ERC FUNDED PROJECTS

This long-term research project is based on the data-mining of the Llibres d'Esposalles conserved at the Archives of the Barcelona Cathedral, an extraordinary data source comprising 244 books of marriage licenses records. It covers about 550.000 unions from over 250 parishes of the Diocese between 1451 and 1905. Its impeccable conservation is a miracle in a region where parish archives have undergone massive destruction. The books include data on the tax posed on each couple depending on their social class, on an eight-tiered scale. These data allow for research on multiple aspects of demographic research, especially on the very long run, such as: population estimates, marriage dynamics, cycles, and indirect estimations for fertility, migration and survival, as well as socio-economic studies related to social homogamy, social mobility, and transmission of social and occupational position. Being continuous over five centuries, the source constitutes a unique instrument to study the dynamics of population distribution, the expansion of the city of Barcelona and the constitution of its metropolitan area, as well as the chronology and the geography in the constitution of new social classes. To this end, a digital library and a database, the Barcelona Historical Marriages Database (BHiMaD), are to be created and completed. An ERC-AG will help doing so while undertaking the research analysis of the database in parallel. The research team, at the U. Autònoma de Barcelona, involves researchers from the Center for Demo-graphic Studies and the Computer Vision Center experts in historical databases and computer-aided recognition of ancient manuscripts. 5CofM will serve the preservation of the original “Llibres d’Esposalles” and unlock the full potential embedded in the collection.

1 847 400 €

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

Aftermath seeks to understand the legacy of the East Asian War of 1592-1598. This conflict involved over 500,000 combatants from Japan, China, and Korea; up to 100,000 Korean civilians were abducted to Japan. The war caused momentous demographic upheaval and widespread destruction, but also had long-lasting cultural impact as a result of the removal to Japan of Korean technology and skilled labourers. The conflict and its aftermath bear striking parallels to events in East Asia during World War 2, and memories of the 16th century war remain deeply resonant in the region. However, the war and its immediate aftermath are also significant because they occurred at the juncture of periods often characterized as “medieval” and “early modern” in the East Asian case. What were the implications for the social, economic, and cultural contours of early modern East Asia? What can this conflict tell us about war “aftermath” across historical periods and about such periodization itself? There is little Western scholarship on the war and few studies in any language cross linguistic, disciplinary, and national boundaries to achieve a regional perspective that reflects the interconnected history of East Asia. Aftermath will radically alter our understanding of the region’s history by providing the first analysis of the state of East Asia as a result of the war. The focus will be on the period up to the middle of the 17th century, but not precluding ongoing effects. The team, with expertise covering Japan, Korea, and China, will investigate three themes: the movement of people and demographic change, the impact on the natural environment, and technological diffusion. The project will be the first large scale investigation to use Japanese, Korean, and Chinese sources to understand the war’s aftermath. It will broaden understandings of the early modern world, and push the boundaries of war legacy studies by exploring the meanings of “aftermath” in the early modern East Asian context.

1 444 980 €

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

Air pollution is the main urban-related environmental hazard. It appears to affect brain development, although current evidence is inadequate given the lack of studies during the most vulnerable stages of brain development and the lack of brain anatomical structure and regional connectivity data underlying these effects. Of particular interest is the prenatal period, when brain structures are forming and growing, and when the effect of in utero exposure to environmental factors may cause permanent brain injury. I and others have conducted studies focused on effects during school age which could be less profound. I postulate that: pre-natal exposure to urban air pollution during pregnancy impairs foetal and postnatal brain development, mainly by affecting myelination; these effects are at least partially mediated by translocation of airborne particulate matter to the placenta and by placental dysfunction; and prenatal exposure to air pollution impairs post-natal brain development independently of urban context and post-natal exposure to air pollution. I aim to evaluate the effect of pre-natal exposure to urban air pollution on pre- and post-natal brain structure and function by following 900 pregnant women and their neonates with contrasting levels of pre-natal exposure to air pollutants by: i) establishing a new pregnancy cohort and evaluating brain imaging (pre-natal and neo-natal brain structure, connectivity and function), and post-natal motor and cognitive development; ii) measuring total personal exposure and inhaled dose of air pollutants during specific time-windows of gestation, noise, paternal stress and other stressors, using personal samplers and sensors; iii) detecting nanoparticles in placenta and its vascular function; iv) modelling mathematical causality and mediation, including a replication study in an external cohort. The expected results will create an impulse to implement policy interventions that genuinely protect the health of urban citizens.

