebrated effect of disorder is Anderson localization of single particles, but many other more complex phenomena arise in interacting, many-body systems. A full understanding of how disorder affects the behavior of quantum systems is still missing, also because of the unavoidable presence of nonlinearities, dissipation and thermal effects that make a careful exploration of real condensed-matter systems very difficult. In this project we want to fully exploit the unprecedented potentialities offered by ultracold atomic quantum gases to explore some of the present challenges for our understanding of the physics of disorder. These systems offer indeed the possibility of controlling to a great extent crucial parameters such as the type of disorder, the nonlinearities due to interactions, the temperature and density, the dimensionality, the quantum statistics. A variety of advanced diagnostic techniques allow to gain detailed information on the static and dynamic properties of the system. The potentialities of atomic quantum gases for the study of disorder have already showed up in recent breakthrough experiments. The project aims at an experimental exploration, supported by advanced theory, of the current issues in disordered quantum systems. We will investigate a few frontier themes of general interest: 1) Anderson localization and the interplay of disorder and a weak interaction; 2) strongly correlated, disordered bosonic systems; 3) disordered, interacting fermionic systems. In the research we will employ atomic Bose and Fermi gases with tunable interactions and advanced diagnostic techniques that we have recently contributed to develop. A successful completion of the project will push forward our understanding of the behaviour of quantum systems with disorder, with a potentially large impact on many fields of physics.

2 500 000 €

Start date: 2010-03-01, End date: 2015-02-28

Molecular recognition plays a fundamental role in nearly all chemical and biological processes. The objective of this research project is to develop new methodology for studying and utilizing the noncovalent recognition between two molecular entities, focussing on biomolecular receptors and catalysts. A dynamic covalent capture strategy is proposed, characterized by the following strongholds. The target itself self-selects the best component out of a combinatorial library. The approach has a very high sensitivity, because molecular recognition occurs intramolecularly, and is very flexible, which allows for an easy implementation in very diverse research areas simply by changing the target. The dynamic covalent capture strategy is strongly embedded in the fields of supramolecular chemistry and (physical) organic chemistry. Nonetheless, the different work programmes strongly rely on the input from other areas, such as combinatorial chemistry, bioorganic chemistry, catalysis and computational chemistry, which renders the project highly interdisciplinary. Identified targets are new synthetic catalysts for the selective cleavage of biologically relevant compounds (D-Ala-D-Lac, cocaine and acetylcholine, and in a later stage peptides and DNA/RNA). Applicative work programmes are dedicated to the dynamic imprinting of monolayers on nanoparticles for multivalent recognition and cleavage of biologically relevant targets in vivo and to the development of new screening methodology for measuring chemical equilibria and, specifically, for the discovery of new HIV-1 fusion inhibitors.

1 400 000 €

Start date: 2009-10-01, End date: 2014-09-30

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

Every day, everywhere, people make unethical choices ranging from minor selfish lies to massive frauds, with dramatic individual and societal costs. Embodied cognition theories posit that even seemingly abstract processes (like grammar) may be biased by the body-related signals used for building and maintaining self-consciousness, the fundamental experience of owning a body (ownership) and being the author of an action (agency), that is at the basis of self-other distinction. Applying this framework to morality, we hypothesize that strengthening or weakening participants’ bodily self-consciousness towards virtual avatars or real others will influence dishonesty in real, virtual, and web-based interactions. To test this hypothesis, we will measure: i) individual dishonesty after modifying body ownership (e.g., by changing the appearance of the virtual body) and agency (e.g., by changing the temporal synchrony between participant’s and avatar’s actions) over an avatar through which decisions are made; ii) intergroup dishonesty after inducing inter-individual sharing of body self-consciousness (e.g., blur self-other distinction via facial visuo-tactile stimulation); iii) individual and intergroup dishonesty by manipulating exteroceptive (e.g., the external features of a virtual body) or interoceptive (e.g., changing the degree of synchronicity between participant’s and avatar/real person’s breathing rhythm) bodily inputs. Dishonesty will be assessed through novel ecological tasks based on virtual reality and web-based interactions. Behavioural (e.g., subjective reports, kinematics), autonomic (e.g., heartbeat, thermal imaging) and brain (e.g., EEG, TMS, lesion analyses) measures of dishonesty will be recorded in healthy and clinical populations. Our person-based, embodied approach to dishonesty complements cross-cultural, large-scale, societal investigations and may inspire new strategies for contrasting dishonesty and other unethical behaviours.

