ERC FUNDED PROJECTS

The Collaborative Economy (CE) is rapidly expanding through new forms of Internet labor and commerce, from Wikipedia to Kickstarter and Airbnb. However, it suffers from 3 main challenges: (1) Infrastructure: centralized surveillance that the central hubs of information exercise over their users, (2) Governance: disempowered communities which do not have any decision-making influence over the platform, and (3) Economy: concentration of profits in a few major players who do not proportionally redistribute them to the contributors. How can CE software platforms be implemented for solving these challenges? P2PMODELS explores a new way of building CE software platforms harnessing the blockchain, an emerging technology that enables autonomous agent-mediated organizations, in order to (1) provide a software framework to build decentralized infrastructure for Collaborative Economy organizations that do not depend on central authorities, (2) enable democratic-by-design models of governance for communities, by encoding rules directly into the software platform, and (3) enable fairer value distribution models, thus improving the economic sustainability of both CE contributors and organizations. Together, these 3 objectives will bootstrap the emergence of a new generation of self-governed and more economically sustainable peer-to-peer CE communities. The interdisciplinary nature of P2PMODELS will open a new research field around agent-mediated organizations for collaborative communities and their self-enforcing rules for automatic governance and economic rewarding. Bringing this proposal to life requires a funding scheme compatible with a high-risk/high-gain vision to finance a fully dedicated and highly motivated research team with multidisciplinary skills.

1 498 855 €

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

Cell fate decisions rely on signaling pathways that integrate external signals to coordinate specific intracellular programs. One of these pathways leads to the activation of p38α MAPK, which plays key roles in cell responses to many types of stresses as well as chemotherapeutic agents and oncogenes. Importantly, p38α acts in a cell context-specific and cell type-specific manner to integrate signals that affect cell proliferation, differentiation and survival. Evidence from mouse models and human cell lines indicates that p38α can negatively regulate tumor initiation at different levels. Intriguingly, recent results suggest that p38α activation may also sometimes have pro-tumorigenic functions. The molecular basis for the different functions of p38α are not well understood but it is likely that the network of substrates phosphorylated by p38α plays a major role. This project proposes to investigate molecular mechanisms of p38 MAPK signaling during tumorigenesis including the systematic identification of substrates and how they contribute to the different functions of this pathway. An important part of the studies will focus on the mechanisms underlying the rewiring of p38α signaling to serve pro-tumorigenic functions, including in-depth characterization of how p38α regulates the survival, proliferation and spreading of cancer cells, as well as its role in the interplay between cancer cells and stromal cells. We also plan to investigate the implication of p38α in tumor progression in vivo, using both xenografts and genetically modified mice that we have generated to either inactivate or hyperactivate the p38 MAPK pathway. These models will allow us to analyze the role of this signaling pathway in the regulation of tumor initiation, growth and spreading in different tissues. Taken together, this project will address important questions on cellular signaling and tumor development, which might be also useful for more rational anti-tumoral treatments.

2 497 800 €

Start date: 2012-07-01, End date: 2017-12-31

Pancreatic adenocarcinoma is the deadliest solid cancer and currently the fourth most frequent cause for cancer related deaths. Over the past decades, there has hardly been any substantial therapeutic progress regarding clinical endpoints. New hope has now been generated by the re-emerging cancer stem cell (CSC) concept. We have identified and characterized pancreatic CSC in the context of tumour growth, metastasis, and resistance to chemotherapy. To eventually be able to develop a targeted therapy for eliminating CSCs as the root of the tumour, we will perform comparative functional and genomic analyses of the identified, highly purified human CSC populations, their more differentiated progenies, normal tissue resident stem cells, and hematopoietic stem cells. For these analyses, we are also focusing on their demonstrated resistance of CSC to chemotherapy as well as their invasive properties and tumour-initiating capacity as demonstrated in our orthotopic mouse models. Subsequent functional characterization of newly identified genes regarding their biological function for tumour angiogenesis, invasiveness, and metastasis will be carried out. Moreover, it is similarly important to investigate in parallel the origin of CSCs, which may aid us to develop new therapeutic strategies to prevent transformation of tissue-resident stem cells. The role of risk factors that have been associated with the development of pancreatic cancer, namely smoking and chronic pancreatitis will be investigated in this context. Together, the above experiments will generate important clues how CSCs circumvent the physiological regulatory elements of stem cell functionality and, even more importantly, how these cells escape the response to standard cancer therapy. Eventually, these new insights may allow us to develop novel targeted and multimodal treatment modalities for the successful elimination of these cells as the previously unrecognized root of the tumour.

2 335 105 €

Start date: 2009-07-01, End date: 2014-12-31

Evolution of marine algae over the last 60 million years has resulted in a fundamental change in the efficiency of biological carbon pump and shift from communities dominated by calcifying algae (like coccolithophorids) to siliceous diatoms and major size class changes among these groups. The inferred shift in atmospheric CO2 over this time period has been suggested as an important selective pressure on some of these responses, including diatom adaptation to lower atmospheric CO2 concentrations via use of the C4 photosynthetic pathway, and trends towards smaller coccolithophorid cell sizes in response to greater C limitation. If current trends continue, future changes in atmospheric CO2 from anthropogenic activities are likely to reach levels last seen in the Eocene by the end of the next century; such changes will also be accompanied by ocean acidification and changes in stratification. Evidence suggests that modern calcifying algae and diatoms may employ a range of carbon acquisition strategies (such as active carbon concentrating mechanisms) according to the pH and carbon speciation of the seawater in which they live. However calcifying populations from 60 million years ago apparently had a single or less diverse array of carbon acquisition strategies. In this project we thus seek to 1) to identify and calibrate novel fossil indicators for adaptation and evolution in carbon acquisition strategies in eukaryotic algae in response to past changes in the carbon cycle and atmospheric CO2, and 2) apply these indicators to establish the nature and timing of changes in carbon acquisition strategies by algae over the past 60 million years.

1 774 875 €

Start date: 2009-12-01, End date: 2015-11-30

Who were the Neanderthals and what caused their demise? To answer these questions, the classic approach in archaeology relies on the analysis of the Neanderthals' stone-tool assemblages and the mineralized bone remains of their dietary intake. Although this approach has yielded a great deal of important information about the Neanderthals’ fate, it is also limited in the sense that the only evidence that is considered is in-organic in nature. In the current proposal, we attempt to answer these questions by considering microscopic and molecular evidence that is organic in nature. By studying the organic sedimentary record at such fine scales, we are able to extract information about, for example, the fat contents of the Neanderthal food, the way they made fire, the arrangements of their living spaces, their surrounding vegetation and the climatic conditions where they lived. By combining these different sources of information we aim to provide a more complete picture of the Neanderthals and the reason of their disappearance. Specifically, the PALEOCHAR project examines how Neanderthal diet, fire technology, settlement patterns, and surrounding vegetation were affected by changing climatic conditions. To do so, the project will integrate methodologies from micromorphology and organic geochemistry. A key and innovative aspect of the proposal is the consideration of microscopic and molecular evidence that is both organic and charred in nature. Climatic changes and behavioural responses will be examined at two Iberian sites which represent two key points along the Neanderthal time-line. The results of this project will make important contributions to the development of new methods for archaeological research, train a new generation of skilled geoarchaeologists knowledgeable in microstratigraphy and applied chemistry, and yield new insights into the Neanderthals and their demise.

1 996 750 €

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

This project deals with one of the big gaps of knowledge in prehistory, how plant foods and resources were used by preagrarian societies. Plants have been fundamental for human societies across the planet. However, it is a blank when it comes to archaeological evidence of humans eating and exploiting them during most part of Prehistory. This work aims at changing the meat/hunting centred paradigm of Palaeolithic subsistence by readdressing human plant exploitation through a novel interdisciplinary approach. The main objectives are: 1) To assess wild plant exploitation among Palaeolithic-Epipalaeolithic societies, 2) To appraise resilience and change in Palaeolithic-Epipalaeolithic plant use, and 3) To improve archaeological methodology and fieldwork. The chronology of analysis –from the Late Middle Palaeolithic to the Epipalaeolithic- includes two extremely interesting periods: a) the transition from the middle to the upper Palaeolithic with neanderthal extinction and early presence of modern humans which gives us the opportunity to explore and compare whether these groups exploit plant resources in a different way, and b) the climatic change from the Late Pleistocene to the early Holocene which allows to evaluate how last hunter-gatherers from the region adapt to climatic change and new ecological conditions. The challenge of the work is to obtain archaeological visibility of plant use through and interdisciplinary approach that combines: pollen analysis, the study of plant macroremains including underground storage organs (USOs), micromorphology, analysis of microremains such as phytoliths and starch, ethnobotany and use-wear analyses on tools. The different types of evidence to be analysed come from relevant archaeological sites from Spain, Portugal and Morocco. Because a project at this scale has not been developed before, major scientific developments and impact in archaeological science can be safely expected.

