ERC FUNDED PROJECTS

As an onco-hematologist with a strong expertise in genomics, I significantly contributed to the understanding of multiple myeloma (MM) heterogeneity and its evolution over time, driven by genotypic and phenotypic features carried by different subpopulations of cells. MM is preceded by prevalent, asymptomatic stages that may evolve with variable frequency, not accurately captured by current clinical prognostic scores. Supported by preliminary data, my hypothesis is that the same heterogeneity is present early on the disease course, and identification of the biological determinants of evolution at this stage will allow better prediction of its evolutionary trajectory, if not its control. In this proposal I will therefore make a sharp change from conventional approaches and move to early stages of MM using unique retrospective sample cohorts and ambitious prospective sampling. To identify clonal MM cells in the elderly before a monoclonal gammopathy can be detected, I will collect bone marrow (BM) from hundreds of hip replacement specimens, and analyze archive peripheral blood samples of thousands of healthy individuals with years of annotated clinical follow-up. This will identify early genomic alterations that are permissive to disease initiation/evolution and may serve as biomarkers for clinical screening. Through innovative, integrated single-cell genotyping and phenotyping of hundreds of asymptomatic MMs, I will functionally dissect heterogeneity and characterize the BM microenvironment to look for determinants of disease progression. Correlation with clinical outcome and mini-invasive serial sampling of circulating cell-free DNA will identify candidate biological markers to better predict evolution. Last, aggressive modelling of candidate early lesions and modifier screens will offer a list of vulnerabilities that could be exploited for rationale therapies. These methodologies will deliver a paradigm for the use of molecularly-driven precision medicine in cancer.

1 998 781 €

Start date: 2019-03-01, End date: 2024-02-29

The composition and molecular features of tumours vary during the course of the disease, and the selection pressure imposed by the environment is a central component in this process. Evolutionary principles have been exploited to explain the genomic aberrations in cancer. However, the phenotypic changes underlying disease progression remain poorly understood. In the past years, I have contributed to identify and characterise the therapeutic implications underlying metabolic alterations that are intrinsic to primary tumours or metastasis. In CancerADAPT I postulate that cancer cells rely on adaptive transcriptional & metabolic mechanisms [converging on a Metabolic Phenotype] in order to rapidly succeed in their establishment in new microenvironments along disease progression. I aim to predict the molecular cues that govern the adaptive properties in prostate cancer (PCa), one of the most commonly diagnosed cancers in men and an important source of cancer-related deaths. I will exploit single cell RNASeq, spatial transcriptomics and multiregional OMICs in order to identify the transcriptional and metabolic diversity within tumours and along disease progression. I will complement experimental strategies with computational analyses that identify and classify the predicted adaptation strategies of PCa cells in response to variations in the tumour microenvironment. Metabolic phenotypes postulated to sustain PCa adaptability will be functionally and mechanistically deconstructed. We will identify therapeutic strategies emanating from these results through in silico methodologies and small molecule high-throughput screening, and evaluate their potential to hamper the adaptability of tumour cells in vitro and in vivo, in two specific aspects: metastasis and therapy response. CancerADAPT will generate fundamental understanding on how cancer cells adapt in our organism, in turn leading to therapeutic strategies that increase the efficacy of current treatments.

