ERC FUNDED PROJECTS

Label-free optical nanoscopy, free from photobleaching and photochemical toxicity of fluorescence labels and yielding 3D morphological resolution of <50 nm, is the future of live cell imaging. 3D-nanoMorph breaks the diffraction barrier and shifts the paradigm in label-free nanoscopy, providing isotropic 3D resolution of <50 nm. To achieve this, 3D-nanoMorph performs non-linear inverse scattering for the first time in nanoscopy and decodes scattering between sub-cellular structures (organelles). 3D-nanoMorph innovatively devises complementary roles of light measurement system and computational nanoscopy algorithm. A novel illumination system and a novel light collection system together enable measurement of only the most relevant intensity component and create a fresh perspective about label-free measurements. A new computational nanoscopy approach employs non-linear inverse scattering. Harnessing non-linear inverse scattering for resolution enhancement in nanoscopy opens new possibilities in label-free 3D nanoscopy. I will apply 3D-nanoMorph to study organelle degradation (autophagy) in live cancer cells over extended duration with high spatial and temporal resolution, presently limited by the lack of high-resolution label-free 3D morphological nanoscopy. Successful 3D mapping of nanoscale biological process of autophagy will open new avenues for cancer treatment and showcase 3D-nanoMorph for wider applications. My cross-disciplinary expertise of 14 years spanning inverse problems, electromagnetism, optical microscopy, integrated optics and live cell nanoscopy paves path for successful implementation of 3D-nanoMorph.

1 499 999 €

Start date: 2019-07-01, End date: 2024-06-30

How does the inside of the proton look like? What generates its spin?
3DSPIN will deliver essential information to answer these questions at the frontier of subnuclear physics. At present, we have detailed maps of the distribution of quarks and gluons in the nucleon in 1D (as a function of their momentum in a single direction). We also know that quark spins account for only about 1/3 of the spin of the nucleon. 3DSPIN will lead the way into a new stage of nucleon mapping, explore the distribution of quarks in full 3D momentum space and obtain unprecedented information on orbital angular momentum. Goals 1. extract from experimental data the 3D distribution of quarks (in momentum space), as described by Transverse-Momentum Distributions (TMDs); 2. obtain from TMDs information on quark Orbital Angular Momentum (OAM). Methodology 3DSPIN will implement state-of-the-art fitting procedures to analyze relevant experimental data and extract quark TMDs, similarly to global fits of standard parton distribution functions. Information about quark angular momentum will be obtained through assumptions based on theoretical considerations. The next five years represent an ideal time window to accomplish our goals, thanks to the wealth of expected data from deep-inelastic scattering experiments (COMPASS, Jefferson Lab), hadronic colliders (Fermilab, BNL, LHC), and electron-positron colliders (BELLE, BABAR). The PI has a strong reputation in this field. The group will operate in partnership with the Italian National Institute of Nuclear Physics and in close interaction with leading experts and experimental collaborations worldwide. Impact Mapping the 3D structure of chemical compounds has revolutionized chemistry. Similarly, mapping the 3D structure of the nucleon will have a deep impact on our understanding of the fundamental constituents of matter. We will open new perspectives on the dynamics of quarks and gluons and sharpen our view of high-energy processes involving nucleons.