384 345 €

Start date: 2014-07-01, End date: 2015-12-31

The DNA uptake competence system of the intracellular bacterial pathogen Listeria monocytogenes was considered non-functional. There are no known conditions for DNA transformation and the competence master activator gene, comK, is interrupted by a temperate (lysogenic) prophage. We have shown recently that the L. monocytogenes competence system is required during infection to promote bacterial escape from macrophage phagosomes, in a manner that is independent of DNA uptake. Remarkably, we found that regulation of the competence system relies on the formation of a functional comK gene via a controlled process of prophage excision. Prophage excision was specifically induced during intracellular growth, primarily within phagosomes, yet, unlike classic prophage induction, progeny virions were not produced and bacterial lysis did not occur. This study revealed a unique adaptation of a prophage to the intracellular life style of its host, whereby the prophage serves as a genetic switch to modulate the virulence of its host. In the proposed project we aim to investigate this phenomenon and study the give-and-take interactions between the L. monocytogenes 10403S strain and its ϕ10403S-prophage during mammalian infection. We will study the prophage determinants and mechanisms that control intracellular excision and maintenance as well as the mechanisms that prevent its virions production and bacterial lysis. We will explore the crosstalk between phage and bacterial regulatory factors and characterize the mammalian host signals/conditions that trigger this unique prophage response. Lastly, we will investigate the unexpected function of the competence system in phagosomal escape. In particular, we will explore the possibility that the competence system serves as an auxiliary secretion system, which secretes proteins that promote phagosomal escape.

1 490 400 €

Start date: 2013-10-01, End date: 2018-09-30

Being among the most significant challenges facing modern medicine, the massive growth of multi-drug resistance prolongs illnesses and increases the risk of early death, thus creating a global clinical threat. The limited arsenal of available antibiotics dictates an urgent need for novel approaches, as it suffers from (i) resistance to one or several antibiotics and (ii) marginal distinction between the antibiotics sites in bacteria and in patients, causing toxicity or side effects. As resistance-acquiring mechanisms are species-specific and as many antibiotics target ribosomes, we developed novel methodologies for increasing the battery of available potent antibiotics by benefiting from the breakthroughs of our NOVRIB ERC funded project: the unexpected rapid determination of the only available high resolution structure of a ribosome from a genuine pathogen, worldwide. In this PoC project we propose to exploit the unique tools provided by this structure for the commercialization of newly discovered binding sites and contact-networks, for suggesting novel synthetic antibiotics and/or for structure-based alterations of existing ones. Thus, we identified chemical elements associated solely with pathogenic specificity that can provide valuable clues for designing modifications that should increase the potency of the currently known antibiotics; alongside proposing novel binding sites on the ribosome surface. The advantages of our approach are (1) less chance of fast developing resistance, (2) reduced toxicity, (3) potential of decelerating multi-drug antimicrobial resistance development, (4) improved existing ribosomal antibiotics. The significance of our innovating approach stems also from the potential market and the compelling socioeconomic benefits. Hence, we are currently approaching the stage of commercialization and public dissemination.

150 000 €

Start date: 2014-05-01, End date: 2015-04-30

Computer Science, in particular, Analysis of Algorithms and Computational-Complexity theory, classify algorithmic-problems into feasible ones and those that cannot be efficiently-solved. Many fundamental problems were shown NP-hard, therefore, unless P=NP, they are infeasible. Consequently, research efforts shifted towards approximation algorithms, which find close-to-optimal solutions for NP-hard optimization problems. The PCP Theorem and its application to infeasibility of approximation establish that, unless P=NP, there are no efficient approximation algorithms for numerous classical problems; research that won the authors --the PI included-- the 2001 Godel prize. To show infeasibility of approximation of some fundamental problems, however, a stronger PCP was postulated in 2002, namely, Khot's Unique-Games Conjecture. It has transformed our understanding of optimization problems, provoked new tools in order to refute it and motivating new sophisticated techniques aimed at proving it. Recently Khot, Minzer (a student of the PI) and the PI proved a related conjecture: the 2-to-2-Games conjecture (our paper just won Best Paper award at FOCS'18). In light of that progress, recognized by the community as half the distance towards the Unique-Games conjecture, resolving the Unique-Games conjecture seems much more likely. A field that plays a crucial role in this progress is Analysis of Boolean-functions. For the recent breakthrough we had to dive deep into expansion properties of the Grassmann-graph. The insight was subsequently applied to achieve much awaited progress on fundamental properties of the Johnson-graph. With the emergence of cloud-computing, cryptocurrency, public-ledger and Blockchain technologies, the PCP methodology has found new and exciting applications. This framework governs SNARKs, which is a new, emerging technology, and the ZCASH technology on top of Blockchain. This is a thriving research area, but also an extremely vibrant High-Tech sector.

2 059 375 €

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

Our understanding of Parkinson’s disease (PD) pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic, most frequent, form of PD. It may be possible to overcome these challenges by reprogramming somatic cells from patients into induced pluripotent stem cells (iPSC). In preliminary studies, we have generated a collection of 50 iPSC lines representing both sporadic PD and familial PD patients, and identified distinct PD-related neurodegeneration phenotypes arising, upon long-term culture, in DAn differentiated from these PD-iPSC. Here, I propose to take advantage of this genuinely human PD model to investigate: i) mechanistic insights responsible for the PD phenotype identified in our model (by combining molecular and biochemical analyses to study mitochondrial function and redox profile, as well as genome-wide transcriptional profile of control versus PD-patient specific iPSC-derived DAn); ii) early functional alterations in patient-specific iPSC-derived DAn, which would predate neurodegeneration signs and provide valuable information as to ways to prevent, rather than rescue, neurodegeneration in PD patients (by electrophysiological recordings in in vitro reconstructed neuronal/glial networks to assess synaptic dynamics together with neuronal excitability); iii) further refinements in our iPSC-based PD model, including the generation of iPSC lines representing asymptomatic patients carrying pathogenic mutations, and the correction of known mutations by gene edition, all of which will allow exploring the relationship between pathogenic mutations and the genetic makeup of patients; and iv) whether DAn degeneration in PD is solely a cell-autonomous phenomenon, or whether it is influenced by an altered cross-talk between DAn and glial cells. These studies may impact significantly on our understanding of PD pathogenesis and on the development of new therapy strategy.

1 324 802 €

Start date: 2013-07-01, End date: 2018-06-30

The goal of this project is to provide, to the large community of scientist working in molecular target therapies, a fast and accurate tool capable of obtaining an atomic detailed mechanism of the protein-ligand induced fit, of its recognition process and of the ligand migration. Understanding these aspects is essential to obtain better drugs with the ability, for example, of bypassing drug resistance induced by protein mutations. This resistance mechanism is currently a fundamental process that will be increasing substantially with further development of specific molecular targets. The main ideas are based on state of the art methodologies recently developed in our laboratory capable of describing these processes. PELE, our novel technology based on protein structure prediction algorithms and a Monte Carlo sampling, is capable of describing the all atom dynamical interaction between a protein and a ligand. The proposed objectives includes: 1) Continue the methodological development of PELE, 2) developing automatic protocols for the study of the drug-protein dynamical interaction, and 3) building a web server allowing public use of these development The resulting technology will allow scientist to understand the atomic mechanism for drug delivery, drug resistance, etc., in only few days, approximately in 100 hours of CPU, allowing for a la carte design of improved inhibitors in a timely fast manner (essential when probing hundreds of compounds!). The development of the modelling tools, disseminated and freely accessible by means of a web server, will be conducted at the Barcelona Supercomputing Center, the Spanish national supercomputing center with one of the best computational infrastructures in Europe.

1 399 999 €

Start date: 2010-05-01, End date: 2015-04-30

Quantum communication networks consist of several nodes that are connected by quantum channels. By exchanging quantum particles, the nodes share quantum correlations, also know as entanglement. Essential for the future development of quantum communication is to understand the design of efficient protocols for the distribution of entanglement between arbitrarily distant nodes. The main objective of the present proposal is to construct the theory of entanglement distribution through quantum networks. At present, very little is known about this fundamental problem, namely about which properties of a quantum network are required to be able to establish entanglement over large distances. Very recently, we have proved that the distribution of entanglement through quantum networks defines a new type of critical phenomenon, an entanglement phase transition called entanglement percolation. These surprising effects do not appear in the standard repeater configuration previously considered. Crucial for the construction of these examples is the use of concepts already known in statistical mechanics, such as percolation. Our scope is to go far beyond these proof-of principle examples and derive the general theoretical framework describing entanglement percolation, exploiting the connection between statistical concepts and entanglement theory. The obtained framework will also be applied to other information resources, such as secret bits. Then, the ultimate aim of the project is to provide a global picture of the distribution of quantum information resources over realistic quantum communication networks.