2 497 188 €

Start date: 2018-11-01, End date: 2023-10-31

ENERGYA will improve our understanding of how energy and energy services can be used by households and industries to adapt to the risk posed by climate change. Specifically, the project will develop an interdisciplinary and scalable research framework integrating data and methods from economics with geography, climate science, and integrated assessment modelling to provide new knowledge concerning heterogeneity in energy use across countries, sectors, socioeconomic conditions and income groups, and assess the broad implications adaptation-driven energy use can have on the economy, the environment, and welfare. The key novelty of ENERGYA is to link energy statistics and energy survey data with high spatial resolution data from climate science and remote sensing, including high-resolution spatial data on meteorology, population and economic activity distribution, electrification, and the built environment. ENERGYA has three main objectives. First, it will produce novel statistical and econometric analyses for OECD and major emerging countries (Brazil, Mexico, India, and Indonesia) to shed light on the underlying mechanisms driving energy use. Second, it will infer future potential impacts from long-run climate and socioeconomic changes building on historical empirical evidence. Third, it will analyse the macro and distributional implications of adaptation-driven energy use with an economy-energy model characterising the distribution of energy use dynamics across and within countries. Given the central role of energy as multiplier for socioeconomic development and as enabling condition for climate resilience, the research proposed in ENERGYA will result in timely insights for the transition towards sustainability described by the Sustainable Development Goals adopted by the United Nations as well as the Paris International Climate Agreement.

1 495 000 €

Start date: 2018-03-01, End date: 2023-02-28

"Given the alarming progression of chronic and relapsing infections in the last decades, and the even more alarming predictions for the upcoming years, it is urgent for chemists to be able to provide new molecular tools to study, and ultimately solve, these complex biological problems. Bacterial persisters are an elusive ""dormant"" phenotype that play a pivotal role in chronic infections, with mechanisms that remain to be fully unravelled. Current knowledge suggests that bacterial persisters are not genetically resistant to antibiotic treatment; they simply appear to shut down through a cascade of biochemical events called the stringent response (SR), becoming insensitive to current drugs. This subpopulation remains unaffected during the time of pharmacological treatment and represents a reservoir that sustains pathogen survival and resurgence. The goal of this project is to fill the knowledge gap between persisters formation and infection eradication, providing the community with potent and selective small molecular tools that can be used to challenge complementary survival mechanisms. I will adopt a combined approach targeting a specific cellular trigger of the persister phenotype with small molecules designed ad hoc in order to switch it off. The target is a bacterial protein involved in the SR cascade, whose activity is proposed to be allosterically regulated. Coordination propensity analysis of the dynamic behaviour of the target will highlight regulation sites exploitable to modulate and control the protein activity. Structure-based design, virtual fragment screening and chemical synthesis will operate in synergy. Experimental screening methodologies intrinsically rich in structural information, such as those based on NMR spectroscopy, will be privileged. The overarching goal is to identify molecules able to prevent the insurgence of the ""dormant"" drug-tolerant state and, possibly, revert the persisters already present to the ""awake"" drug-sensitive phenotype. "