1 509 000 €

Start date: 2015-07-01, End date: 2020-06-30

Quantum chemistry provides two approaches to molecular electronic-structure calculations: the systematically refinable but expensive many-body wave-function methods and the inexpensive but not systematically refinable Kohn Sham method of density-functional theory (DFT). The accuracy of Kohn Sham calculations is determined by the quality of the exchange correlation functional, from which the effects of exchange and correlation among the electrons are extracted using the density rather than the wave function. However, the exact exchange correlation functional is unknown—instead, many approximate forms have been developed, by fitting to experimental data or by satisfying exact relations. Here, a new approach to density-functional analysis and construction is proposed: the Lieb variation principle, usually regarded as conceptually important but impracticable. By invoking the Lieb principle, it becomes possible to approach the development of approximate functionals in a novel manner, being directly guided by the behaviour of exact functional, accurately calculated for a wide variety of chemical systems. In particular, this principle will be used to calculate ab-initio adiabatic connection curves, studying the exchange correlation functional for a fixed density as the electronic interactions are turned on from zero to one. Pilot calculations have indicated the feasibility of this approach in simple cases—here, a comprehensive set of adiabatic-connection curves will be generated and utilized for calibration, construction, and analysis of density functionals, the objective being to produce improved functionals for Kohn Sham calculations by modelling or fitting such curves. The ABACUS approach will be particularly important in cases where little experimental information is available—for example, for understanding and modelling the behaviour of the exchange correlation functional in electromagnetic fields.

2 017 932 €

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

Arctic sea ice decline is the exponent of the rapidly transforming Arctic climate. The ensuing local and global implications can be understood by studying past climate transitions, yet few methods are available to examine past Arctic sea ice cover, severely restricting our understanding of sea ice in the climate system. The decline in Arctic sea ice cover is a ‘canary in the coalmine’ for the state of our climate, and if greenhouse gas emissions remain unchecked, summer sea ice loss may pass a critical threshold that could drastically transform the Arctic. Because historical observations are limited, it is crucial to have reliable proxies for assessing natural sea ice variability, its stability and sensitivity to climate forcing on different time scales. Current proxies address aspects of sea ice variability, but are limited due to a selective fossil record, preservation effects, regional applicability, or being semi-quantitative. With such restraints on our knowledge about natural variations and drivers, major uncertainties about the future remain. I propose to develop and apply a novel sea ice proxy that exploits genetic information stored in marine sediments, sedimentary ancient DNA (sedaDNA). This innovation uses the genetic signature of phytoplankton communities from surface waters and sea ice as it gets stored in sediments. This wealth of information has not been explored before for reconstructing sea ice conditions. Preliminary results from my cross-disciplinary team indicate that our unconventional approach can provide a detailed, qualitative account of past sea ice ecosystems and quantitative estimates of sea ice parameters. I will address fundamental questions about past Arctic sea ice variability on different timescales, information essential to provide a framework upon which to assess the ecological and socio-economic consequences of a changing Arctic. This new proxy is not limited to sea ice research and can transform the field of paleoceanography.

2 615 858 €

Start date: 2019-08-01, End date: 2024-07-31

"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

Zinc finger (ZF) and transcription activator-like effector (TALE) based technologies are been allowing the tailored design of “artificial” DNA-binding proteins targeted to specific and unique DNA genomic sequences. Coupling DNA binding proteins to effectors domains enables the constitution of DNA binding factors for genomic directed transcriptional modulation or targeted genomic editing. We have demonstrated that pairing a ZF DNA binding protein to the transcriptional repressor Kruppel-associated box enables in vivo, the transcriptional repression of one of the most abundantly expressed gene in mammals, the human rhodopsin gene (RHO). We propose to generate RHO DNA binding silencers (“AlleleChoker”), which inactivate RHO either by transcriptional repression or targeted genome modification, irrespectively to wild-type or mutated alleles (mutational-independent approach), and combine RHO endogenous silencing to RHO replacement (silencing-replacement strategy). With this strategy in principle a single bimodal bio-therapeutic will enable the correction of any photoreceptor disease associated with RHO mutation. Adeno-associated viral (AAV) vector-based delivery will be used for photoreceptors gene transfer. Specifically our objectives are: 1) Construction of transcriptional repressors and nucleases for RHO silencing. Characterization and comparison of RHO silencing mediated by transcriptional repressors (ZFR/ TALER) or nucleases (ZFN/ TALEN) to generate genomic directed inactivation by non-homologous end-joining (NHEJ), and refer these results to RNA interference (RNAi) targeted to RHO; 2) RHO silencing in photoreceptors. to determine genome-wide DNA binding specificity of silencers, chromatin modifications and expression profile on human retinal explants; 3) Tuning silencing and replacement. To determine the impact of gene silencing-replacement strategy on disease progression in animal models of autosomal dominant retinitis pigmentosa (adRP) associated to RHO mutations