699 600 €

Start date: 2008-11-01, End date: 2013-12-31

In 2007 the US and Europe were overwhelmed by a banking crisis, which was followed by a severe economic recession. Historical studies show that financial crises are followed by periods of substantially stronger contraction of aggregate output and employment than non-financial recessions. Those studies also point out that the best predictor of financial crises is an ex-ante strong credit boom which, after the beginning of the crisis, followed by negative overall credit growth. Lastly, financial crises take a long time until recovering the pre-crisis levels. Why are the effects of credit shocks so strong and persistent over time? Is this effect explained by costly household deleveraging? What is the effect of household debt on consumption, savings and employment? Are there any benefits of debt in crises? Do some effects of the financial crisis work through a reduction in credit supply to firms and projects with high innovative content and productivity (high overall return, but with high credit and liquidity risk for the lenders)? Or are the cleansing effects in financial crises concentrated on the less productive firms? Can macroprudential policies based on strict control of loan-to-value ratios stop the building up of excessive household debt? We plan to construct several new datasets to study these issues by merging information from different sources. For some issues, like the analysis of the effect of household debt on consumption and employment, we can take advantage of a natural experiment of randomized allocation of debt among individuals derived from the use of lotteries to allocate the rights to buy housing in Spain. In comparison to the existing literature, we can exploit the exogenous variation generated by these lotteries and some other combination of data (including exhaustive credit data) to obtain causal evidence and quantification on the interaction between debt, systemic risk, crises, and the new macroprudential policy.

1 308 676 €

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

Between the years 1050 and 1300 the European landscape turned to stone. It was a structural transformation that led to the birth of a new, long-lasting panorama and helped in the creation of individual, collective and regional identities: a landscape epitomising the way we see the space and territory of Europe. Petrifying Wealth seeks to rewrite the social history of the central Middle Ages, emphasizing the need to reassess from an untried perspective an element that has always been present in our vision of the period—the sudden ubiquity of masonry construction—but which has hardly been given the opportunity to provide in-depth explanations for complex social dynamics. This project seeks to offer novel explanations to previously unasked questions about wealth, building, and collective identity. The speed, extent, and systematization of the construction of churches, towers, castle walls, palaces, and houses within castles and cities provide evidence of an underlying, if unaddressed, issue. That is, it is precisely in the twelfth and thirteenth centuries that the structural link can most clearly be seen between both private and collective wealth, and the investment in stone structures built to last. Our study of the shift involving new institutional dynamics, but also unprecedented social practices, as well as ideological concepts radically different from those that had prevailed until then, aims to break down assumptions that have naturalized this truly astonishing process while using as case studies the undervalued regions of southern Europe to explore the larger questions. By inverting the standard approach that sees the heart of the former Carolingian empire (present-day France and Germany) as the wellspring from which other “peripheral” territories drank, we bring new light to probe the greater meaning behind the process of masonry building as an investment in social identity in the central Middle Ages.

2 491 799 €

Start date: 2017-01-01, End date: 2021-12-31

The perpetual arms race between bacteria and phage has resulted in the evolution of efficient resistance systems that protect bacteria from phage infection. Such systems, which include restriction enzymes and CRISPR-Cas, have major influence on the evolution of both bacteria and phage, and have also proven to be invaluable for molecular and biotechnological applications. Although much have been learned on the biology of bacterial defense against phage, more than half of all sequenced bacteria do not contain CRISPR-Cas, and it is estimated that many additional, yet-uncharacterized anti-phage defense systems are encoded in bacterial genomes. The goal of this project is to systematically understand the arsenal of defense mechanisms that are at the disposal of microbes in their struggle against phages. The project combines computational genomics, synthetic biology, high-throughput robotic assays, and deep genetic and biochemical experiments to discover, verify, and study the properties of anti-phage defense systems.

2 000 000 €

Start date: 2016-07-01, End date: 2021-06-30

The boost experienced by acoustic and elastic (phononic) metamaterial research during the past years has been driven by the ability to sculpture the flow of sound waves at will. Thanks to recent developments at the frontiers of phononic metamaterials it can be identified that active phononic control is at the cutting edge of the current research on phononic metamaterials. Introducing piezoelectric semiconductors as a material platform to discover new avenues in wave physics will have the potential to open horizons of opportunities in science of acoustic wave control. Electrically biased piezoelectric semiconductors are non-reciprocal by nature, produce mechanical gain and are highly tunable. The aim is to explore novel properties of sound and the ability to design Parity-Time (PT) symmetric systems that define a consistent unitary extension of quantum mechanics. Through cunningly contrived piezoelectric media sculpturing balanced loss and gain units, these structures have neither parity symmetry nor time-reversal symmetry, but are nevertheless symmetric in the product of both. PHONOMETA is inspired and driven by these common notions of quantum mechanics that I wish to translate into classical acoustics with unprecedented knowledge for the case of sound. I expect that the successful realization of PHONOMETA has the potential to revolutionize acoustics in our daily life. Environmental and ambient noise stem from multiple scattering and reflections of sound in our surrounding. The extraordinary properties of PT acoustic metamaterials have the groundbreaking potential to push forward physical acoustics with new paradigms to design tunable diode-like behaviour with zero reflections, which is applicable for noise pollution mitigation. Also I anticipate to impact the progress on invisibility cloaks by introducing PT symmetry based acoustic stealth coatings for hiding submarines.

1 325 158 €

Start date: 2016-12-01, End date: 2021-11-30

Cyanobacteria play a key role in marine photosynthesis, contributing almost 50% of primary production in oligotrophic regions of the ocean. Marine cyanophages were recently discovered to carry photosystem II (PSII) genes, and it was suggested that these genes increase phage fitness by helping the phages to maintain photosynthesis in the infected bacterial cells. We recently showed evidence for the presence of photosystem I (PSI) genes in genomes of marine cyanophages [Sharon et al. 2009 Nature 461, 258-262]. Cyanobacterial core PSI gene cassettes, containing psaJFABCDEK, or psaDCAB gene cassettes forms unique clusters in cyanophage genomes, suggestive of selection for a distinct function in virus reproduction. Potentially, the proteins encoded by the viral genes are sufficient for forming intact monomeric PSI complexes. Projection of viral predicted peptides on the cyanobacterial PSI crystal structure suggests that the viral PSI components provide a unique way for funneling reducing power from respiratory and other electron transfer chains to PSI, therefore bypassing the need to rely solely on reducing power from the photosystem electron transfer chain. The main goals of this proposal are: (1) To determine how much of oceanic photosynthesis is actually performed with viral proteins. (2) To establish a model system to understand the role of modified photosynthetic viral proteins in photosynthesis We hypothesize that viral photosynthetic peptides are integrated into the bacterial photosynthetic membranes in order to maintain photosynthesis in infected cells, that otherwise stop to photosynthesize, and that changes are introduced to the system as a whole. The proposed research will integrate concepts and techniques from metagenomics, metaproteomics and bioinformatics techniques to explore the interaction of viral PSII and PSI proteins with their host reaction center complexes, and to examine their influence on global marine photosynthesis production

1 933 800 €

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

Understanding the evolution of all living organisms is one of the fundamental challenges in biology. The phylogenetic analysis of whole genomes has already proven very useful to decipher not only their history, but also their organization and function. Indeed, the accuracy of these inferences is intimately related to the quality of the models assumed. Despite important advances, models of genome evolution are still in its infancy, and more realistic models are needed to provide more precise and reliable inferences from genome data. In addition, a number of phylogenomic algorithms have been proposed to estimate phylogenies from complete genomes based on different genomic features. Although the application of these methods has already led to critical conclusions regarding the tree of life, the relative performance of these algorithms has not been properly evaluated yet. The first objective of this grant is to develop more realistic models of genome evolution, integrating changes in gene content and changes in gene sequences, and allowing for model variation along different branches of the phylogeny. In order to avoid model overparameterization, a statistical framework for the selection of best-fit models of genome evolution for the data at hand will also be implemented. Genome data simulated under these models will be used to compare the performance of different phylogenomic algorithms. Optimized phylogenomic strategies will then be applied to available genomes in order to decipher unresolved portions of the tree of life. Finally, all the bioinformatic tools developed under this grant will be made freely available to the scientific community.