1 500 000 €

Start date: 2018-02-01, End date: 2023-01-31

Sudden cardiac death (SCD) is a leading cause of death in western countries: coronary artery disease is the major cause of SCD in older subjects while inherited arrhythmogenic diseases are the leading cause of SCD in younger individuals. After 25 years dedicated to research of the molecular bases of heritable arrhythmias, the PI of this proposal now intends to pioneer gene therapy for prevention of SCD: a virtually unexplored field. The development of molecular therapies for rhythm disturbances is a high risk effort however, if successful, it will be highly rewarding. The PI has envisioned an ambitious and comprehensive project to target two severe inherited arrhythmogenic diseases: dominant catecholaminergic polymorphic ventricular tachycardia (CPVT) and Long QT syndrome type 8 (LQT8). The availability of a clinically relevant model is critical to ensure clinical translation of results: the team will exploit an existing CPVT model and will engineer a knock-in pig to model LQT8. The PI and her team will investigate innovative strategies of gene-delivery, gene-silencing and gene-editing to the heart comparing efficacy of different constructs and promoters. The team will also carefully engineer novel gene-therapy approaches to avoid the development of regional inhomogeneity in protein expression that may facilitate proarrhythmic events. Such a comprehensive approach will provide a most valuable core of knowledge on the comparative efficacy of a broad range of molecular strategies on the electrical milieu of the heart. It is expected that these results will not only benefit CPVT and LQT8 but rather they will foster development of gene therapy for other inherited and acquired arrhythmias.

2 314 029 €

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

The aim of this project is to map and publish in a critical edition the extensive correspondence of European intellectuals with the Swiss cultural historian Jacob Burckhardt over a period of more than half a century, from 1842 to 1897. This correspondence documents a crucial period in European history and culture, one which witnessed the emergence of art history as a separate discipline; serious political conflict in France, Germany, Italy and Switzerland; the birth of the nation-states of Italy and Germany; debate on the meaning and consequences of democracy as a system of government; and the rise of Caesarism in France. The effects of modernism are also discussed in this correspondence, from the culture of museums, art exhibitions and the first universal expositions (e.g., the Expositions Universelles in Paris) to the clash between industrial culture and neo-humanist ideals of education. The large body of correspondence received by Jacob Burckhardt (about two thousand letters conserved in various libraries and private archives) provides a cultural map of this crucial phase in the development of a new European identity.

1 215 600 €

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

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

FLOS will focus on the metamorphoses of Greek Christian thought in Syriac (Aramaic) and Arabic in Late Antiquity, within the timeframe of the first millennium CE. Syriac Christianity was a pivotal mediator of culture in the Late Antique epistemic space, but is little-known today. FLOS aims to bring to light for the first time a body of highly relevant Syriac and Christian Arabic sources that have hardly ever been studied before. At the end of the millennium, in Islamic-ruled Syria, Mesopotamia, and Iran, Syriac Christians strived to define their religious identity. One of their strategies was the production of florilegia, i.e. anthologies that they used to excerpt and reinvent the patristic canon, a corpus of Greek Christian works of the 2nd–6th centuries shared by European and Middle Eastern Christian cultures. A Greco-centric bias has prevented scholars from viewing these florilegia as laboratories of cultural creativity. FLOS will reverse the state of the art through two groundbreaking endeavours: 1) open-access digital editions of a set of Syriac florilegia of the 8th–10th centuries; 2) a study of many neglected writings of Syriac and Christian Arabic authors of the 8th–11th centuries. These tremendously important writings drew from Syriac patristic florilegia to pinpoint topics like incarnation and the Trinity against other Christians or Islam, showing how patristic sources were used to create new knowledge for the entangled environment of the Abbasid era. FLOS will thus dramatically improve our understanding of the cultural dynamics of Late Antiquity; patristic Christianity will emerge as a bridge between the intellectual history of Europe and of the Middle East. By studying how this shared patrimony was transformed in situations of interreligious interaction, especially with Islam, FLOS will facilitate the comprehension of Europe’s current religious discourses, and the preservation of the endangered cultural heritage of the Syriac Christians.

1 343 175 €

Start date: 2018-03-01, End date: 2023-02-28

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

A central challenge in theoretical physics is to develop non-perturbative or exact methods to describe quantitatively the dynamics of strongly coupled quantum fields. This proposal aims to establish new exact methods for the study of supersymmetric quantum field theories thereby unveiling new integrable structures and fostering new correspondences and dualities. We will develop a new cut-and-sew formalism to compute partition functions and expectation values of observables of supersymmetric gauge theories on compact manifolds through the gluing of a fundamental set of building blocks, the holomorphic blocks. The decomposition of partition functions into holomorphic blocks corresponds to the geometric decomposition of compact manifolds into standard simpler pieces. Similarly the gluing rules for the holomorphic blocks correspond to the geometric gluing rules. The key insight required to exploit the holomorphic block formalism is the deep connection between supersymmetric gauge theories and low dimensional exactly solvable systems such as 2d CFTs, TQFTs and spin chains. Two and four dimensional holomorphic blocks can be reinterpreted as conformal blocks in Liouville theory through an established correspondence between supersymmetric gauge theories and Liouville theory. We will provide a similar realisation of three and five dimensional holomorphic blocks in a new theory, a q-deformed version of Liouville theory where the Virasoro algebra is replaced by the q-deformed Virasoro algebra. We will develop this theory classifying the symmetries of correlation functions. These symmetries will be realised as gauge theory dualities, while the language of the q-deformed Liouville theory will become a new powerful tool to investigate supersymmetric gauge theories.