1 999 882 €

Start date: 2019-11-01, End date: 2024-10-31

Multicore processors are present nowadays in most digital devices, from smartphones to high-performance servers. The increasing computational power of these processors is essential for enabling many important emerging application domains such as big-data, media, medical, or scientific modeling. A fundamental technique to improve performance is speculation, a technique that consists in executing work before it is known if it is actually needed. In hardware, speculation significantly increases energy consumption by performing unnecessary operations, while speculation in software (e.g., compilers) is not the default thus preventing performance optimizations. Since performance in current multicores is limited by their power budget, it is imperative to make multicores as energy-efficient as possible to increase performance even further. In a multicore architecture, the cache coherence protocol is an essential component since its unique but challenging role is to offer a simple and unified view of the memory hierarchy. This project envisions that extending the role of the coherence protocol to simplify other system components will be the key to overcome the performance and energy limitations of current multicores. In particular, ECHO proposes to add simple but effective extensions to the cache coherence protocol in order to (i) reduce and even eliminate misspeculations at the processing cores and synchronization mechanisms and to (ii) enable speculative optimizations at compile time. The goal of this innovative approach is to improve the performance and energy efficiency of future multicore architectures. To accomplish the objectives proposed in this project, I will build on my 14 years expertise in cache coherence, documented in over 40 publications of high impact.

1 999 955 €

Start date: 2019-09-01, End date: 2024-08-31

FACETS studies the meaning of the face in contemporary visual cultures. There are two complementary research foci: widespread practices of face exhibition in social networks like Facebook, Instagram, Snapchat, and Tinder; and minority practices of occultation, including the mask in anti-establishment political activism (e.g., Anonymous) and in anti-surveillance artistic provocation (e.g., Leonardo Selvaggio). Arguably, the meaning of the human face is currently changing on a global scale: through the invention and diffusion of new visual technologies (e.g., digital photography, visual filters, as well as software for automatic face recognition); through the creation and establishment of novel genres of face representation (e.g., the selfie); and through new approaches to face perception, reading, and memorization (e.g., the ‘scrolling’ of faces on Tinder). Cognitions, emotions, and actions that people attach to the interaction with one’s and others’ faces might soon be undergoing dramatic shifts. In FACETS, an interdisciplinary but focused approach combines visual history, semiotics, phenomenology, visual anthropology, but also face perception studies and collection, analysis, and social contextualization of big data, so as to study the cultural and technological causes of these changes and their effects in terms of alterations in self-perception and communicative interaction. In the tension between, on the one hand, political and economic agencies pressing for increasing disclosure, detection, and marketing of the human face (for reasons of security and control, for commercial or bureaucratic purposes) and, on the other hand, the counter-trends of face occultation (writers and artists like Banksy, Ferrante, Sia, or Christopher Sievey / Frank Sidebottom choosing not to reveal their faces), the visual syntax, the semantics, and the pragmatics of the human face are rapidly evolving. FACETS carries on an innovative, cross-disciplinary survey of this phenomenon.

1 997 803 €

Start date: 2019-06-01, End date: 2024-05-31

Recently, there has been a paradigmatic shift in experimental molecular spectroscopy, with new methods focusing on the study of molecules embedded within complex supramolecular/nanostructured aggregates. In the past, molecular spectroscopy has benefitted from the synergistic developments of accurate and cost-effective computational protocols for the simulation of a wide variety of spectroscopies. These methods, however, have been limited to isolated molecules or systems in solution, therefore are inadequate to describe the spectroscopy of complex nanostructured systems. The aim of GEMS is to bridge this gap, and to provide a coherent theoretical description and cost-effective computational tools for the simulation of spectra of molecules interacting with metal nano-particles, metal nanoaggregates and graphene sheets. To this end, I will develop a novel frequency-dependent multilayer Quantum Mechanical (QM)/Molecular Mechanics (MM) embedding approach, general enough to be extendable to spectroscopic signals by using the machinery of quantum chemistry and able to treat any kind of plasmonic external environment by resorting to the same theoretical framework, but introducing its specificities through an accurate modelling and parametrization of the classical portion. The model will be interfaced with widely used computational chemistry software packages, so to maximize its use by the scientific community, and especially by non-specialists. As pilot applications, GEMS will study the Surface-Enhanced Raman (SERS) spectra of systems that have found applications in the biosensor field, SERS of organic molecules in subnanometre junctions, enhanced infrared (IR) spectra of oligopeptides adsorbed on graphene, Graphene Enhanced Raman Scattering (GERS) of organic dyes, and the transmission of stereochemical response from a chiral analyte to an achiral molecule in the vicinity of a plasmon resonance of an achiral metallic nanostructure, as measured by Raman Optical Activity-ROA