994 800 €

Start date: 2008-10-01, End date: 2013-09-30

Future, large galaxy surveys (such as BOSS, DES, LSST, EUCLID, ADEPT etc.) will cover of the order of 10000 square degrees on the sky, with the primary science goal to unravel the nature of the physics responsible for the current accelerated expansion of the universe. This acceleration likely involves new physics which could imply ether a modification of our understanding of particles and fields (if the acceleration is caused by a new negative pressure-component) or a change in our understanding of space and time (by modifying Einstein's General Relativity laws). The unprecedented and exquisite data provided by these surveys will make possible also other interesting science with implications for fundamental physics (e.g., inflation, neutrino properties) and astrophysics (e.g., biasing, galaxy formation). The success of future large-scale galaxy surveys evidently requires a correct interpretation of their data. The current proposal, which benefits from the interaction of Cosmology, astrophysics and particle physics, aims at building up a set of robust tools to maximize the physics extracted from large-scale structure data. Such an interplay is mandatory to ensure a suitable modeling of the observables and a meaningful comparison with the theoretical predictions. The PI is involved with surveys such as BOSS, ADEPT and LSST and for the past year has been leading a working group with the goal of bringing together particle physicists and cosmology to better understand dark energy. The methods developed in the proposal presented here are expected to be used by the international community involved in future surveys. This would imply a big step for Spanish groups joining or even leading future Cosmology or Astro-particle physics projects.

1 395 000 €

Start date: 2009-11-01, End date: 2015-10-31

Background: Our recent studies implicate p53 in gut tissue homeostasis - suppressing epithelial invasion. This function is tightly linked to suppression of a gene cluster (PSIS- p53-Suppressed Invasiveness Signature), which requires Wnt activation and other cues, yet is only expressed upon loss of p53. The invasive signature explains a broad spectrum of the invasiveness property, from the loss of enterocyte polarity to matrix degradation, pointing to a concerted action. We documented a tight association between invasiveness and coexpression of several PSIS genes in different mouse models and showed that PSIS expression is essential in mediating epithelial cell invasiveness following p53 depletion. Goal: Elucidate functions of p53 activation which are of particular importance for epithelial tissues. Understand how WT p53 contributes to preserving epithelial boundaries, prohibiting invasion and abnormal cell mixture and controlling stem cell dynamics under tissue stress. Methodology: We will investigate the epithelial role of p53 and the invasive signature genes in several mouse models of inflammatory bowel diseases and intestinal cancer. These models will incorporate p53-modulating switchable genetic elements and cell-tracking genetic markers for monitoring tissue dynamics. Analyses of relevant human pathology samples will complement the mouse studies. Significance: Invasion is a defining hallmark of malignancy and understanding early invasion of tumor cells is of fundamental importance in designing future therapies for cancer - targeting PSIS is an example. PSIS database may also be used to develop biomarkers for distinguishing malignant tumors from benign ones, a critical determinant of therapeutic options in several types of cancers, currently solely based on morphologic assessment. A molecular definition of early invasive lesions may allow early implementation of curative treatments while withholding patient overtreatment which often results in serious morbidity.

2 500 000 €

Start date: 2012-10-01, End date: 2017-09-30

The reinforcement of polymers with carbon nanotube fillers has been one of the most active areas of research in CNT science. Several materials where the mechanical and/or electrical properties of polymers have been significantly improved using nanotube fillers have been demonstrated. However, the improvement in mechanical properties of the CNT-polymer composites remains far behind the idealized theoretical predictions. These disappointing experimental results are due to a combination of imperfect individualization of the CNTs and poor load transfer from the polymer to the CNTs. To address these problems, several approaches have been investigated, including covalent and supramolecular modification of the CNTs, and different fabrication methods for the CNT-polymer composites, but none has been completely successful. We will explore the direct connection of the polymer matrix to the macrocycles to form Polymers Interlocked with carbon NanoTubes (PINTs). In PINTs, the polymer and SWNTs are linked through mechanical bonds, and therefore form a single molecular entity, a true conceptual leap from previous approximations. The PINT strategy addresses all the critical issues for SWNT-polymer composites at the same time: effective control of SWNT-polymer interface through non-covalent but very strong mechanical bonds, SWNT-polymer alignment, and individualization of the SWNTs. The IP and business parts of this proposal will be carried out in collaboration with Nanocore (http://www.nanocore.com/), a company based in Denmark specialized in the reinforcement of polymers with carbon nanomaterials. In direct cooperation with Nanocore, we will explore the first steps towards commercialization of the technologies developed.

145 938 €

Start date: 2019-04-01, End date: 2020-09-30

The discovery of the first extra solar planet, merely twelve years ago, ushered an explosive growth in our knowledge of planetary systems. Extrasolar planets have been detected with ever-smaller masses and today Earth analogs orbiting other stars are on the discovery horizon! Observations of disks around young stars reveal the initial conditions for planet formation while detections of debris disks probe post formation stages. Closer to home, exploration of the Kuiper Belt provides new clues on planet migration and on the intermediate stages of planetary accretion. Some discoveries, like extrasolar planets with short orbital periods and high eccentricities, have led to a complete overhaul of previously accepted planet formation theories. The increasing wealth of observations creates a unique opportunity to answer fundamental questions pertaining to planets and planetary systems. The relevant objects include on one hand giant extrasolar planets, a thousand times more massive than Earth, and on the other hand rocky and icy Kuiper Belt Objects, a millionth of the Earth mass. The physical processes vary from the resonant interaction of giant extrasolar planets with gas disks to collisions of solid bodies in the outer solar system. Still, much of the underlying physics, especially orbital dynamics, is common. We propose, therefore, an innovative program of integrated studies of the above subjects. A unique aspect of my group’s approach is utilizing the common physics for a synergic treatment of these traditionally separated topics. By answering open questions in dynamics, investigating the inner workings of planetesimal coagulation and interpreting the properties of extrasolar planets we will make significant breakthroughs in the understanding of planet formation and its possible outcomes. This will illuminate our place in the universe and will guide farther searches of planets. Our exploration is at the beginning of a long voyage seeking life around nearby stars.

1 000 000 €

Start date: 2008-06-01, End date: 2013-05-31

This project will identify the principles governing genome replication in relation to the chromatin landscape and how they impact on plant organ growth. The results will provide the basis to design novel strategies to improve plant growth performance. The large plant genomes, as in all eukaryotes, must be faithfully duplicated every cell cycle, a process regulated at the level of DNA replication origins (ORIs). Our understanding of how ORIs are determined is still very limited. Most of our knowledge comes from cultured cells, precluding the identification of regulatory layers operating at the organism level. Importantly, genome replication can offer unexplored possibilities to modulate plant architecture and growth and, consequently, plant performance. Results generated so far unable us to address a fundamental question: what are the regulatory mechanisms of DNA and genome replication and how they can be exploited to design improved plant growth strategies. This innovative perspective will reveal how genome replication is regulated by DNA sequence context, replication factors and chromatin landscape. Integration of molecular, cellular, genomic and genetic approaches in a whole organism will serve to evaluate the phenotypic effects of modulating genome replication on organ growth. We will also learn how DNA replication control is exerted during endoreplication and in coordination with transcriptional programs, both crucial for plant organogenesis, growth and response to environmental stresses. This program goes beyond incremental research, is timely, innovative, ambitious but realistic, and high risk/high gain, combining different approaches to address a fundamental process. Given the conservation of proteins and pathways, and the availability of well-annotated genomic information for many plant species, PLANTGROWTH will pave the way to translate the technological and conceptual know-how derived from this program to crop species to improve yield.

2 497 800 €

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

At this point in time where plasmon optics has become a mature field of research, we propose here to create new bridges with other scientific disciplines in which the optical properties of plasmonic nanostructures could successfully address major roadblocks. The proposed scientific project consists of two independent parts, in which plasmonics is combined with Nanochemistry and Quantum optics, respectively. First, we will investigate how plasmonics could contribute to control with nanometer accuracy the deposition of a wide range of molecules or other nano-objects at a surface pre-patterned with noble metal nanostructures. Our approach is foreseen to overpass some of the major limitations of existing methods by combining parallel patterning over large areas with a resolution down to 10nm. Beyond demonstrating the feasibility of this novel approach, we propose to exploit it to increase the sensitivity of bio-chemical plasmonic sensing and surface enhanced Raman scattering. The second part of the project will study the use of the recent concept of plasmon nano-optical tweezers to develop a novel integrated quantum platform. The developed platform will be tested for applications to quantum simulation.

1 146 496 €

Start date: 2011-04-01, End date: 2015-08-31

Antibiotics are essential tools in modern medicine and are indispensable not only for the treatment of infectious diseases but also to support other key interventions such as surgery and cancer chemotherapy. However, the extensive and inappropriate use of antibiotics has fuelled the spread of resistance mechanisms in pathogenic bacteria, leading to the dawn of a post-antibiotic era. Plasmids play a pivotal role in the evolution of antibiotic resistance (AR) because they drive the horizontal transfer of resistance genes between pathogenic bacteria by conjugation. Some of these plasmid-bacterium associations become particularly successful, creating superbugs that spread uncontrollably in clinical settings. The rise of these clones is mainly constricted because plasmids entail a fitness cost when they arrive in a new bacterial host. This cost can be subsequently alleviated through compensatory adaptation during plasmid-bacterium coevolution. Despite the importance of this cost-compensation dynamic in the evolution of plasmid-mediated AR, it remains completely unexplored in clinical contexts. In this project I plan to bridge this gap by exploring the genetic basis underlying the evolution of plasmid-mediated AR in clinically relevant scenarios. We will study, for the first time, the intra-patient transmission, fitness cost and adaptation of AR plasmids in the gut microbiome of hospitalized patients (obj. 1). We will analyse the molecular mechanisms that determine the success of AR plasmids and bacterial clone associations (obj. 2). Finally, we will develop new technology to test how antibiotic treatments affect AR plasmids dynamics in the gut microbiome at an unprecedentedly high-resolution (obj. 3). This ground-breaking project will allow a new understanding of the evolution of plasmid-mediated AR in real life, opening new research avenues and providing a major step towards meeting one of the central challenges facing our society: controlling the spread of AR.