1 354 840 €

Start date: 2013-02-01, End date: 2018-01-31

New neurons are continuously generated in certain regions of adult mammalian brain. One of those regions is the dentate gyrus, a subregion of hippocampus, which is essential for memory formation. Although these new neurons in the adult dentate gyrus are thought to have an important role in learning and memory, it is largely unclear how new neurons are involved in information processing and storage underlying memory. Because new neurons constitute a minor portion of intermingled local neuronal population, simple application of conventional techniques such as multi-unit extracellular recording and pharmacological lesion are not suitable for the functional analysis of new neurons. In this proposed research program, I will combine multi-unit recording and behavioral analysis with virus mediated, cell-type-specific genetic manipulation of neuronal activity, to investigate computational roles of new neurons in learning and memory. Specifically, I will determine: 1) specific memory processes that require new neurons, 2) dynamic patterns of activity that new neurons express during memory-related behavior, 3) influence of new neurons on their downstream structure. Further, based on the information obtained by these three lines of studies, we will establish causal relationship between specific memory-related behavior and specific pattern of activity in new neurons. Solving these issues will cooperatively provide important insight into the understanding of computational roles performed by adult neurogenesis. The information on the function of new neurons in normal brain could contribute to future development of efficient therapeutic strategy for a variety of brain disorders.

1 991 743 €

Start date: 2009-01-01, End date: 2013-12-31

"During the last decade, a strikingly successful cosmological concordance model has been established. With only six free parameters, nearly all observables, comprising millions of data points, may be fitted with outstanding precision. However, in this beautiful picture a few ""blemishes"" have turned up, apparently not consistent with the standard model: While the model predicts that the universe is isotropic (i.e., looks the same in all directions) and homogeneous (i.e., the statistical properties are the same everywhere), subtle hints of the contrary are now seen. For instance, peculiar preferred directions and correlations are observed in the cosmic microwave background; some studies considering nearby galaxies suggest the existence of anomalous large-scale cosmic flows; a study of distant quasars hints towards unexpected large-scale correlations. All of these reports are individually highly intriguing, and together they hint toward a more complicated and interesting universe than previously imagined -- but none of the reports can be considered decisive. One major obstacle in many cases has been the relatively poor data quality. This is currently about to change, as the next generation of new and far more powerful experiments are coming online. Of special interest to me are Planck, an ESA-funded CMB satellite currently taking data; QUIET, a ground-based CMB polarization experiment located in Chile; and various large-scale structure (LSS) data sets, such as the SDSS and 2dF surveys, and in the future Euclid, a proposed galaxy survey satellite also funded by ESA. By combining the world s best data from both CMB and LSS measurements, I will in the proposed project attempt to settle this question: Is our universe really anisotropic? Or are these recent claims only the results of systematic errors or statistical flukes? If the claims turn out to hold against this tide of new and high-quality data, then cosmology as a whole may need to be re-written."

1 500 000 €

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

Isoperimetric and Sobolev inequalities are the best known examples of geometric-functional inequalities. In recent years the PI and collaborators have obtained new and sharp quantitative versions of these and other important related inequalities. These results have been obtained by the combined use of classical symmetrization methods, new tools coming from mass transportation theory, deep geometric measure tools and ad hoc symmetrizations. The objective of this project is to further develop thes techniques in order to get: sharp quantitative versions of Faber-Krahn inequality, Gaussian isoperimetric inequality, Brunn-Minkowski inequality, Poincaré and Sobolev logarithm inequalities; sharp decay rates for the quantitative Sobolev inequalities and Polya-Szegö inequality.