1 609 500 €

Start date: 2019-06-01, End date: 2024-05-31

The low gene manipulation efficiency of human hematopoietic stem cells (HSC) remains a major hurdle for sustainable and broad clinical application of innovative therapies for a wide range of disorders. Indeed, high vector doses and prolonged ex vivo culture are still required for clinically relevant levels of gene transfer even with the most established lentiviral vector-based delivery platforms. Current and emerging gene transfer and editing technologies expose HSC to components potentially recognized by host antiviral factors and nucleic acid sensors that likely restrict their genetic engineering and contribute to broad individual variability in clinical outcomes observed in recent gene therapy trials. Nevertheless, specific effectors are yet to be identified in HSC. We have recently identified an antiviral factor that potently blocks gene transfer in HSC and have discovered small molecules that efficiently counteract it. This is the first example of how manipulating a single host factor can significantly impact gene transfer efficiencies in HSC but likely represents the mere tip of the iceberg of the plethora of innate sensing mechanisms potentially hampering genetic manipulation of this primitive cell compartment. This proposal aims to identify the antiviral factors and innate sensing pathways that prevent efficient modification of HSC and to mitigate their effects using methods developed through a thorough understanding of their mechanisms of action. My approach builds on the innovative concept that understanding the crosstalk between HSC and viral vectors will instruct us on which immune sensors and effectors to avoid and how, with direct implications for all gene engineering technologies. Successful completion of this project will deliver broadly exportable novel paradigms of innate pathogen recognition that will allow ground-breaking progress in the development of cutting-edge cell and gene therapies and to fight infectious and autoimmune diseases.

1 994 375 €

Start date: 2019-03-01, End date: 2024-02-29

InOutBioLight aims to design multifunctional rubbers with enhanced mechanical, thermal, color-converting, and light-guiding features towards advanced biohybrid lighting and photovoltaic technologies. The latter are placed at the forefront of the EU efforts for low-cost production and efficient consumption of electricity, a critical issue for a sustainable development. In this context, the use of biomolecules as functional components in lighting and photovoltaic devices is still a challenge, as they quickly denature under storage and device operation conditions. This paradigm has changed using an innovative rubber-like material, in which the biofunctionality is long preserved. As a proof-of-concept, color down-converting rubbers based on fluorescent proteins were used to design the first biohybrid white light-emitting diode (bio-HWLED). To develop a new generation of biohybrid devices, InOutBioLight will address the following critical issues, namely i) the nature of the protein-matrix stabilization, ii) how to enhance the thermal/mechanical features, iii) how to design multifunctional rubbers, iv) how to mimic natural patterns for light-guiding, and v) how to expand the technological use of the rubber approach. To achieve these goals, InOutBioLight involves comprehensive spectroscopic, microscopic, and mechanical studies to investigate the protein-matrix interaction using new polymer matrices, additives, and protein-based nanoparticles. In addition, the mechanical, thermal, and light-coupling features will be enhanced using structural biocompounds and reproducing biomorphic patterns. As such, InOutBioLight offers three major advances: i) a thorough scientific basis for the rubber approach, ii) a significant thrust of the emerging bio-HWLEDs, and iii) innovative breakthroughs beyond state-of-the-art biohybrid solar cells.