1 497 314 €

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

"Thousands of cancer patients worldwide are taking RANKL inhibitors for the management of bone metastasis, based on the key role of RANKL and its receptor, RANK, in osteoclasts. RANK signaling has multiple divergent effects in immunity and inflammation, both in the generation of active immune responses, as well as in the induction of tolerance. We showed that RANK overexpression induces stemness and interferes with differentiation in non transformed mammary epithelial cells and promotes mammary tumorigenesis, acting as a paracrine mediator of progesterone. However, the therapeutic potential of inhibiting RANK signaling once tumors develop and its effects on tumor immunity remain unexplored. Our proposal tackles novel concepts: Is RANK a better therapeutic target than RANKL? Does RANK induce ""stemness"" in other epithelia and solid tumors and how? Does RANK regulate the tumor-immune cell crosstalk? Would inhibition of RANK signaling in tumor and immune cells result in synergistic or opposing effects on tumor outcome? We hypotesize that RANK activation in solid tumors expands the cancer stem cells pool and induces an immnunosuppressive environment leading to tumor recurrence and metastasis. In PLEIO-RANK we aim to: 1. Define the contribution of RANK to the epithelial hierarchy in mammary, skin and colon, during homeostasis and tumorigenesis, undertaking lineage tracing approaches. 2. Dissect the impact of RANK loss in the epithelial or the immune compartment in tumor outcome, exploiting tissue inducible models, in breast cancer and solid tumors driven by chronic inflammation. 3. Validate the clinical implications of our findings using patient derived xenografts and human tumor samples. Based on the results of our proposal RANK inhibition could become a unique targeted therapy able to reduce metastasis and mortality in solid tumors for its pleiotropic antitumor effects in cancer stem cells, immune cells and their crosstalk. "

1 999 960 €

Start date: 2016-10-01, End date: 2021-09-30

Strong electronic correlations often produce intertwined phases where multiple length scales coexist. These produce spatially varying electronic properties containing unique insight on the many-body effects that determine the emergence of novel collective behavior. Addressing the problem of electron correlations requires powerful microscopes probing electronic properties down to atomic scale. A major challenge in electron correlated materials is to understand the emergence of high critical temperature (HTc) superconductivity. Fe-based superconductivity offers ultra-pure materials easily tunable through relevant phases emerging from electron correlations (antiferromagnetism, nematicity and superconductivity), providing a tremendous opportunity to unveil the microscopic pairing mechanism behind HTc superconductivity. High magnetic fields are needed to disentangle the electronic correlations, because they enable comparison between normal and superconducting phases and unveil quantum critical behavior and vortex physics. Traditional research under very high magnetic fields uses macroscopic measurements of the spatially averaged magnetic and electronic properties. The goal of PNICTEYES project is to combine very high magnetic fields with scanning tunneling microscopy (STM) to visualize spatial electronic heterogeneity in Fe-based superconductors. The microscopes developed within this project will operate up to 22 T using superconducting coils in-house and above 30 T using resistive and hybrid magnets at international high magnetic field facilities. Implementing novel spectroscopic methods, such as Landau level spectroscopy, we will disentangle the electronic correlations behind the microscopic mechanism of HTc superconductivity in Fe-based superconductors. The success of this project will provide new insights in fundamentals of HTc superconductivity and first enable ultra-high magnetic field STM opening innovative opportunities in other fields as graphene or magnetism.

1 704 375 €

Start date: 2016-03-01, End date: 2021-02-28

A general and versatile technology to engineer visible light-responsive biological agents will enable spatio-temporal manipulation and interrogation of proteins, pathways, and cells, and the design of “smart” biomaterials that can direct and respond to biological processes on-demand. Site specific incorporation of multiple visible-light-responsive chemical groups at the polypeptide level will constitute a universal methodology for precise production of light-responsive proteins and protein-based materials. However, inadequate engineering of the protein translation apparatus limits the number and complexity of chemical groups that can be incorporated into proteins as synthetic amino acids (sAAs). This limitation precludes the incorporation of recently discovered visible-light-responsive chemical groups, hinders protein engineering efforts, and excludes production of biomaterials in which multiple identical sAAs provide new physical or biophysical properties. We propose to overcome this challenge by generating a genomic-engineering based platform for co-evolution of multiple components of the translation machinery (the aminoacyl tRNA synthetase, tRNA, and elongation factor) to select for cellular machinery capable of multi-site incorporation of highly substituted azobenzenes with a range of biologically relevant photochemical properties. We will then utilize these translation systems to produce libraries of azobenzene-containing protein-based materials to elucidate the sequence-function requirements for directing light-responsive self-assembly of macromolecular structures, and to generate biomaterial formulations for control of various intra- and extra-cellular processes. By developing and marrying technologies in synthetic biology, chemistry, and biomaterials, this study will enable the synthesis of light-responsive proteins, deepen our understanding of natural and evolved translation systems, and create new classes of functional light-responsive biomaterials.

1 328 712 €

Start date: 2017-11-01, End date: 2022-10-31

POLMAG aims at a true breakthrough in the development and application of polarized radiation diagnostic methods for exploring the magnetic fields of the chromosphere, transition region and corona of the Sun via the interpretation of the Stokes profiles produced by optically polarized atoms and the Hanle and Zeeman effects in ultraviolet (UV), visible and near-infrared spectral lines. To this end, POLMAG will combine and expand expertise on atomic physics, on the quantum theory of radiation, on high-precision spectropolarimetry, on advanced methods in numerical radiative transfer, and on the confrontation of spectropolarimetric observations with spectral synthesis in increasingly realistic three-dimensional (3D) numerical models of the solar atmosphere. POLMAG targets the following very challenging issues: - Which are the optimum spectral lines for probing the magnetism of the outer solar atmosphere? - How to compute efficiently the Stokes profiles taking into account partial frequency redistribution, J-state quantum interference and the Hanle and Zeeman effects? - How to determine the magnetic, thermal and dynamic structure of the outer solar atmosphere through confrontations with spectropolarimetric observations? POLMAG will go well beyond the current state of the art as follows: - Applying and extending the quantum theory of light polarization - Developing and applying efficient radiative transfer codes - Modeling the Ly-alpha and Mg II h & k observations of our CLASP suborbital rocket experiments - Developing novel coronal magnetometry methods by complementing for the first time the information provided by forbidden and permitted lines - Developing the plasma diagnostic techniques needed for the scientific exploitation of spectropolarimetric observations with the new generation of solar telescopes and putting them at the disposal of the astrophysical community POLMAG will open up a new diagnostic window in astrophysics.

2 478 750 €

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

Tumor progression is dependent on a number of sequential steps, including initial tumor-vascular interactions and recruitment of blood vessels, as well as an established interaction of tumor cells with their surrounding microenvironment. Failure of a microscopic tumor, either primary, recurrent or metastatic, to complete one or more of these early stages may lead to delayed clinical manifestation of the cancer and a state of stable non-progressing disease. Micrometastasis, dormant tumors, and residual tumor cells contribute to the occurrence of relapse, and constitute fundamental clinical manifestations of tumor dormancy that together are responsible for the vast majority of cancer deaths. However, although the tumor dormancy phenomenon has critical implications for early detection and treatment of cancer, its biology and genetic characteristics are poorly understood. We now propose to investigate the molecular and cellular changes in tumor-host interactions that govern tumor dormancy, which may lead to the discovery of novel tumor dormancy targets and provide tools for dormancy-dependent tumor therapy strategies. In order to achieve this goal, we will integrate the following basic and translational approaches: (i) Establishment of mouse models of dormant and fast-growing tumor pairs; (ii) Functional and molecular characterization of dormant versus fast-growing tumors, (iii) Design of dormancy-promoting tailor-made polymer therapeutics delivering a combination of microRNAs with chemotherapies; (iv) Polymer conjugation to a prodrug designed to be activated by specific enzymes overexpressed in tumors, Turning-ON a near infra-red (NIR) fluorescence signal. When completed, this proposal will shed light on this fundamental cancer biology phenomenon. A better understanding of tumor dormancy and the availability of markers and therapeutic targets will most likely change our perception of tumor progression and, consequently, the way we diagnose and treat the disease.