600 000 €

Start date: 2009-01-01, End date: 2013-12-31

The goal of the ARS project is the derivation of a unified framework for the autonomous execution of robotic tasks in challenging environments in which accurate performance and safety are of paramount importance. We have chosen surgery as the research scenario because of its importance, its intrinsic challenges, and the presence of three factors that make this project feasible and timely. In fact, we have recently concluded the I-SUR project demonstrating the feasibility of autonomous surgical actions, we have access to the first big data made available to researchers of clinical robotic surgeries, and we will be able to demonstrate the project results on the high performance surgical robot “da Vinci Research Kit”. The impact of autonomous robots on the workforce is a current subject of discussion, but surgical autonomy will be welcome by the medical personnel, e.g. to carry out simple intervention steps, react faster to unexpected events, or monitor the insurgence of fatigue. The framework for autonomous robotic surgery will include five main research objectives. The first will address the analysis of robotic surgery data set to extract action and knowledge models of the intervention. The second objective will focus on planning, which will consist of instantiating the intervention models to a patient specific anatomy. The third objective will address the design of the hybrid controllers for the discrete and continuous parts of the intervention. The fourth research objective will focus on real time reasoning to assess the intervention state and the overall surgical situation. Finally, the last research objective will address the verification, validation and benchmark of the autonomous surgical robotic capabilities. The research results to be achieved by ARS will contribute to paving the way towards enhancing autonomy and operational capabilities of service robots, with the ambitious goal of bridging the gap between robotic and human task execution capability.

2 750 000 €

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

Massive black hole binaries (MBHBs) are the most extreme, fascinating yet elusive astrophysical objects in the Universe. Establishing observationally their existence will be a milestone for contemporary astronomy, providing a fundamental missing piece in the puzzle of galaxy formation, piercing through the (hydro)dynamical physical processes shaping dense galactic nuclei from parsec scales down to the event horizon, and probing gravity in extreme conditions. We can both see and listen to MBHBs. Remarkably, besides arguably being among the brightest variable objects shining in the Cosmos, MBHBs are also the loudest gravitational wave (GW) sources in the Universe. As such, we shall take advantage of both the type of messengers – photons and gravitons – they are sending to us, which can now be probed by all-sky time-domain surveys and radio pulsar timing arrays (PTAs) respectively. B MASSIVE leverages on a unique comprehensive approach combining theoretical astrophysics, radio and gravitational-wave astronomy and time-domain surveys, with state of the art data analysis techniques to: i) observationally prove the existence of MBHBs, ii) understand and constrain their astrophysics and dynamics, iii) enable and bring closer in time the direct detection of GWs with PTA. As European PTA (EPTA) executive committee member and former I International PTA (IPTA) chair, I am a driving force in the development of pulsar timing science world-wide, and the project will build on the profound knowledge, broad vision and wide collaboration network that established me as a world leader in the field of MBHB and GW astrophysics. B MASSIVE is extremely timely; a pulsar timing data set of unprecedented quality is being assembled by EPTA/IPTA, and Time-Domain astronomy surveys are at their dawn. In the long term, B MASSIVE will be a fundamental milestone establishing European leadership in the cutting-edge field of MBHB astrophysics in the era of LSST, SKA and LISA.