2 499 992 €

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

"We propose to study different questions in the area of the so called geometric analysis. Most of the topics we are interested in deal with the connection between the behavior of singular integrals and the geometry of sets and measures. The study of this connection has been shown to be extremely helpful in the solution of certain long standing problems in the last years, such as the solution of the Painlev\'e problem or the obtaining of the optimal distortion bounds for quasiconformal mappings by Astala. More specifically, we would like to study the relationship between the L^2 boundedness of singular integrals associated with Riesz and other related kernels, and rectifiability and other geometric notions. The so called David-Semmes problem is probably the main open problem in this area. Up to now, the techniques used to deal with this problem come from multiscale analysis and involve ideas from Littlewood-Paley theory and quantitative techniques of rectifiability. We propose to apply new ideas that combine variational arguments with other techniques which have connections with mass transportation. Further, we think that it is worth to explore in more detail the connection among mass transportation, singular integrals, and uniform rectifiability. We are also interested in the field of quasiconformal mappings. We plan to study a problem regarding the quasiconformal distortion of quasicircles. This problem consists in proving that the bounds obtained recently by S. Smirnov on the dimension of K-quasicircles are optimal. We want to apply techniques from quantitative geometric measure theory to deal with this question. Another question that we intend to explore lies in the interplay of harmonic analysis, geometric measure theory and partial differential equations. This concerns an old problem on the unique continuation of harmonic functions at the boundary open C^1 or Lipschitz domain. All the results known by now deal with smoother Dini domains."

1 105 930 €

Start date: 2013-05-01, End date: 2018-04-30

Our research interests lie in breaking new ground in studying mechanism-based functions of AP-1 (Fos/Jun) in vivo with the aim of obtaining a more global perspective on AP-1 in human physiology and disease/cancer. The unresolved issues regarding the AP-1 subunit composition will be tackled biochemically and genetically in various cell types including bone, liver and skin, the primary organs affected by altered AP-1 activity. I plan to utilize the knowledge gained on AP-1 functions in the mouse and transfer it to human disease. The opportunities here lie in exploiting the knowledge of AP-1 target genes and utilizing this information to interfere with pathways involved in normal physiology and disease/cancer. The past investigations revealed that the functions of AP-1 are an essential node at the crossroads between life and death in different cellular systems. I plan to further exploit our findings and concentrate on utilising better mouse models to define these connections. The emphasis will be on identifying molecular signatures and potential treatments in models for cancer, inflammatory and fibrotic diseases. Exploring genetically modified stem cell-based therapies in murine and human cells is an ongoing challenge I would like to meet in the forthcoming years at the CNIO. In addition, the mouse models will be used for mechanism-driven therapeutic strategies and these studies will be undertaken in collaboration with the Experimental Therapeutics Division and the service units such as the tumor bank. The project proposal is divided into 6 Goals (see also Figure 1): Some are a logical continuation based on previous work with completely new aspects (Goal 1-2), some focussing on in depth molecular analyses of disease models with innovative and unconventional concepts, such as for inflammation and cancer, psoriasis and fibrosis (Goal 3-5). A final section is devoted to mouse and human ES cells and their impact for regenerative medicine in bone diseases and cancer.

2 500 000 €

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

Based on the APMPAL (ERC) project we continue to develop the frameworks of internal rationality (IR) and optimal signal extraction (OSE). Under IR investors/consumers behave rationally given their subjective beliefs about prices, these beliefs are compatible with data. Under OSE the government has partial information, it knows how policy influences observed variables and signal extraction. We develop further the foundations of IR and OSE with an emphasis on heterogeneous agents. We study sovereign bond crisis and heterogeneity of beliefs in asset pricing models under IR, using survey data on expectations. Under IR the assets’ stochastic discount factor depends on the agents’ decision function and beliefs; this modifies some key asset pricing results. We extend OSE to models with state variables, forward-looking constraints and heterogeneity. Under IR agents’ prior beliefs determine the effects of a policy reform. If the government does not observe prior beliefs it has partial information, thus OSE should be used to analyse policy reforms under IR. If IR heterogeneous workers forecast their productivity either from their own wage or their neighbours’ in a network, low current wages discourage search and human capital accumulation, leading to low productivity. This can explain low development of a country or social exclusion of a group. Worker subsidies redistribute wealth and can increase productivity if they “teach” agents to exit a low-wage state. We build DSGE models under IR for prediction and policy analysis. We develop time-series tools for predicting macro and asset market variables, using information available to the analyst, and we introduce non-linearities and survey expectations using insights from models under IR. We study how IR and OSE change the view on macro policy issues such as tax smoothing, debt management, Taylor rule, level of inflation, fiscal/monetary policy coordination, factor taxation or redistribution.