1 999 188 €

Start date: 2020-01-01, End date: 2024-12-31

The gravitational wave window is now open. It is then imperative to build quantitative models of neutron stars that use all the available tracers to constrain fundamental physics at the highest densities and magnetic fields. The most magnetic neutron stars, the magnetars, have been recently suggested to be powering a large variety of explosive and transient events. The enormous rotational power at birth, and the magnetic energy they can release via large flares, put the magnetars in the (yet) hand-wavy interpretations of gamma-ray bursts, the early phases of double neutron star mergers, super-luminous supernovae, hypernovae, fast radio bursts, and ultra-luminous X-ray sources. However, despite knowing about 30 magnetars, we are lacking a census of how many we expect within the pulsar population, nor we have robust constraints on their flaring rates. The recent discovery of transient magnetars, of magnetar-like flares from sources with measured low dipolar magnetic fields and from typical radio pulsars, clearly showed that the magnetar census in our Galaxy is largely under-estimated. This hampers our understanding not only of the pulsar and magnetar populations, but also of them as possibly related to many of Universe’s explosive events. MAGNESIA will infer a sound Magnetar Census via an innovative approach that will build the first Pulsar Population Synthesis model able to cope with constraints/limits from multi-band observations, and taking into account 3D magnetic field evolution models and flaring rates for neutron stars. Combining expertise in multi-band observations, numerical modeling, nuclear physics, and computation, MAGNESIA will solve the physics, the observational systematic errors, and the computational challenges that inhibited previous works, to finally constrain the spin period and magnetic field distribution at birth of the neutron star population.

2 263 148 €

Start date: 2019-06-01, End date: 2024-05-31

Cardiac toxicity is one of the most frequent serious side effects of cancer therapy, affecting up to 30% of treated patients. Cancer treatment-induced cardiotoxicity (CTiCT) can result in severe heart failure. The trade-off between cancer and chronic heart failure is an immense personal burden with physical and psychological consequences. Current therapies for CTiCT are suboptimal, featuring poor early detection algorithms and nonspecific heart failure treatments. Based on our recently published results and additional preliminary data presented here, we propose that CTiCT is associated with altered mitochondrial dynamics, triggering a cardiomyocyte metabolic reprogramming. MATRIX represents a holistic approach to tackling mitochondrial dysfunction in CTiCT. Our hypothesis is that reverting metabolic reprogramming by shifting mitochondrial substrate utilization could represent a new paradigm in the treatment of early-stage CTiCT. By refining a novel imaging-based algorithm recently developed in our group, we will achieve very early detection of myocardial damage in patients treated with commonly prescribed cancer therapies, long before clinically used parameters become abnormal. Such early detection, not available currently, is crucial for implementation of early therapies. We also hypothesize that in end-stage CTiCT, mitochondrial dysfunction has passed a no-return point, and the failing heart will only be rescued by a strategy to replenish the myocardium with fresh healthy mitochondria. This will be achieved with a radical new therapeutic option: in-vivo mitochondrial transplantation. The MATRIX project has broad translational potential, including a new therapeutic approach to a clinically relevant condition, the development of technology for early diagnosis, and advances in knowledge of basic disease mechanisms.

1 999 375 €

Start date: 2019-09-01, End date: 2024-08-31

Humankind advancement is connected to the use and development of metal forms. Recent works have unveiled exceptional properties –such as luminescence, biocompatibility, antitumoral activity or a superlative catalytic activity– for small aggregations of metal atoms, so–called sub–nanometer metal clusters (SNMCs). Despite this importance, the gram-scale synthesis of structurally and electronically well–defined SNMCs is still far from being a reality. The present proposal situates at the centre of such weakness and aims at making a breakthrough step-change on the use of metal-organic frameworks (MOFs) as chemical reactors for the in–situ synthesis of stable ligand-free SNMCs with such unique properties. This challenging synthetic strategy, which is assisted by striking published and inedited preliminary results, has solid foundations. Firstly, the design and large-scale preparation of cheap and novel families of highly robust and crystalline MOFs with tailor-made functional channels to be used as chemical reactors. Secondly, the application of solid-state post-synthetic methods to drive the multigram-scale preparation of unique ligand-free homo- and heterometallic SNMCs, which are, in the best-case scenario, very difficult to be obtained and stabilised outside the channels. Last but not least, single-crystal X-Ray diffraction will be used as the definitive tool for the characterisation, at the atomic level, of such ultrasmall species offering unprecedented snapshots about their real structures and formation mechanisms. The ultimate goal will be upscaling this synthetic strategy aiming at the large-scale fabrication of SNMCs and their industrial application will be then evaluated. A successful achievement of all the aforementioned objectives of this ground-breaking project would open new routes for the use of MOFs as chemical reactors to manufacture, at competitive prices, MOF-driven, structurally and electronically well–defined, ligand–free SNMCs in a multigram-scale.