1 532 750 €

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

Monoclonal antibodies against the EGF receptor (EGFR) provide substantive benefit to colorectal cancer (CRC) patients. However, no genetic lesions that robustly predict ‘addiction’ to the EGFR pathway have been yet identified. Further, even in tumours that regress after EGFR blockade, subsets of drug-tolerant cells often linger and foster ‘minimal residual disease’ (MRD), which portends tumour relapse. Our preliminary evidence suggests that reliance on EGFR activity, as opposed to MRD persistence, could be assisted by genetically-based variations in transcription factor partnerships and activities, gene expression outputs, and biological fates controlled by the WNT/beta-catenin pathway. On such premises, BEAT (Beta-catenin and EGFR Abrogation Therapy) will elucidate the mechanisms of EGFR dependency, and escape from it, with the goal to identify biomarkers for more efficient clinical management of CRC and develop new therapies for MRD eradication. A multidisciplinary approach will be pursued spanning from integrative gene regulation analyses to functional genomics in vitro, pharmacological experiments in vivo, and clinical investigation, to address whether: (i) specific genetic alterations of the WNT pathway affect anti-EGFR sensitivity; (ii) combined neutralisation of EGFR and WNT signals fuels MRD deterioration; (iii) data from analysis of this synergy can lead to the discovery of clinically meaningful biomarkers with predictive and prognostic significance. This proposal capitalises on a unique proprietary platform for high-content studies based on a large biobank of viable CRC samples, which ensures strong analytical power and unprecedented biological flexibility. By providing fresh insight into the mechanisms whereby WNT/beta-catenin signalling differentially sustains EGFR dependency or drug tolerance, the project is expected to put forward an innovative reinterpretation of CRC molecular bases and advance the rational application of more effective therapies.

1 793 421 €

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

The use of bioinorganic nanohybrids (nanoscaled systems based on an inorganic and a biological component) has already resulted in several innovative medical breakthroughs for drug delivery, therapeutics, imaging, diagnosis and biocompatibility. However, researchers still know relatively little about the structure, function and mechanism of these nanodevices. Theoretical investigations of bioinorganic interfaces are mostly limited to force-field approaches which cannot grasp the details of the physicochemical mechanisms. The BIOINOHYB project proposes to capitalize on recent massively parallelized codes to investigate bioinorganic nanohybrids by advanced quantum chemical methods. This approach will allow to master the chemical and electronic interplay between the bio and the inorganic components in the first part of the project, and the interaction of the hybrid systems with light in the second part. The ultimate goal is to provide the design principles for novel, unconventional assemblies with unprecedented functionalities and strong impact potential in nanomedicine. More specifically, in this project the traditional metallic nanoparticle will be substituted by emerging semiconducting metal oxide nanostructures with photocatalytic or magnetic properties capable of opening totally new horizons in nanomedicine (e.g. photocatalytic therapy, a new class of contrast agents, magnetically guided drug delivery). Potentially efficient linkers will be screened regarding their ability both to anchor surfaces and to bind biomolecules. Different kinds of biomolecules (from oligopeptides and oligonucleotides to small drugs) will be tethered to the activated surface according to the desired functionality. The key computational challenge, requiring the recourse to more sophisticated methods, will be the investigation of the photo-response to light of the assembled bioinorganic systems, also with specific reference to their labelling with fluorescent markers and contrast agents.

1 748 125 €

Start date: 2016-02-01, End date: 2021-01-31

The BioMNP objective is the molecular-level understanding of the interactions between surface functionalized metal nanoparticles and biological membranes, by means of cutting-edge computational techniques and new molecular models. Metal nanoparticles (NP) play more and more important roles in pharmaceutical and medical technology as diagnostic or therapeutic devices. Metal NPs can nowadays be engineered in a multitude of shapes, sizes and compositions, and they can be decorated with an almost infinite variety of functionalities. Despite such technological advances, there is still poor understanding of the molecular processes that drive the interactions of metal NPs with cells. Cell membranes are the first barrier encountered by NPs entering living organisms. The understanding and control of the interaction of nanoparticles with biological membranes is therefore of paramount importance to understand the molecular basis of the NP biological effects. BioMNP will go beyond the state of the art by rationalizing the complex interplay of NP size, composition, functionalization and aggregation state during the interaction with model biomembranes. Membranes, in turn, will be modelled at an increasing level of complexity in terms of lipid composition and phase. BioMNP will rely on cutting-edge simulation techniques and facilities, and develop new coarse-grained models grounded on finer-level atomistic simulations, to study the NP-membrane interactions on an extremely large range of length and time scales. BioMNP will benefit from important and complementary experimental collaborations, will propose interpretations of the available experimental data and make predictions to guide the design of functional, non-toxic metal nanoparticles for biomedical applications. BioMNP aims at answering fundamental questions at the crossroads of physics, biology and chemistry. Its results will have an impact on nanomedicine, toxicology, nanotechnology and material sciences.