1 524 144 €

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

European incursions onto the narrow isthmian pass that divided and connected the Atlantic and Pacific oceans made it a strategic node of the Spanish Empire and a crucial site for early modern globalization. On the front lines of the convergence of four continents, Old Panama offers an unusual opportunity for examining the diverse, often asymmetrical impacts of cultural and commercial contacts. The role of Italian, Portuguese, British, Dutch, and French interests in the area, as well as an influx of African slaves and Asian merchandise, have left a unique material legacy that requires an integrated, interdisciplinary approach to its varied sources. Bones, teeth and artifacts on this artery of Empire offer the possibility of new insights into the cultural and biological impact of early globalization. They also invite an interdisciplinary approach to different groups’ tactics for survival, including possible dietary changes, and the pursuit of profit. Such strategies may have led the diverse peoples inhabiting this junction, from indigenous allies to African and Asian bandits to European corsairs, to develop and to favor local production and Pacific trade networks at the expense of commerce with the metropolis. This project applies historical, archaeological and archaeometric methodologies to evidence of encounters between peoples and goods from Europe, America, Africa and Asia that took place on the Isthmus of Panama during the sixteenth and seventeenth centuries. Forging an interdisciplinary approach to early globalization, it challenges both Euro-centric and Hispano-phobic interpretations of the impact of the conquest of America, traditionally seen as a demographic catastrophe that reached its nadir in the so-called seventeenth-century crisis. Rather than applying quantitative methods to incomplete source material, researchers will adopt a contextualized, inter-disciplinary, qualitative approach to diverse agents involved in cultural and commercial exchange.

1 998 875 €

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

The prognosis of patients with metastatic pancreatic cancer (PDAC) is very poor. Recent studies have started to elucidate the genetic landscape of this disease to show that PDAC is a genetically complex, unstable, and heterogeneous cancer. However, in-depth analysis of individual patient genomes couple with personalize Avatar mouse models is providing highly effective therapeutic opportunities for the individual patient. Thus, metastatic PDAC appears a candidate disease to implement a genomics-base, personalized treatment approach. In this project, we will conduct an open label, multicenter, randomized phase III study in patients with standard of care resistant metastatic pancreatic cancer aiming to test the hypothesis that an integrated personalized treatment approach improves survival compare to a conventional treatment. Patients randomized to the personalize treatment arm will undergo a biopsy of a metastatic lesion to perform a targeted genome analysis using next generation sequencing. In addition, we will generate a personalize Avatar mouse model from the same patient. We will employ sophisticated bioinformatic analysis as well as mining of drug response-genetic databases to select, for each individual patient, candidate therapeutic targets that will be experimentally tested in the patient´s Avatar model to select the most effective regimen that will ultimately applied to the patient. In addition, based on the genomic data, we will design an individualized monitoring plan for each patient using BEAMing technology to monitor circulating levels of mutated genes. Furthermore, with a discovery goal, we will perform in depth genomic analysis of metastatic PDAC lesions in this cohort of clinically well-annotated patients with Avatar mouse models for therapeutic validation. Overall we expect this work will contribute to our understanding of PDAC and will favourably impact the treatment of this dismal cancer.

2 498 688 €

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

Sustainable agriculture is an ambitious concept conceived to improve productivity but minimizing side effects. Why the efficiency of a biocontrol agent is so variable? How can different therapies be efficiently exploited in a combined way to combat microbial diseases? These are questions that need investigation to convey with criteria of sustainability. What I present is an integral proposal aim to study the microbial ecology and specifically bacterial biofilms as a central axis of two differential but likely interconnected scenarios in plant health: i) the beneficial interaction of the biocontrol agent (BCA) Bacillus subtilis, and ii) the non-conventional interaction of the food-borne pathogen Bacillus cereus. I will start working with B. subtilis, and reasons are: 1) Different isolates are promising BCAs and are commercialized for such purpose, 2) There exist vast information of the genetics circuitries that govern important aspects of B. subtilis physiology as antibiotic production, cell differentiation, and biofilm formation. In parallel I propose to study the way B. cereus, a food-borne pathogenic bacterium interacts with vegetables. I am planning to set up a multidisciplinary approach that will combine genetics, biochemistry, proteomics, cell biology and molecular biology to visualize how these bacterial population interacts, communicates with plants and other microorganisms, or how all these factors trigger or inhibit the developmental program ending in biofilm formation. I am also interested on knowing if structural components of the bacterial extracellular matrix (exopolysaccharides or amyloid proteins) are important for bacterial fitness. If this were the case, I will also investigate which external factors affect their expression and assembly in functional biofilms. The insights get on these studies are committed to impulse our knowledge on microbial ecology and their biotechnological applicability to sustainable agriculture and food safety.