2 255 920 €

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

Modern society demands for materials that are reliable, for safety reasons, durable, to offer prolonged service lifetimes, and cost- and energy-efficient, to preserve natural resources and produce minimum waste and environmental impact. In this context, self-healing polymers are “smart” materials with the ability to repair themselves autonomously or to heal on-demand upon exposure to an external stimulus. However, the broad commercialization and universal use of self-healing thermoplastic polymers is still hampered by a main problem that resides in the balance between self-healing ability and mechanical properties at working conditions. Along the ERC-StG project PROGRAM-NANO, we found a quite promising solution by introducing cooperative effects in supramolecular polymers. In this way, thermoplastic materials were obtained that combined toughness and resistance with self-healing ability at ambient temperature. This PoC Project now focus on evaluating the viability of our approach for producing commercial self-healing thermoplastic coatings by addressing 3 strongly interconnected milestones: 1) Test and Validate the technical characteristics of the materials and the self-healing process; 2) Design and implement a market analysis and study the best IPR strategy for this new technology; and 3) Optimize an efficient methodology toward a primary commercial product with optimum performance and minimum cost. These tasks require the assembly of a team comprising experienced researchers on one hand, to validate PolyHeal performance through well-established standard tests, and management, market and IPR experts on the other, to find the suitable market niches and develop the most convenient strategy for the exploitation of our technology. Due to its innovative nature and versatility, PolyHeal has a great potential to open up important technological and commercial opportunities by the design and application of plastic coatings with the ability to heal autonomously.

150 000 €

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

POSTCELL aims at laying the foundation for future generations of wireless networks as they move past the reigning cell-centric paradigm and into the post-cellular era. This entails the definition of a new architecture for such networks and the characterization of the ensuing performance. For the future of wireless communications, the implications would be far-reaching. The growth of wireless traffic is relentless, and it is actually gaining new momentum on account of fresh mechanisms: smartphones, cloud computing, and machine-to-machine communication. As a result, the volume of wireless traffic is poised to increase to truly staggering levels and, to face this challenge, wireless networks need to enter a new stage. There is a fledging awareness that this challenge can only be fended off by a process of network massification, with two views about it. In the first view, densification is the only strategy through which dramatic improvements can be attained hereafter; this leads to a vision where base stations become tiny and exceedingly abundant. The second view, in turn, is built on the idea of dramatically scaling the number of colocated antennas per base station from the current handful to possibly hundreds. One of the seeds of POSTCELL is that, since neither form of massification can by itself resolve the challenge facing wireless systems, the two forms will have to end up coexisting. Reconciling these two forms of massification and enabling a truly phenomenal scaling calls for an entirely new architecture where cells and physical base stations become things of the past, replaced by dynamically defined virtual base stations, powerful caches, and the possibility of device clustering, among other leaps forward. The signal processing needs to shift away from base stations, which become deconstructed, so as to gather at new places. POSTCELL seeks to drive this transformation and to gauge the performance of post-cellular wireless networks.

1 876 846 €

Start date: 2016-10-01, End date: 2021-09-30

Deciphering the interactions within and between the three major components of living organisms, DNA, RNA and Protein, is at the heart of biological research. New large-scale experimental methods have dramatically advanced genome-wide detection of protein-protein, protein-DNA, protein-RNA and protein-mediated RNA-RNA interactions. However, at present there is no large-scale method that could detect all RNA-RNA interactions independent of a mediator protein, or when the mediator protein is unknown. Attaining such a method is of utmost importance and is very timely, as it is now evident that RNA-RNA interactions play central roles in cellular life. In particular, hundreds of expressed small RNA (sRNA) molecules were discovered in both pro- and eukaryotes, many of which act as posttranscriptional regulators of gene expression by base-pairing with their mRNA targets. It seems that in many organisms the layer of posttranscriptional regulation is as widespread as transcription regulation, presenting a major challenge towards achieving functional and mechanistic understanding of this regulation level. Here we propose to develop an innovative methodology for genome-wide detection of the sRNA targetome, all mRNA targets of cellular sRNAs. This new methodology combines in vivo structural probing with deep sequencing and is independent of protein considerations. We will apply this method to deciper the sRNA targetome of the model organism Escherichia coli, which encodes over 100 sRNAs. We will use the sRNA targetome data as the foundation for a systematic ‘bottom-up’ computational analysis of multifaceted aspects of sRNA-mediated posttranscriptional regulation, encompassing the basic underlying rules of sRNA-mRNA target recognition, the design principles of the posttranscriptional regulatory network and its integration with the transcriptional and metabolic networks, and the evolution of posttranscriptional regulation.

2 329 360 €

Start date: 2013-02-01, End date: 2019-01-31

The impact of weight loss on cardiovascular disease risk within the frame of the Mediterranean dietary pattern has not yet been tested using a sufficiently large randomized trial (Malik, Hu, 2007). We propose to run a parallel group, multi-center, randomized, primary prevention trial (PREDIMED PLUS) on men aged 55-75 years and women 65-75 years, with a body mass index ≥27 to <40 kg/m2 and meeting at least 3 criteria for the metabolic syndrome. The objective of the present research is to address the cardiovascular effect of an intensive weight-loss lifestyle intervention based on an energy-restricted traditional Mediterranean diet in comparison with a less intensive program using Mediterranean diet, but with no energy restriction, behavioural intervention or physical activity programme. The end-point is a composite of major hard clinical cardiovascular events. We hypothesize that an intensive weight-loss lifestyle intervention, including physical activity, based on the traditional Mediterranean food pattern is a sustainable long-term approach for weight reduction among overweight/obese adults and that the achieved lifestyle changes will exert beneficial effects on cardiovascular disease incidence, according to our experience (Estruch R et al., 2012) and research by other investigators (Shai et al., 2008). The rationale for the proposed investigation is that it can provide a new, affordable, and sustainable approach to reduce excess cardiovascular morbidity and mortality among overweight/obese adults, beyond what was already observed in the PREDIMED I trial.

2 078 970 €

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

How does experience alter the functional architecture of synaptic connections in neural circuits? This question is particularly pertinent for the complex circuits of the medial prefrontal cortex (mPFC), a high-order associative neocortical area that plays a crucial role in flexible, goal-directed behavior. The mPFC is densely interconnected with cortical and subcortical circuits, and its neurons were shown to undergo substantial experience-dependent structural remodeling that is thought to support learning and memory consolidation. However, little is known regarding the synaptic organization of this complex circuit, and of the functional implications of its experience-dependent structural remodeling. In this proposal, we aim to uncover the organization and learning-associated dynamics of functional connectivity in the mouse mPFC. To obtain high-resolution maps of cell type-specific synaptic connectivity in the mPFC, we will combine single-cell optogenetic manipulation with calcium imaging and electrophysiology in vitro, and establish the circuit-wide organization of connectivity within and between defined projecting neuron populations. We will test the hypothesis that pyramidal neurons projecting to subcortical targets form tightly interconnected subnetworks, and that inhibitory inputs to these networks, through selective innervation, can modulate information output from the mPFC. To understand how learning changes the functional synaptic organization of the mPFC, we will establish an all-optical system for interrogation of synaptic connectivity in vivo. We will utilize this powerful platform to test the hypothesis that prefrontal-dependent learning is associated with reorganization of local-circuit functional connectivity among identified subcortically-projecting cell assemblies. Our innovative technology will be widely applicable for neural circuit analysis in a variety of systems, and allow us to gain new insights into the complex circuitry of the mPFC.

1 880 003 €

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

The human crystalline lens has the capability to dynamically change its shape to focus near and far objects. By age 55, the accommodation capability is lost and optical aids are needed for near vision. Many questions remain open that are critical to understand accommodation, the failure in presbyopia, and the prospects for its correction. Multifocal presbyopic corrections are increasingly used. However, the ideal multifocal pattern, and the optical factors affecting depth-of-focus and adaptation to simultaneous vision remain to be elucidated. The most satisfactory treatment of presbyopia should rely on the restoration of the dynamic and continuous focusing ability of the eye, and this could be achieved in the form of accommodative intraocular lenses (IOLs). Current approaches, relying on potential IOL axial shifts, have proved little effective accommodative amplitude. The project will seek in nature innovative solutions to treat presbyopia. Deeper understanding of the crystalline lens changes with dynamic accommodation and aging will be gained. Novel imaging techniques will be developed and used to assess the dynamic changes of crystalline lens structure, gradient index distribution and microscopic structure of the lens fibers and capsule. In addition, the treatment of presbyopia by multifocal corrections will be explored. Wavefront sensing and optical coherence tomography will be used to understand the bases for the multifocality found in some animal species (as possible inspiration for multifocal patterns), and adaptive optics and visual simulation to understand the reasons for the limited performance of current multifocal treatments, to investigate neural adaptation to the blur in simultaneous vision and to test the proposed new multifocal patterns. Finally, the understanding of the crystalline lens properties and the biomechanics of the implanted IOLs gained in the project will allow to develop a first prototype of crystalline-lens mimicking accommodative IOL.