1 131 250 €

Start date: 2016-04-01, End date: 2021-03-31

Multiferroics (i.e. materials where ferroelectricity and magnetism coexist) are presently drawing enormous interests, due to their technologically-relevant multifunctional character and to the astoundingly rich playground for fundamental condensed-matter physics they constitute. Here, we put forward several concepts on how to break inversion symmetry and achieve sizable ferroelectricity in collinear magnets; our approach is corroborated via first-principles calculations as tools to quantitatively estimate relevant ferroelectric and magnetic properties as well as to reveal ab-initio the main mechanisms behind the dipolar and magnetic orders. In closer detail, we focus on the interplay between ferroelectricity and electronic degrees of freedom in magnets, i.e. on those cases where spin- or orbital- or charge-ordering can be the driving force for a spontaneous polarization to develop. Antiferromagnetism will be considered as a primary mechanism for lifting inversion symmetry; however, the effects of charge disproportionation and orbital ordering will also be studied by examining a wide class of materials, including ortho-manganites with E-type spin-arrangement, non-E-type antiferromagnets, nickelates, etc. Finally, as an example of materials-design accessible to our ab-initio approach, we use “chemistry” to break inversion symmetry by artificially constructing an oxide superlattice and propose a way to switch, via an electric field, from antiferromagnetism to ferrimagnetism. To our knowledge, the link between electronic degrees of freedom and ferroelectricity in collinear magnets is an almost totally unexplored field by ab-initio methods; indeed, its clear understanding and optimization would lead to a scientific breakthrough in the multiferroics area. Technologically, it would pave the way to materials design of magnetic ferroelectrics with properties persisting above room temperature and, therefore, to a novel generation of electrically-controlled spintronic devices

684 000 €

Start date: 2008-05-01, End date: 2012-04-30

The standard variational principles (VPs) are cornerstones of quantum mechanics, and one can hardly overestimate their usefulness as tools for generating approximations to the time-independent and time-dependent Schröodinger equations. The aim of the proposal is to study and apply a generalization of these, the bivariational principles (BIVPs), which arise naturally when one does not assume a priori that the system Hamiltonian is Hermitian. This unconventional approach may have transformative impact on development of ab initio methodology, both for electronic structure and dynamics. The first objective is to establish the mathematical foundation for the BIVPs. This opens up a whole new axis of method development for ab initio approaches. For instance, it is a largely ignored fact that the popular traditional coupled cluster (TCC) method can be neatly formulated with the BIVPs, and TCC is both polynomially scaling with the number of electrons and size-consistent. No “variational” method enjoys these properties simultaneously, indeed this seems to be incompatible with the standard VPs. Armed with the BIVPs, the project aims to develop new and understand existing ab initio methods. The second objective is thus a systematic multireference coupled cluster theory (MRCC) based on the BIVPs. This is in itself a novel approach that carries large potential benefits and impact. The third and last objective is an implementation of a new coupled-cluster type method where the orbitals are bivariational parameters. This gives a size-consistent hierarchy of approximations to multiconfiguration Hartree--Fock. The PI's broad contact with and background in scientific disciplines such as applied mathematics and nuclear physics in addition to quantum chemistry increases the feasibility of the project.