1 453 563 €

Start date: 2015-03-01, End date: 2021-02-28

In many European countries with ostensibly liberal abortion laws, women face legal restrictions to abortion beyond the first trimester of pregnancy, as well as other barriers to legal abortion, in particular shortages of providers willing and able to offer abortion due to poor training and to conscientious objection among physicians. The Council of Europe has recognized that conscientious objection can make access to safe abortion more difficult or impossible, particularly in rural areas and for low income women, who are forced to travel far to seek abortion care, including abroad. The WHO also highlights that delaying abortion care increases risks for women’s reproductive health. Despite the relevance of this topic from a public health and human rights perspective, the impact of procedural and social barriers to legal abortion on women in countries with ostensibly liberal abortion laws has not been studied by social scientists in Europe. This five-year research project is envisaged as a ground-breaking multi-disciplinary, mixed-methods investigation that will fill this gap, by capitalizing on previous, pioneer anthropological research of the PI on abortion and conscientious objection. It will contribute to the anthropology of reproduction in Europe, and particularly to the existing literature on abortion, conscientious objection and the medicalization of reproduction, and to the international debate on gender inequalities and citizenship, by exploring how barriers to legal abortion are constructed and how women embody and challenge them in different countries, by travelling or seeking illegal abortion, as well as their conceptualizations of abortion and their self perception as moral/political subjects. The project will be carried out in France, Italy and Spain, where the few existing studies show that women face several barriers to legal abortion as well as in the UK, the Netherlands and Spain, where Italian and French women travel to seek abortion care.

1 495 753 €

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

The proposed project offers a new, pan-European intellectual history of the political imagination in the interwar period that places the demise of historicism and progressivism – and the emerging anti-teleological visions of time – at the center of some of its most innovative ethical, political and methodological pursuits. It argues that only a distinctively cross-disciplinary and European narrative can capture the full ramifications and legacies of a fundamental rupture in thought conventionally, yet inadequately confined to the German cultural space and termed “anti-historicism”. It innovates narratively by exploring politically and theoretically interlaced reinventions of temporality across and between different disciplines (theology, jurisprudence, classical studies, literary theory, linguistics, sociology, philosophy), as well as other creative fields. It experiments methodologically by reconstructing the dynamics of political thought prosopographically, through intellectual groupings at the forefront of the scholarly and political debates of the period. It challenges the sufficiency of the standard focus in interwar intellectual history on one or two, at most three (usually “Western” European) national contexts by following out the interactions of these groupings in France, Britain, Germany, Russia, Czechoslovakia, and Romania – groupings whose members frequently moved across national contexts. What were the political languages encoded in the reinventions of time, and vice versa – how were political aims translated into and advanced through theoretical innovation? How did these differ in different national contexts, and why? What are the fragmented legacies of this rupture, disbursed in and through the philosophical, methodological and political dicta and dogmas that rooted themselves in post-1945 thought? This project provides the first comprehensive answer to these fundamental questions about the intellectual identity of Europe and its historicities.

1 425 000 €

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

Increases in nutrient availability and temperature, and changes in precipitation patterns and biodiversity are important components of global environmental change. Thus, it is imperative to understand their impacts on the functioning of natural ecosystems. Substantial research efforts are being currently devoted to predict how biodiversity will respond to global change. However, little is known on the relative importance of biodiversity against other attributes of biotic communities, such as species cover and spatial pattern, as a driver of ecosystem processes. Furthermore, the effects of global change on the relationships between these attributes and ecosystem functioning are virtually unknown. This project aims to evaluate the relationships between community attributes (species richness, composition, evenness, cover, and spatial pattern) and key processes related to ecosystem functioning under different global change scenarios. Its specific objectives are to: i) evaluate the relative importance of community attributes as drivers of ecosystem functioning, ii) assess how multiple global change drivers will affect key ecosystem processes, iii) test whether global change drivers modify observed community attributes-ecosystem functioning relationships, iv) develop models to forecast global change effects on ecosystem functioning, and v) set up protocols for the establishment of mitigation actions based on the results obtained. They will be achieved by integrating experimental and modeling approaches conducted with multiple biotic communities at different spatial scales. Such integrated framework has not been tackled before, and constitutes a ground breaking advance over current research efforts on global change. This proposal will also open the door to new research lines exploring the functional role of community attributes and their importance as modulators of ecosystem responses to global change.