2 399 548 €

Start date: 2012-05-01, End date: 2018-04-30

Structural variation and copy-number variant regions (CNVs) (including segmental duplications) are usually underrepresented in genome analyses but are becoming a prominent feature in understanding the organization of genomes as well as many diseases. Large-scale comparative sequencing projects promised a golden era in the study of human evolution, however, many genome regions, especially these complicated regions, are clearly not solved. Despite international efforts to characterize thousand of human genomes to understand the extent of structural variants in the human species, primates (our closest relatives) have somehow been forgotten. Yet, they are the ideal set of species to study the evolution of these features from both mechanistic and adaptive points of view. Most genome projects include only one individual as a reference but in order to understand the impact of structural variants in the evolution of every species we need to re-sequence multiple individuals of each species. We can only understand the origins of genomic variants and phenotypical differences among species if we can model variation within species and compare it to a proper perspective with the differences among species. The object of this proposal is to discover the extent of genome structural polymorphism within the great ape species by generating next-generation sequencing datasets at high coverage from multiple individuals of diverse species and subspecies, characterizing structural variants and validating them experimentally. The results of these analyses will assess the rate of genome variation in primate evolution, characterize regional deletions and copy-number expansions as well as determine the patterns of selection acting upon them and whether the diversity of these segments is consistent with other forms of genetic variation among humans and great apes. In so doing, a fundamental insight will be provided into evolutionary variation of these regions among primates and into the mechanisms of disease-causing rearrangements with multiple repercussions in the understanding of evolution and human disease.

1 599 999 €

Start date: 2010-12-01, End date: 2014-11-30

Just as our experience has its origin in our perceptions, our perceptions are fundamentally shaped by our experience. How does the brain build expectations from experience and how do expectations impact perception? In a Bayesian framework, expectations determine the environment’s prior probability, which combined with stimulus information, can yield optimal decisions. While the accumulation-to-bound model describes temporal integration of sensory inputs and their combination with the prior, we still lack electrophysiological evidence showing neural circuits that integrate previous events adaptively to generate advantageous expectations. I aim to understand (1) how circuits in the cerebral cortex integrate the recent history of stimuli and rewards to generate expectations, (2) how expectations are combined with sensory input across the processing hierarchy to bias decisions and (3) whether the dynamics of the expectation can dominate neuronal and choice variability. I will train rats in a new auditory discrimination task using predictable stimulus sequences that, once learned, are used to compute adaptive priors that improve discrimination. I will perform population recordings and optogenetic manipulations to identify the brain areas involved in the computation of priors in the task. To reveal the circuit mechanisms underlying the observed dynamics I will train a computational network model to classify fluctuating inputs and, by adapting its dynamics to the statistics of the stimulus sequence, accumulate evidence across trials to maximize performance. The model will generalize the accumulation-to-bound model by integrating information across various time scales and will partition choice variability into that caused by the dynamics of the prior or by fluctuations in the stimulus response. My proposal points at a paradigm shift from viewing neuronal variability as a corrupting source of noise to the result of our brain’s inevitable tendency to predict the future.

2 000 000 €

Start date: 2016-09-01, End date: 2021-08-31

In the context of data-intensive systems, data provenance captures the way in which data is used, combined and manipulated by the system. Provenance information can for instance be used to reveal whether data was illegitimately used, to reason about hypothetical data modifications, to assess the trustworthiness of a computation result, or to explain the rationale underlying the computation. As data-intensive systems constantly grow in use, in complexity and in the size of data they manipulate, provenance tracking becomes of paramount importance. In its absence, it is next to impossible to follow the flow of data through the system. This in turn is extremely harmful for the quality of results, for enforcing policies, and for the public trust in the systems. Despite important advancements in research on data provenance, and its possible revolutionary impact, it is unfortunately uncommon for practical data-intensive systems to support provenance tracking. The goal of the proposed research is to develop models, algorithms and tools that facilitate provenance tracking for a wide range of data-intensive systems, that can be applied to large-scale data analytics, allowing to explain and reason about the computation that took place. Towards this goal, we will address the following main objectives: (1) supporting provenance for modern data analytics frameworks such as data exploration and data science, (2) overcoming the computational overhead incurred by provenance tracking, (3) the development of user-friendly, provenance-based analysis tools and (4) experimental validation based on the development of prototype tools and benchmarks.

1 306 250 €

Start date: 2018-12-01, End date: 2023-11-30

The herpesvirus human cytomegalovirus (HCMV) infects the majority of the world's population, leading to severe diseases in millions of newborns and immunocompromised adults annually. During infection, HCMV extensively manipulates cellular gene expression to maintain conditions favorable for efficient viral propagation. Identifying the pathways that the virus relies on or subverts is of great interest as they have the potential to provide new therapeutic windows and reveal novel principles in cell biology. Over the past years high-throughput analyses have profoundly broadened our understanding of the processes that occur during HCMV infection. However, much of this analysis is focused on transcriptional changes at the lytic phase of infection leaving posttranscriptional regulation and the latent phase of the virus relatively untouched. Novel emerging technologies have the potential to extend our knowledge in areas that were heretofore unattainable. My overall goal is to decipher the multiple mechanisms by which HCMV modulates the host cell. For this, I will use multiple cutting-edge deep-sequencing and imaging technologies that will allow the analysis of novel aspects of host gene regulation during infection. Accordingly, the primary objectives of this research proposal are: 1) Deciphering posttranscriptional mechanisms that control cellular gene expression during HCMV infection; 2) Identifying and characterizing cellular protein diversification during infection; and 3) Uncovering the changes that occur in infected cells during latent infection. The knowledge generated from these objectives will provide us with a clearer depiction of the changes that take place during HCMV infection, which in turn can facilitate the development of novel anti-viral strategies. More broadly, with its comprehensive and complementarity approaches, this work will provide a paradigm for understanding how gene expression is regulated during a complex biological process.

1 500 000 €

Start date: 2015-06-01, End date: 2020-05-31

“Program-Nano” aims at establishing unconventional and versatile strategies towards organic architectures whose size, composition, internal structure, and function can be rationally predesigned and controlled. In a bio-inspired manner, we will “program” functional molecules with the required information to self-assemble into unique, well-defined nanofibers or nanotubes. We want to focus on two main ambitious objectives for the application of such organic nanostructured materials. 1) The design and preparation of optoelectronic devices, such as plastic solar cells, where nanostructured fibers are integrated within the active layers. The major goal is to determine the influence of the molecular organization and the morphology at the nanoscale on the performance of the device, and to try in this way to set new records in device efficiency. 2) The fabrication of plastic nanoporous materials for the separation, storage or catalytic transformation of (bio)molecules in which the size, the shape ratio, and the internal functionalization of the nanopores can be custom-tailored.

1 300 932 €

Start date: 2011-11-01, End date: 2016-10-31

The growth rate of both bacterial and human cells has a central role in the clinical management of infectious diseases and malignancies. Virulent and aggressive bacterial strains have higher growth rates, which will decrease in response to successful treatment. Proliferation rates are also instrumental in the diagnosis, prognosis, and treatment of various cancer types, as the proliferation rate of human cells is one of the hallmarks of malignancy, evident by the widespread use of various proliferation indices such as mitotic figure counting, PCNA and Ki-67 antibodies. An integral part of cell growth is DNA replication; in mid-replication, each replicating cell will have a second, partial, currently synthesized genome. This creates variations in DNA copy-number along the genome across a population of cells from which growth-rate is inferable.
 Based on our novel ERC-funded method, which accurately measures bacterial growth rates from metagenomic samples, we will further the development of our methods towards obtaining an entirely new facet of information about pathogens in infectious diseases, or an accurate estimation of tumor proliferation rates. Our approach is expected to be superior to the current state-of-the-art as sample preparation is simple and requires no immunological staining or examination by an experienced pathologist, increasing validity and reproducibility.