1 499 572 €

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

Plate tectonics characterises the complex and dynamic evolution of the outer shell of the Earth in terms of rigid plates. These tectonic plates overlie and interact with the Earth's mantle, which is slowly convecting owing to energy released by the decay of radioactive nuclides in the Earth's interior. Even though links between mantle convection and plate tectonics are becoming more evident, notably through subsurface tomographic images, advances in mineral physics and improved absolute plate motion reference frames, there is still no generally accepted mechanism that consistently explains plate tectonics and mantle convection in one framework. We will integrate plate tectonics into mantle dynamics and develop a theory that explains plate motions quantitatively and dynamically. This requires consistent and detailed reconstructions of plate motions through time (Objective 1). A new model of plate kinematics will be linked to the mantle with the aid of a new global reference frame based on moving hotspots and on palaeomagnetic data. The global reference frame will be corrected for true polar wander in order to develop a global plate motion reference frame with respect to the mantle back to Pangea (ca. 320 million years) and possibly Gondwana assembly (ca. 550 million years). The resulting plate reconstructions will constitute the input to subduction models that are meant to test the consistency between the reference frame and subduction histories. The final outcome will be a novel global subduction reference frame, to be used to unravel links between the surface and deep Earth (Objective 2).

2 499 010 €

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

In spite of their significance in a variety of volcanological aspects, gas observations at volcanoes have lagged behind geophysical studies for a long time. This has primarily reflected the inherent technical limitations met by gas geochemists in capturing volcanic gas properties (chemistry and flux) at high-rate (1 Hz), and using permanent instrumental arrays. The poor temporal resolution of volcanic gas observations has, in addition, precluded the real-time analysis of fast-occurring volcanic processes, as those occurring shortly prior to eruptions, therefore generally limiting the use of gas geochemistry in volcanic hazard assessment. However, the recent progresses made by modern multi-component/high frequency measurement techniques now open the way for decisive step ahead in the current state-of-the-art to be finally attempted. The BRIDGE research proposal has the ambitious goals to bridge the existing technological gap between geochemical and geophysical observations at volcanoes. This will be achieved by designing, setting up, and deploying in the field, innovative instruments for 1 Hz observations of volcanic SO2 and CO2 fluxes. From this, the co-acquired volcanic gas and geophysical information will be then combined within a single interpretative framework, therefore contributing to fill our current gap of knowledge on fast (timescales of seconds/minutes) degassing processes, and to deeper exploration of the role played by gas exsolution from (and migration through) silicate liquids as effective source mechanism of the physical signals (e.g., LP and VLP seismicity, and tremor) measured at volcanoes. Finally, this combined volcanic gas-geophysical approach will be used to yield improved modelling/understanding of a variety of volcanic features, including modes/rates of gas separation from magmas, mechanisms of gas flow in conduits, and trigger mechanisms of explosive volcanic eruptions.

1 496 222 €

Start date: 2012-10-01, End date: 2016-09-30

The oral cavity is the gateway to the lower respiratory tract, and oral bacteria are likely to play a role in lung health. This may be the case for pathogens as well as commensal bacteria and the balance between species. The oral bacterial community of patients with periodontitis is dominated by gram-negative bacteria and a higher lipopolysaccharide (LPS) activity than in healthy microbiota. Furthermore, bacteria with especially potent pro-inflammatory LPS have been shown to be more common in the lungs of asthmatic than in healthy individuals. The working hypothesis of BRuSH is that microbiome communities dominated by LPS-producing bacteria which induce a particularly strong pro-inflammatory immune response in the host, will have a negative effect on respiratory health. I will test this hypothesis in two longitudinally designed population-based lung health studies. I aim to identify whether specific bacterial composition and types of LPS producing bacteria in oral and dust samples predict lung function and respiratory health over time; and if the different types of LPS-producing bacteria affect LPS in saliva saliva and dust. BRuSH will apply functional genome annotation that can assign biological significance to raw bacterial DNA sequences. With this bioinformatics tool I will cluster microbiome data into various LPS-producers: bacteria with LPS with strong inflammatory effects and others with weak- or antagonistic effects. The epidemiological studies will be supported by mice-models of asthma and cell assays of human bronchial epithelial cells, by exposing mice and bronchial cells to chemically synthesized Lipid A (the component that drive the LPS-induced immune responses) of various potency. The goal of BRuSH is to prove a causal relationship between oral microbiome and lung health, and gain knowledge that will enable us to make oral health a feasible target for intervention programs aimed at optimizing lung health and preventing respiratory disease.