1 463 374 €

Start date: 2010-01-01, End date: 2015-09-30

Changes in climate and land use (e.g., increased grazing pressure), are two main global change components that also act as major desertification drivers. Understanding how drylands will respond to these drivers is crucial because they occupy 41% of the terrestrial surface and are home to over 38% of the world’s human population. Land degradation already affects ~250 million people in the developing world, which rely upon the provision of many ecosystem processes (multifunctionality). This proposal aims to develop a better understanding of the functioning and resilience of drylands (i.e. their ability to respond to and recover from disturbances) to major desertification drivers. Its objectives are to: 1) test how changes in climate and grazing pressure determine spatiotemporal patterns in multifunctionality in global drylands, 2) assess how biotic attributes (e.g., biodiversity, cover) modulate ecosystem resilience to climate change and grazing pressure at various spatial scales, 3) test and develop early warning indicators of desertification, and 4) forecast the onset of desertification and its ecological consequences under different climate and grazing scenarios. I will use various biotic communities/attributes, ecosystem services and spatial scales (from local to global), and will combine approaches from several disciplines. Such comprehensive and highly integrated research endeavor is novel and constitutes a ground breaking advance over current research efforts on desertification. This project will provide a mechanistic understanding on the processes driving multifunctionality under different global change scenarios, as well as key insights to forecast future scenarios for the provisioning of ecosystem services in drylands, and to test and develop early warning indicators of desertification. This is of major importance to attain global sustainability and key Millennium Development Goals, such as the eradication of poverty.

1 894 450 €

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

Fish are the phylogenetically oldest vertebrate group with an immune system with clear similarities to the immune system of mammals. However, it is an actual matter of fact that the current knowledge of the fish immune system seems to lack the key piece to complete the puzzle. In 1953 Nelson described a new role of human red blood cells (RBCs) which would go beyond the simple transport of O2 to the tissues. This new role, involved in the defence against microbes, described the antibody and complement-dependent binding of microbial immune complexes to RBCs. Regardless of the importance of this finding in the field of microbial infection, this phenomenon has been poorly evaluated. Just recently, a set of biological processes relevant to immunity have been described in the RBCs of a diverse group of organisms, which include: pathogen recognition, pathogen binding and clearance and cytokines production. Furthermore, it has been demonstrated that nucleated erythrocytes from fish and avian species develop specific responses to different pathogen associated molecular patterns and produce soluble factors that modulate leukocyte activity. In the light of these pieces of evidences, and in an attempt to improve the knowledge of the immune mechanism(s) responsible for fish protection against viral infections, we raised the question: could nucleated fish erythrocytes be the key mediators of the antiviral responses? To answer this question we decided to focus our project on the evaluation of the crosstalk between red and white blood cells in the scenario of fish viral infections and prophylaxis. For that a working model composed of the rainbow trout and the viral haemorrhagic septicaemia virus (VHSV) was chosen, being the objectives of the project to evaluate: i) the implication trout RBCs (tRBCs) in the clearance of VHSV, and ii) the involvement of tRBCs in the blood transportation of the glycoprotein G of VHSV (GVHSV), the antigen encoded by the DNA vaccine.

1 823 250 €

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

In order to celebrate mathematics in the new millennium, the Clay Mathematics Institute established seven $1.000.000 Prize Problems. One of these is the conjecture of Birch and Swinnerton-Dyer (BSD), widely open since the 1960's. The main object of this proposal is developing innovative and unconventional strategies for proving groundbreaking results towards the resolution of this problem and their generalizations by Bloch and Kato (BK). Breakthroughs on BSD were achieved by Coates-Wiles, Gross, Zagier and Kolyvagin, and Kato. Since then, there have been nearly no new ideas on how to tackle BSD. Only very recently, three independent revolutionary approaches have seen the light: the works of (1) the Fields medalist Bhargava, (2) Skinner and Urban, and (3) myself and my collaborators. In spite of that, our knowledge of BSD is rather poor. In my proposal I suggest innovating strategies for approaching new horizons in BSD and BK that I aim to develop with the team of PhD and postdoctoral researchers that the CoG may allow me to consolidate. The results I plan to prove represent a departure from the achievements obtained with my coauthors during the past years: I. BSD over totally real number fields. I plan to prove new ground-breaking instances of BSD in rank 0 for elliptic curves over totally real number fields, generalizing the theorem of Kato (by providing a new proof) and covering many new scenarios that have never been considered before. II. BSD in rank r=2. Most of the literature on BSD applies when r=0 or 1. I expect to prove p-adic versions of the theorems of Gross-Zagier and Kolyvagin in rank 2. III. Darmon's 2000 conjecture on Stark-Heegner points. I plan to prove Darmon’s striking conjecture announced at the ICM2000 by recasting it in terms of special values of p-adic L-functions.