1 886 000 €

Start date: 2019-03-01, End date: 2024-02-29

Earth is inhabited by an energy hungry human society. The Sun, with a global radiation at the ground level of more than 1 kW/m^2, is our largest source of energy. However, 45% of the total radiation is in the near infrared (NIR) and is not absorbed by most photovoltaic materials. PAIDEIA focuses on two main advantages aiming to enhance the capacity of solar energy conversion: i) plasmon assisted hot carriers extraction from NIR plasmonic materials; ii) linewidth narrowing in plasmonic nanoparticle films that enhances the lifetime of hot carriers and, thus, boosts the efficiency of light driven carrier extraction. Instead of metals, which operate mostly in the visible region, we will make use of doped semiconductor nanocrystals (DSNCs) as hot electron extraction materials possessing a plasmonic response tunable in the range 800 nm – 4000 nm. Three different innovative architectures will be used for improved device performance: i) improved Schottky junctions (DSNC/wide band gap semiconductor nanocomposites); ii) ultrathin devices (DSNCs/2D quantum materials); iii) maximized interface DSNC/semiconductor bulk hetero-Schottky junctions. By combining both concepts in advanced architectures we aim to produce a solar cell device that functions in the NIR with efficiencies of up to 10%. A tandem solar cell that combines the conventional power conversion efficiency, up to ~1100 nm, of a commercial Si solar cell (~20%) with the new PAIDEIA based device is expected to reach a total power conversion efficiency of 30% by extending the width of wavelengths that are converted to the full spectral range delivered by the Sun. PAIDEIA has a deeply fundamental character impacting several areas in the field of nanophysics, nanochemistry and materials processing and, at the same time, having a high impact on the study of solar energy conversion. Finally, PAIDEIA will provide answers to the fundamental questions regarding the physical behaviour of plasmonic/semiconductor interfaces.

1 815 445 €

Start date: 2019-04-01, End date: 2024-03-31

The main goal of this project is to demonstrate that reading acquisition (RA) drastically reshapes our phonemic inventory, and to investigate the time-course and fine-grained properties of this recalibration. The main innovative and ground-breaking aspect of this project is the merging of two research fields, (1) reading acquisition and (2) phonemic recalibration, together with a deep and extensive exploration of the (3) perception-production link, which results in a new research line that pushes the boundaries of our understanding of the complex interactions between auditory and visual language perception and production. We will demonstrate that phonemic representations (PRs) become more stable (less dispersed) during the process of learning to read, and that this recalibration varies according to the grapheme-phoneme conversion rules of the reading system. We will explore such recalibration by means of the first cross-linguistic longitudinal study examining the position and dispersion of PRs, both in perception and production of phonemes and words. Secondly, we will explore how recalibration develops when RA is impaired as is the case in dyslexic children –informing the research field on (4) dyslexia– and when pre-reading PRs are unstable as is the case in deaf children with cochlear implants –informing the research field on (5) deafness. Finally, the research will also be extended to PR recalibration during RA in a second language –informing the research on (6) bilingualism. This proposal provides the first systematic investigation of phonemic recalibration during literacy acquisition, and will provide important insight for pragmatic research and theoretical accounts of language perception and production and phonemic recalibration. This project will also have major implications for the clinical field (theories and remediation of dyslexia and deafness) and for social policies and education (bilingualism, spoken and written language teaching).