1 287 088 €

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

Singular solutions to variational problems and to partial differential equations are naturally ubiquitous in many contexts, and among these minimal surfaces theory and free boundary problems are two prominent examples both for their analytical content and their physical interest. A crucial aspect in this regard is the co-dimension of the objects under consideration: indeed, many of the analytical and geometric principles which are valid for minimal hypersurfaces or regular points of the free boundary do not apply to higher co-dimension surfaces or singular free boundary points. The aim of this project is to investigate some of the most compelling questions about the singularities of two classical problems in the geometric calculus of variations in higher co-dimension: I. Mass-minimizing integer rectifiable currents, i.e. solutions to the Plateau problem of finding the surfaces of least area, attacking specific conjectures about the structure of the singular set, most prominently the boundedness of its measure. II. The thin obstacle problem, consisting in minimizing the Dirichlet energy (or a variant of it) among functions constrained above an obstacle that is assigned on a lower dimensional space, with the purpose of answering some of the main open questions on the singular free boundary points. The main unifying theme of the project is the central role played by geometric measure theory, which underlines various common aspects of these two problems and makes them suited to be treated in an unified framework. Although these are classical questions with a long tradition, our knowledge about them is still limited and their investigation is among the most challenging issues in regularity theory. This is the central focus of the project, with the final goal to develop suitable analytical techniques that provides valuable insights on the mathematics at the basis of higher co-dimension singularities, eventually fruitful in other geometric and analytical settings.

1 341 250 €

Start date: 2018-02-01, End date: 2023-01-31

"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

Integrated DEsign and control of Sustainable CommUnities during Emergencies

1 271 138 €

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

Impact investing is a major emerging phenomenon in global finance that promises to reconcile capitalism with sustainability. It is increasingly embraced by governments, civil society and the private sector in the Global North and South to solve social and environmental problems. The combined crises of climate change, inequality and mass migration in a context of economic austerity have spurred cross-sectoral impact investing partnerships in areas such as green infrastructure, women’s entrepreneurship, agroecology, refugee support and disease prevention. This burgeoning $200bn market promises flexible, holistic and profitable paths to sustainability, attracting major philanthropic organisations and institutional investors boasting fresh ethical and responsible mandates. Is impact investing merely a new frontier for capitalism, or does it represent a revolutionary chapter in global history? Will it benefit communities better than conventional development programmes? The time to answer these questions is now, as impact investing is still in its infancy and the first green and social stock exchanges are opening around the world. IMPACT HAU is an innovative, critical and comparative anthropological study of the moral and political dimensions of impact investing. Inspired by Marcel Mauss’s classic use of the Maori concept of hau, the ‘spirit of the gift’, it focuses on the designers, traders and beneficiaries of impact bonds to produce an empirically driven analysis of the multiple moral orders within contemporary capitalism. Six ethnographic case studies will provide grounded, detailed accounts of the design and implementation of impact investing in Africa, Asia, Europe and the Americas. These will support a critical appraisal of the current consensus among global policymakers and business leaders giving markets a determining role in the ecological transition, testing the theories of sustainability that underpin hopes for a socially inclusive green economy.