1 428 588 €

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

"In recent years, we have made significant contributions to the understanding of the tumour suppressors p53, p16INK4a, and ARF, particularly in relation with cellular senescence and aging. The current project is motivated by two hypothesis: 1) that the INK4/ARF locus is a sensor of epigenetic damage and this is at the basis of its activation by oncogenes and aging; and, 2) that the accumulation of cellular damage and stress is at the basis of both cancer and aging, and consequently ""anti-damage genes"", such as tumour suppressors, simultaneously counteract both cancer and aging. With regard to the INK4/ARF locus, the project includes: 1.1) the generation of null mice for the Regulatory Domain (RD) thought to be essential for the proper regulation of the locus; 1.2) the study of the INK4/ARF anti-sense transcription and its importance for the assembly of Polycomb repressive complexes; 1.3) the generation of mice carrying the human INK4/ARF locus to analyze, among other aspects, whether the known differences between the human and murine loci are ""locus autonomous""; and, 1.4) to analyze the INK4/ARF locus in the process of epigenetic reprogramming both from ES cells to differentiated cells and, conversely, from differentiated cells to induced-pluripotent stem (iPS) cells. With regard to the impact of ""anti-damage genes"" on cancer and aging, the project includes: 2.1) the analysis of the aging of super-INK4/ARF mice and super-p53 mice; 2.2) we have generated super-PTEN mice and we will examine whether PTEN not only confers cancer resistance but also anti-aging activity; and, finally, 2.3) we have generated super-SIRT1 mice, which is among the best-characterized anti-aging genes in non-mammalian model systems (where it is named Sir2) involved in protection from metabolic damage, and we will study the cancer and aging of these mice. Together, this project will significantly advance our understanding of the molecular mechanisms underlying cancer and aging."

2 000 000 €

Start date: 2009-04-01, End date: 2015-03-31

Mammalian cells express thousands of RNA molecules structurally similar to protein coding genes –they are large, spliced, poly-adenylated, transcribed by RNA Pol II, with conserved promoters and exonic structures –however lack coding capacity. Although thousands exist, only few of these large intergenic non-coding RNAs (lincRNAs) have been characterized. The few that have, show powerful biological roles as regulators of gene expression by diverse epigenetic and non-epigenetic mechanisms. Significantly, their expression patterns suggest that some lincRNAs are involved in cellular pathways critical in cancer, like the p53 pathway. I explored this association demonstrating that p53 induces the expression of many lincRNAs. One them, named lincRNA-p21, is directly induced by p53 to play a critical role in the p53 response, being required for the global repression of genes that interfere with p53 induction of apoptosis. My results, together with the emerging evidence in the field, suggest that lincRNAs may play key roles in numerous tumor-suppressor and oncogenic pathways, representing an unknown paradigm in cellular transformation. However, their mechanisms of function and biological roles remain largely unexplored. The goal of this project is to decipher the functional and biological roles of lincRNAs in the context of oncogenic pathways to better understand the cellular mechanisms of gene regulation at the epigenetic and non-epigenetic levels, and be able to implement lincRNA use for diagnostics and therapies. In order to accomplish these goals we will integrate molecular and cell biology techniques with functional genomics approaches and in vivo studies. Importantly, the profiling of patient samples will reveal the relevance of our findings in human disease. Together, the functional study of lincRNAs will not only be crucial for developing improved diagnostics and therapies, but also will help a better understanding of the mechanisms that govern cellular network.

1 500 000 €

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

The discovery of adult neural stem cells (NSCs) has broaden our view of the physiological plasticity of the nervous system, and has opened new perspectives on the possibility of tissue regeneration and repair in the brain. NSCs reside in specialized niches in the adult mammalian nervous system, where they are exposed to specific paracrine signals regulating their behavior. These neural progenitors are generally in a quiescent state within their niche, and they activate their proliferation depending on tissue regenerative and growth needs. Understanding the mechanisms by which NSCs enter and exit the quiescent state is crucial for the comprehension of the physiology of the adult nervous system. In this project we will study the behavior of a specific subpopulation of adult neural stem cells recently described by our group in the carotid body (CB). This small organ constitutes the most important chemosensor of the peripheral nervous system and has neuronal glomus cells responsible for the chemosensing, and glia-like sustentacular cells which were thought to have just a supportive role. We recently described that these sustentacular cells are dormant stem cells able to activate their proliferation in response to a physiological stimulus like hypoxia, and to differentiate into new glomus cells necessary for the adaptation of the organ. Due to our precise experimental control of the activation and deactivation of the CB neurogenic niche, we believe the CB is an ideal model to study fundamental questions about adult neural stem cell physiology and the interaction with the niche. We propose to study the cellular and molecular mechanisms by which these carotid body stem cells enter and exit the quiescent state, which will help us understand the physiology of adult neurogenic niches. Likewise, understanding this neurogenic process will improve the efficacy of using glomus cells for cell therapy against neurological disease, and might help us understand some neural tumors.

1 476 000 €

Start date: 2010-11-01, End date: 2015-10-31

The search of singularities in incompressible flows has become a major challenge in the area of non-linear partial differential equations and is relevant in applied mathematics, physics and engineering. The existence of such singularities would have important consequences for the understanding of turbulence. One way to make progress in this direction, is to study plausible scenarios for the singularities supported by experiments or numerical analysis. With the more sophisticated numerical tools now available, the subject has recently gained considerable momentum. The main goal of this project is to study analytically several incompressible fluid models. In particular solutions that involve the possible formation of singularities or quasi-singular structures.