1 499 938 €

Start date: 2019-01-01, End date: 2023-12-31

"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

We propose the development of novel nanodevices, such as nanoscale bridges and nanovectors, based on functionalized carbon nanotubes (CNT) for manipulating neurons and neuronal network activity in vitro. The main aim is to put forward innovative solutions that have the potential to circumvent the problems currently faced by spinal cord lesions or by neurodegenerative diseases. The unifying theme is to use recent advances in chemistry and nanotechnology to gain insight into the functioning of hybrid neuronal/CNT networks, relevant for the development of novel implantable devices to control neuronal signaling and improve synapse formation in a controlled fashion. The proposal s core strategy is to exploit the expertise of the PI in the chemical control of CNT properties to develop devices reaching various degrees of functional integration with the physiological electrical activity of cells and their networks, and to understand how such global dynamics are orchestrated when integrated by different substrates. An unconventional strategy will be represented by the electrical characterization of micro and nano patterned substrates by AFM and conductive tip AFM, both before and after neurons have grown on the substrates. We will also use the capability of AFM to identify critical positions in the neuronal network, while delivering time-dependent chemical stimulations. We will apply nanotechnology to contemporary neuroscience in the perspective of novel neuro-implantable devices and drug nanovectors, engineered to treat neurological and neurodegenerative lesions. The scientific strategy at the core of the proposal is the convergence between nanotechnology, chemistry and neurobiology. Such convergence, beyond helping understand the functioning and malfunctioning of the brain, can stimulate further research in this area and may ultimately lead to a new generation of nanomedicine applications in neurology and to new opportunities for the health care industry.

2 500 000 €

Start date: 2009-02-01, End date: 2014-01-31

Contraction and relaxation of cardiac myocytes, and thus the whole heart, are critically dependent on dyads. These functional junctions between t-tubules, which are invaginations of the surface membrane, and the sarcoplasmic reticulum allow efficient control of calcium release into the cytosol, and also its removal. Dyads are formed gradually during development and break down during disease. However, the precise nature of dyadic structure is unclear, even in healthy adult cardiac myocytes, as are the triggers and consequences of altering dyadic integrity. In this proposal, my group will investigate the precise 3-dimensional arrangement of dyads and their proteins during development, adulthood, and heart failure by employing CLEM imaging (PALM and EM tomography). This will be accomplished by developing transgenic mice with fluorescent labels on four dyadic proteins (L-type calcium channel, ryanodine receptor, sodium-calcium exchanger, SERCA), and by imaging tissue from explanted normal and failing human hearts. The signals responsible for controlling dyadic formation, maintenance, and disruption will be determined by performing high-throughput sequencing to identify novel genes involved with these processes in several established model systems. Particular focus will be given to investigating left ventricular wall stress and stretch-dependent gene regulation as controllers of dyadic integrity. Candidate genes will be manipulated in cell models and transgenic animals to promote dyadic formation and maintenance, and reverse dyadic disruption in heart failure. The consequences of dyadic structure for function will be tested experimentally and with mathematical modeling to examine effects on cardiac myocyte calcium homeostasis and whole-heart function. The results of this project are anticipated to yield unprecedented insight into dyadic structure, regulation, and function, and to identify novel therapeutic targets for heart disease patients.

2 000 000 €

Start date: 2015-07-01, End date: 2020-06-30

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

1 367 960 €

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

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

1 123 000 €

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