1 999 999 €

Start date: 2019-02-01, End date: 2024-01-31

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

Writing must rank among mankind’s highest achievements. Yet the factors that enabled its invention independently in different parts of the world have never been subject to an analysis from a multidisciplinary and comparative perspective that encompasses both deciphered and undeciphered scripts. INSCRIBE takes such an approach, combining a study of the world’s first instances of writing, including the earliest in Europe, through the lens of archaeology, anthropology, cultural evolution, cognitive studies and decipherment strategies. This methodology involves three strands of research. First, it will consider the original inventions, all of which are image-based, from Mesopotamia, Egypt, Mesoamerica and China, and other debated cases. The objective is to characterize their conception in terms of visual cognition (why are signs shaped as they are?), archaeological setting (what are the contextual preconditions, why does writing emerge when it does, and only four times in history?), application of use (what are its initial purposes?), and language notation (what are the paths to registering sound?). Second, it will explore the earliest scripts in Europe from the second millennium BC Aegean, whose initial phase is highly iconic. The three undeciphered Aegean scripts (Cretan Hieroglyphic, Linear A and Cypro-Minoan) will be analyzed for the first time from a multistranded perspective that will shed unprecedented light on their creation and development. The objective is to analyze the relationship between these scripts and to apply a multi-stepped (and already successfully piloted) decipherment strategy. Third, INSCRIBE proposes to go beyond the traditional standards applied to the corpora of inscriptions by producing the first complete digital corpus of all three Aegean undeciphered scripts, with 3D interactive models accompanied by a multidimensional interface tagging inscriptions, types of inscribed objects, provenance, archaeological contexts and functions.

1 463 337 €

Start date: 2018-10-01, End date: 2023-09-30

Economists have recently shown that developed economies rely on proper institutions for securing property rights, resolving disputes, etc. Scholars have studied the consequences of alternative legal and political institutions, but much remains to be done. One important and unexplored territory concerns the analysis of how national institutions interact in the international arena. This proposal seeks to study this problem from two perspectives. First, how does the quality of a country s national institutions affect its gains from international integration? Second, how does international integration affect a country s institutional reform path? We address the first question by studying, both theoretically and empirically, the impact of national institutions on sovereign risk, where the latter is defined as the risk that a government unilaterally decides ex-post not to honor its financial obligations with foreigners. While the impact of national institutions on private capital flows has been studied, the role of these same institutions on supporting government debt has so far received scant attention. As for the second question, we study the impact of political and financial integration on countries institutional reform. We model two different motivations towards institutional change in an integrated world: a) direct confrontation in wars and b) competition through world financial markets. The general thrust of these analyses is that institutional reform becomes a strategic variable in international competition, creating cross-country externalities that can shed light on observed episodes of institutional converge or divergence. We also consider the role of institutional harmonization in supporting economic integration.

1 002 000 €

Start date: 2009-09-01, End date: 2015-05-31

The increasingly multiethnic nature of modern societies has spurred academic interest in the consequences of diversity. Recent scholarship has linked ethnoracial diversity to undesirable collective outcomes, e.g., low levels of trust, civic engagement, and social capital. These findings have important policy implications, in part because they resonate with public anxieties about immigration, residential integration, and the role of the welfare state. The proposed research will investigate the micro-mechanisms through which contact promotes or impedes solidarity and cooperation in diverse communities. More generally, this research moves beyond communitarian conceptions of social capital to understand the building blocks of solidarity in contemporary, diverse societies. To investigate the micro-level dynamics that link intergroup contact to solidarity and cooperation, this project takes an innovative field-experimental approach, which moves beyond observational data. In particular, the project uses lab-in-the-field experimental games to assess the dispositional mechanisms – such as generalized altruism, group solidarity, reciprocity, and sanctioning – that bring about solidarity and cooperation in various group settings. This revised version of the proposal addresses all the panel observations and implements changes accordingly. First, I have limited the research to project 3 (P3), and cut projects 1 (P1) and 2 (P2). Second, the duration of the project has been reduced to 48 months. Third, all expenses related to P1 and P2 have been cut.