650 000 €

Start date: 2008-09-01, End date: 2013-08-31

The idea of harnessing living organisms for treating human diseases is not new but, so far, the majority of the living vectors used in human therapy are viruses which have the disadvantage of the limited number of genes and networks that can contain. Bacteria allow the cloning of complex networks and the possibility of making a large plethora of compounds, naturally or through careful redesign. One of the main limitations for the use of bacteria to treat human diseases is their complexity, the existence of a cell wall that difficult the communication with the target cells, the lack of control over its growth and the immune response that will elicit on its target. Ideally one would like to have a very small bacterium (of a mitochondria size), with no cell wall, which could be grown in Vitro, be genetically manipulated, for which we will have enough data to allow a complete understanding of its behaviour and which could live as a human cell parasite. Such a microorganism could in principle be used as a living vector in which genes of interests, or networks producing organic molecules of medical relevance, could be introduced under in Vitro conditions and then inoculated on extracted human cells or in the organism, and then become a new organelle in the host. Then, it could produce and secrete into the host proteins which will be needed to correct a genetic disease, or drugs needed by the patient. To do that, we need to understand in excruciating detail the Biology of the target bacterium and how to interface with the host cell cycle (Systems biology aspect). Then we need to have engineering tools (network design, protein design, simulations) to modify the target bacterium to behave like an organelle once inside the cell (Synthetic biology aspect). M.pneumoniae could be such a bacterium. It is one of the smallest free-living bacterium known (680 genes), has no cell wall, can be cultivated in Vitro, can be genetically manipulated and can enter inside human cells.

2 400 000 €

Start date: 2009-03-01, End date: 2015-02-28

While there is convincing evidence that exposure to particulate air pollution causes cardiovascular mortality and morbidity, nearly all of this evidence is based on populations in high-income countries where concentrations are relatively low. There is large uncertainty regarding the relationship between combustion particles and cardiovascular risk for concentrations higher than outdoor concentrations in urban areas of high-income countries and lower than active smoking. Exposures for our study population are likely to be in this range. We will investigate the cardiovascular health effects of exposure to particles from outdoor and household sources within a prospective cohort in Andhra Pradesh, India. Firstly, we will characterise exposure of participants using an integrated approach utilising outdoor mobile monitoring, personal monitoring, and questionnaire data. We will then collect data on participants’ activities and location using ‘life-logging’ from which activities driving exposure can be identified. Finally, we will quantify the association between exposure to particles and biomarkers of atherosclerosis. This research will shed light on the relationship between particles and cardiovascular risk at concentration ranges where there is the largest uncertainty. It will provide some of the first evidence of the cardiovascular health effects of medium-term exposure to particulate air pollution outside of a high-income country. The research will also provide evidence regarding the relative contribution of sources and activities linked to high exposure, forming the basis of recommendations for exposure reduction.

1 200 000 €

Start date: 2015-01-01, End date: 2018-12-31

With the availability of the essentially complete sequence of the human genome, as well as a rapid development of massive sequencing techniques, the research efforts to understand genetics and disease from a cis standpoint will soon reach an endpoint. However, our emerging knowledge of gene regulation networks reveals that epigenetic regulation of the hereditary information plays crucial roles in various biological events through its influence on processes such as transcription, DNA replication and chromosome architecture. Another scenario in which the control of chromatin structure is crucial is the repair of lesions in genomic DNA. There is mounting evidence, particularly from model organisms such as Saccharomyces cerevisiae, that histone modifying enzymes (acetylases, deacetylases, kinases, …) are essential components of the machinery that maintains genome integrity and thereby guards against cancer, degenerative diseases and ageing. However, little is known about the specific “code” of histone tail modifications that coordinate DNA repair, and the impact that an aberrant “histone code” may have on human health. In CHROMOREPAIR we will systematically analyze the chromatin remodelling process that undergoes at DNA lesions and evaluate the impact that chromatin alterations have on the access, signaling and repair of DNA damage. Furthermore, we propose to translate our in vitro knowledge to the development of mouse models that help us evaluate how modulation of chromatin status impinges on genome maintenance and therefore on cancer and aging. As a provocative line of research and based on our preliminary data, we propose that certain chromatin alterations could not only impair but also in some cases promote a more robust response to DNA breaks, which could be a novel and not yet explored way to potentiate the elimination of pre-cancerous cells.