1 875 000 €

Start date: 2019-10-01, End date: 2024-09-30

This project will develop and integrate the latest optimization and statistical advances into a new generation of resource-efficient algorithms for large-scale machine learning. State-of-the-art machine learning methods provide impressive results, opening new perspectives for science, technology, and society. However, they rely on massive computational resources to process huge manually annotated data-sets. The corresponding costs in terms of energy consumption and human efforts are not sustainable. This project builds on the idea that improving efficiency is a key to scale the ambitions and applicability of machine learning. Achieving efficiency requires overcoming the traditional boundaries between statistics and computations, to develop new theory and algorithms. Within a multidisciplinary approach, we will establish a new regularization theory of efficient machine learning. We will develop models that incorporate budgeted computations, and numerical solutions with resources tailored to the statistically accuracy allowed by the data. Theoretical advances will provide the foundations for novel and sound algorithmic solutions. Close collaborations in diverse applied fields will ensure that our research results and solutions will be apt and immediately applicable to real world scenarios. The new algorithms developed in the project will contribute to boost the possibilities of Artificial Intelligence, modeling and decision making in a world of data with ever-increasing size and complexity.

1 977 500 €

Start date: 2019-11-01, End date: 2024-10-31

The Accademia del Cimento (Florence) is the first European society to put experimentation at the core of scientific activity and to be supported by a public power. It lasted only ten years (1657-1667), the same years that saw the establishment of societies of greater fame and longevity such as the Royal Society and the Académie Royale des Sciences. The copious amount of records – most still unpublished – left by its members casts new light onto the process of establishment of scientific societies in Europe, on the emergence of a shared scientific discourse, and its normalisation. It also clarifies the “viral” aspect of some experiments as well as the dynamics of competition, imitation and (self-) censorship from which these institutional and scientific endeavours originated. This project analyses for the first time in its entirety the extensive corpus of unpublished documents (ca. 15,000 papers), descriptions of experiments and thousands of epistolary exchanges between members of the Cimento and scholars throughout Europe. By looking at the sources in their entirety, it aims at systematically connecting the strictly experimental, theoretical and philosophical aspects of the Accademia with its intellectual history. The research will thus analyse the hundreds of experiments designed and conducted by the members, without losing sight of the specific context in which they were produced and disseminated. It will reassess the Cimento’s contribution to the development of a scientific lexicon and the materiality of its work, which was heavily reliant on the design and use of scientific instruments. The substantive body of correspondence – neglected by historians so far – will uncover members’ aims and philosophical concerns, (self-) censorship mechanisms as well as the Cimento’s ties with scholars in the founding process of other famous academies. This research will thus provide new insights into the origin of scientific institutions in the Early Modern period.

1 708 206 €

Start date: 2019-06-01, End date: 2024-05-31

TRADITION aims to understand the long-term trajectory of human interaction with coastal resources and its legacy to present day small-scale fisheries in Latin America. Founded on traditional knowledge rooted in the past, small-scale fisheries are a crucial source of food and livelihood for millions of people worldwide, and play a pivotal role in poverty eradication in developing countries. A thorough recognition of the cultural and socio-economic significance of Latin American fisheries requires a temporal component that only archaeology and history can provide. TRADITION will investigate a 4000-year record of coastal exploitation in one of the world's most threatened tropical environments: the Atlantic forest of Brazil. We will draw together archaeological, palaeoecological, historical and ethnographic records to address fundamental questions that impinge upon our current understanding of the development of small-scale fisheries in this region. How did coastal economies adapt to the spread of agriculture? What was the impact of past climate and environmental changes on coastal populations? What was the impact of European colonisation of the Americas on the development of small-scale fisheries? What was the role of historical institutions and regulations in the negotiation between traditional and modern practices in small-scale fisheries? How have the historical practices and events shaped current small-scale coastal communities, and can this knowledge benefit current management strategies. The answers will help us understand how coastal economies responded to unprecedented societal and environmental changes by adapting their subsistence practices, technology and culture, while contributing to the foundation of coastal societies in Latin America.

1 877 107 €

Start date: 2019-09-01, End date: 2024-08-31