969 100 €

Start date: 2015-07-01, End date: 2019-11-30

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

Disorders of the central nervous system (CNS) contribute almost 800 billion euros in annual European healthcare costs. New compounds, effective in animal models, hardly work in humans, mostly due to the inability to cross the Brain Blood Barrier (BBB). In these conditions cost-effective tools to alter BBB and, more generally, endothelial layer permeability is desirable before proceeding to expensive and time-consuming animal studies. INVICTUS (IN VItro Cavitation Through UltraSound) originates within the ERC-AdG project Bubbles from Inception to Collapse (BIC) and concerns the development of a biomimetic micro-fluidic platform to be made turnkey available to biologists, clinicians and pharmacologists. The integrated platform exploits endothelial layer permeability enhancement by cavitation bubbles and provides an integrated, low cost platform to develop cavitation enhanced drug delivery under well controlled and reproducible conditions. Its potential is significant, given the well known societal and economical impact of degenerative diseases and the enormous investment and the long times of pre-clinical trials, as confirmed by a leading company operating in the field. Limiting/avoiding animal experimentation has an evident ethical impact and is associated with substantial economic savings and organisational simplification. In few words, micro-bubbles injected into the bloodstream undergo volume oscillations under localised ultrasound irradiation, with local reversible permeability enhancement of the endothelium. Already pursed in in vivo animal models, this approach is extended here to a high-fidelity, in vitro biomimetic device that will bring to market new crucial features such as the three-dimensional geometry of realistic-size vascular channels featuring an actual endothelial barrier, the correct perfusion rate, the appropriate physiological shear stress exerted on the endothelial cells and the ability to reproduce biochemical interactions between different, healthy and diseased, tissues.

150 000 €

Start date: 2017-12-01, End date: 2019-05-31

One main objective of our ERC Advanced Grant project (InMec, No 341131) was to determine how cancer stem cells (CSCs) contribute to tumour growth, and the relative impact of quiescent versus proliferative CSCs. In Acute Myeloid Leukaemia (AML), our results strongly suggest that quiescent leukaemia stem cells are critical for leukaemia maintenance and relapse after treatments. AML is an aggressive and frequently fatal hematologic malignancy. It is usually sensitive to chemotherapy at its onset, leading to disease remission in most patients; however, the majority of patient will later relapse and eventually die. Notably, leukaemia stem cells are often resistant to chemotherapy. We will use our innovative phage-display antibody screening platform to generate antibodies against AMLs. The screening will be performed directly on human AMLs growing in vivo, using an innovative mouse xenotransplantation model followed by an NGS-based antibody selection procedure. We plan to isolate antibodies that selectively recognize leukaemia stem cells, either quiescent or proliferating. Our primary goal is to develop novel therapeutic antibodies for the treatment of AMLs. This project will also indirectly confirm the hypothesis that leukaemia stem cells are the real fuel of the disease. We expect that this project will lead to quick and cheap identification, cloning and validation of human recombinant antibodies towards against AML leukemic stem cells. The use of phage display technology to isolate leukemic stem cell-specific human recombinant antibodies is to our knowledge unprecedented. The development of candidate antibodies against AMLs will be accompanied by the promotion of commercial/exploitation activities such as market and competition analyses, intellectual property management, and product and business development through the activities of our partner TTFactor.

150 000 €

Start date: 2018-01-01, End date: 2019-06-30

Autism spectrum disorders (ASDs) are a heterogeneous set of neurodevelopmental disorders characterized by deficits in social communication and reciprocal interactions, as well as stereotypic behaviours. Although early diagnosis followed by appropriate intervention appears to offer the best chance for significant health improvement and economic gain, diagnosis of autism remains complex and often difficult to obtain. Recent identification of atypical kinematic patterns in children and infants at increased risk for ASDs provides new insights into autism diagnostic and objective profiling. KiD intends to help move these insights into the development of a low cost, easy-to-use, yet reliable wearable tracking system, designed to assist detection and classification of ASDs. The novelty of KiD is to combine informed development of machine learning methods to classify kinematic data with a co-design human factor engineering. KiD holds great potential for translational possibilities into autism clinical practice. The main use of the device will be to assist clinicians to achieve expedited diagnosis, ensuring early and timely access of children at risk of autism to evidence-based intervention programs. Another use will be to examine the quantitative nature of autistic traits, enabling new forms of precision-phenotyping, which is potentially useful for stratifying patients with ASD and developing individualized treatment approaches.

148 413 €

Start date: 2018-07-01, End date: 2019-12-31