150 000 €

Start date: 2017-04-01, End date: 2018-09-30

The precise synthesis of nano-devices with tailored complex structures and properties is a requisite for their use in nanotechnology and medicine. Nowadays, the technology for the generation of these devices lacks the precision to determine their properties, and is accomplished mostly by “trial and error” experimental approaches. Bottom-up self-assembly that relies on highly specific biomolecular interactions of small and simple components, is an attractive approach for nanostructure templating. Here, we propose to overcome aforementioned challenges by using self-assembling protein building blocks as templates for nanofabrication. In nature, protein assemblies govern sophisticated structures and functions, which are inspiration to engineer novel assemblies by exploiting the same set of tools and interactions to create nanostructures with numerous potential applications in synthetic biology and nanotechnology. We hypothesize that we can rationally assemble a variety functional nanostructures by the logical combination of simple protein building blocks with specified properties. We propose to use a designed repeat protein scaffold for which we acquired a deep understanding of its molecular structure, stability, function, and inherent assembly properties. Only few conserved residues define the structure of the building block, which allow us to mutate its sequence to modulate assembly properties and to introduce reactive functionalities without compromising the structure of the scaffolding molecule. First, we will design a collection of protein-based nanostructures. Then, we will introduce reactive functionalities to create hybrid nanostructures with nanoparticles, metals and electro-active molecules. Finally, these conjugates will be used to build nano-devices such as nanocircuits, catalysts and electroactive materials. The outcome of this project will be a modular versatile platform for the fabrication of multiple protein-based hybrid functional nanostructures.

1 718 850 €

Start date: 2016-01-01, End date: 2020-12-31

Milk and its fermentation derivatives, yogurt and cheese, are globally consumed at rates of >750 million tonnes annually, and are responsible for ~10% of the protein consumption worldwide. In the process of yogurt and cheese production, starter cultures of lactic acid bacteria (LAB) are added to milk, leading to fermentative production of the end product. Optimal growth of the lactic acid bacteria within the milk is critical for high-quality fermentation in the manufacturing of such dairy products. During fermentation, growth of starter culture bacteria is frequently impaired by viruses (phages) that infect these bacteria. Phage infection of lactic acid bacteria fermentative cultures is the main cause for incomplete or delayed fermentation processes in the dairy industry, and it is estimated that 10% of dairy fermentation processes fail due to culture infection by phage. This puts an extensive financial burden on the yogurt and cheese industries, a market estimated at >$80B annually. There is therefore a strong need for tools that would protect lactic acid bacteria from phage infection during the fermentation process. In our ERC-funded project we discovered novel defense systems that confer strong resistance against multiple types of phages. We showed that our systems do not impair normal growth of bacteria, and provide efficient phage-resistance features, conferring protection against a broad range of phages. Within the current PoC project we will harness our discoveries to develop non-GMO prototype lactic acid bacteria that are strongly protected against phage infection. This prototype is expected to demonstrate highly resilient, enhanced starter culture bacteria that will have superior durability and resistance over currently available starter culture bacteria used in the market.

150 000 €

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

PROTEUS studies main strategies devised by Western philosophy in representing time in cosmology. It aims at modifying current metaphysics and its relationship with cosmology in the light of recent scientific debates in quantum gravity and quantum cosmology, thereby boosting a new research field in history and philosophy of cosmology. The project is based on two hypotheses: 1) the history of philosophy reveals a guideline that can be traced back to Plato and that characterizes physical and metaphysical approaches to the question of the beginning of the universe in terms of a tension between fundamentality and non-fundamentality of time; 2) there is a conceptual problematic assumption in Western culture and it consists in shaping the problem of the origin of the world as a problem of thinking about the very same conditions of possibility of the origin of a process that is not in time. The project spells out the conceptual roots of current representations of time in quantum gravity and quantum cosmology and highlights the conceptual break that they provide with respect to philosophical concepts of time portrayed in previous systems. PROTEUS explores in detail the notions of time and the paradoxes emerging in the philosophy and cosmology of Plato and Kant and identifies the fundamental characters of emergent time in current quantum gravity theories. In identifying these fundamental features, PROTEUS produces conceptual innovation in metaphysics in such a way that philosophical investigation is complementary to the development of current theories. PROTEUS elaborates alternative argument(s) to anthropic principle, as well as new categories accounting for the notion of ‘contingent necessity’ of the world. The research team includes members from different backgrounds (philosophy, mathematics and physics) and will promote the application of a new methodology emphasizing the relevance of the history of philosophy and the actual interaction between philosophers and scientists.

1 418 869 €

Start date: 2018-09-01, End date: 2023-08-31

"This project aims at producing a fully functional light energy conversion system that is inspired by, but does not necessarily mimic, the fundamental solar energy conversion unit of natural photosynthesis – the photosystem. This is a formidable challenge that can be met with thorough understanding of biological energy and electron transfer processes, and the growing capabilities of computational protein design. Here, this knowledge and capabilities will be further developed and utilized for the design and construction of multi-cofactor, multi-subunit protein complexes with photosystem functionality. These will be designed to efficiently capture light in the visible and near infrared range, exploit it for driving the oxidation of a molecular redox carrier at one end, and providing highly reducing electrons at the other end. Our general goal will be achieved by designing protein-cofactor complexes that will facilitate light-driven electron- and excitation energy-transfer that will make up the reaction center, and light harvesting modules, respectively. Constructing protein scaffolds that will assemble and organize arrays of multiple pigments, and chains of redox cofactors are significant challenges at the forefront of the field of protein de novo design, and current theories of biological energy and electron transfer. Success will set a new standard, well beyond the current state of the art, for our ability to use computational protein design methods for assembling functional protein-cofactor complexes. These can be used as benchmarks to test and validate the engineering principles of biological energy conversion systems, as well as new ideas about their evolution. Practically, it will open new and exciting technological possibilities for constructing artificial solar energy conversion systems from biological building blocks, which may enable their introduction into living systems and the construction of novel bioreactors for light driven fuel production."

1 997 944 €

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

This proof of concept is based on the ERC Advanced Grant TRAVERSE (2009-2015). It will exploit immersive virtual reality in a new form of psychological clinical intervention akin to Gestalt Therapy. The primary aim of this Proof of Concept project is to generate a business model that would allow us to diffuse our technology to thousands of counsellors and psychologists around the world. In order to accomplish that we commission further trials to extend the evidence base of the approach, investigate through market research the extension of the technique for business practice, develop a commercial prototype with consumer equipment that would be low cost but high quality, exhibit our product at international conferences, and make the system available on loan to psychologists or counsellors who wished to try it, and generally start the process of diffusion. Moreover, we that our low cost system incorporates patentable inventions that would be investigated in an IP strategy. Through this approach we will develop the Business Model and a draft Business Plan for mass take up of our applications.

149 950 €

Start date: 2016-07-01, End date: 2017-12-31

Dynamic fragmentation of metals is typically addressed within a statistical framework in which material and geometric flaws limit the energy absorption capacity of protective structures. This project is devised to challenge this idea and establish a new framework which incorporates a deterministic component within the fragmentation mechanisms. In order to check the correctness of this new theory, I will develop a comprehensive experimental, analytical and numerical methodology to address 4 canonical fragmentation problems which respond to distinct geometric and loading conditions which make easily identifiable from a mechanical standpoint. For each canonical problem, I will investigate traditionally-machined and 3D-printed specimens manufactured with 4 different engineering metals widely used in aerospace and civilian-security applications. The goal is to elucidate whether at sufficiently high strain rates there may be a transition in the fragmentation mechanisms from defects–controlled to inertia–controlled. If the new statistical-deterministic framework is proven to be valid, defects may not play the major role in the fragmentation at high strain rates. This would bring down the entry barriers that the 3D-printing technology has found in energy absorption applications, thus reducing production transportation and repairing, energetic and economic costs of protective structures without impairing their energy absorption capacity. It is anticipated that leading this cutting-edge research project will enable me to establish my own research team and help me to achieve career independence in the field of dynamic behaviour of ductile solids.

1 497 507 €

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

A variety of classical optical systems exhibiting rich and complex matter-like behavior have been explored in recent years. Unfortunately in the optical regime, photons – the fundamental constituents of light – do not interact strongly with one another, and therefore cannot be used for studying many-body effects. It is only in the extreme regime of quantum nonlinear optics where effective interactions between photons are made strong. In an atomic gas, strong long-range interactions can be achieved by coupling photons to interacting atoms. First experiments have indicated the formation of a two-photon bound state via this mechanism. The main goal of the proposed research is to develop an optical system based on atomic interactions that realizes quantum many-body physics with optical photons subject to a rich variety of model problems. The proposed method relies on reconfigurable, optically-induced, three-dimensional, structures, which are fully compatible with the underlying atomic process. These structures enable the spatial compression of photons for enhancing the interactions, wave guiding for one-dimensional confinement in long media, and a rich variety of two-dimensional potentials with tunable interactions, from nearly-free photons to various tight-binding models with a controllable level of disorder. Optically-induced structures also offer advantages to optical quantum information, enabling better gate fidelities due to stronger nonlinearities and multimode coupling for processes such as photon routing. Our method has the potential to realize quantum gases and fluids of interacting photons. We can manipulate the effective mass and the band structure, control the potential landscape, and tune the scattering length in the system from attractive to repulsive. In particular, we intend to study few-photon bound states, quantum solitons, Luttinger liquids of photons, and Wigner crystallization in one and two dimensions.

1 500 000 €

Start date: 2016-06-01, End date: 2021-05-31