948 426 €

Start date: 2008-12-01, End date: 2013-11-30

Globalization has brought the world economy unprecedented prosperity, but it poses governance challenges. It needs governments to provide the infrastructure for global economic integration and to refrain from destructive protectionism; yet it can engender popular discontent and a crisis of democracy. My proposal will study when trade- and productivity-enhancing policies enjoy democratic support; why voters may support instead inefficient surplus-reducing policies; and how political structure reacts to globalization. Part A studies the puzzling popularity of protectionism and how lobbies can raise it by manipulating information. It will study empirically if greater transparency causes lower trade barriers. It will introduce salience theory to political economics and argue that voters overweight concentrated losses and disregard diffuse benefits. It will show that lobbies can raise protection by channeling information to insiders and advertising the plight of displaced workers. Part B studies inefficient infrastructure policy and the ensuing spatial misallocation of economic activity. It will show that voters’ unequal knowledge lets local residents capture national policy. They disregard nationwide positive externalities, so investment in major cities is insufficient, but also nationwide taxes, so spending in low-density areas is excessive. It will argue that the fundamental attribution error causes voter opposition to growth-enhancing policies and efficient incentive schemes like congestion pricing. Part C studies how the size of countries and international unions adapts to expanding trade opportunities. It will focus on three forces: cultural diversity, economies of scale and scope in government, and trade-reducing border effects. It will show they explain increasing country size in the 19th century; the rise and fall of colonial empires; and the recent emergence of regional and global economic unions, accompanied by a peaceful increase in the number of countries.

960 000 €

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

Necrosis triggers an inflammatory response driven by macrophages that normally contributes to tissue repair but, under certain conditions, can induce a state of chronic inflammation that forms the basis of many diseases. In addition, dendritic cell (DC)-mediated presentation of antigens from necrotic cells can trigger adaptive immunity in infection-free situations, such as autoimmunity or therapy-induced tumour rejection. Recently, we and others have identified the myeloid C-type lectin receptors (CLRs) CLEC9A (DNGR-1), in DC, and Mincle, in macrophages, as receptors for necrotic cells that can signal via the Syk kinase. Previous studies on similar Syk-coupled CLRs showed that Dectin-1 and Dectin-2 can induce innate and adaptive immune responses. We thus hypothesise that recognition of cell death by myeloid Syk-coupled CLRs is at the root of immune pathologies associated with accumulation of dead cells. The overall objective of this proposal is to investigate necrosis sensing by myeloid cells as a trigger of immunity and to study the underlying molecular mechanisms. Our first goal is to characterise signalling and gene induction via CLEC9A as a model necrosis receptor in DCs. Second, we will investigate the role of myeloid Syk-coupled necrosis-sensing CLRs in animal models of atherosclerosis, lupus and immunity to chemotherapy-treated tumours. Our preliminary data suggest that additional receptors can couple necrosis recognition to the Syk pathway in DC; thus, our third aim is to identify novel myeloid Syk-coupled receptors for necrotic cells. Characterisation of the outcomes of sensing necrosis by myeloid Syk-coupled receptors and their effect on the proposed pathologies promises to identify new mechanisms and targets for the treatment of these diseases.

1 297 671 €

Start date: 2010-12-01, End date: 2016-08-31

In an early sixteenth-century treatise Martín de Figuerola, a convert from Islam who sought to convince the Muslims of Valencia and Aragon to join him, reports a story he claims to have heard from the Muslim judge of Cocentaina (Valencia). The latter had told him that, in marriage contracts between local Muslims, it was customary for women to demand that their husbands take them to the capital city of Valencia for the springtime festivities of Corpus Christi and those of the Virgin Mary in August. Simply put, the purpose of this project is to unravel the complex interplay of all the ingredients that this apparently trivial yet fascinating anecdote encapsulates. It will bring under close analysis the existence in sixteenth-century Iberia of cross-currents common to different religious groups, areas of local religiosity in which different religions overlapped, and vague or hybrid sorts of religiosity which indicate the blurring of clear ascriptions, categories, and borders. At the same time, it will also scrutinize the efforts made by different social actors (and generations of scholars after them) to establish clear, essential differentiations, to define neat categories and ascriptions, and thus to separate, reject, and stigmatize individuals and groups. The project will study adversarial relationships reconceived as dependencies, against a complex backdrop of dramatic religious change: shortly before Martín de Figuerola’s text was written, Iberia's Jews had been expelled, and a few years later its Muslims would be forced to convert to Christianity, only to be expelled in their turn a century later. The multi-faceted analysis of these phenomena will involve unearthing new archival material, most notably Inquisition trials, as well as numerous sixteenth- and seventeenth-century texts (both manuscripts and early modern editions) ranging from new translations of the Qur’an and other Jewish and Islamic classics, to a rich polemical literature.

2 498 026 €

Start date: 2013-04-01, End date: 2019-03-31

COSMOLOCALISM will document, analyse, test, evaluate, and create awareness about an emerging mode of production, based on the confluence of the digital commons (e.g. open knowledge and design) with local manufacturing and automation technologies (from 3D printing and CNC machines to low-tech tools and crafts). This convergence could catalyse the transition to new inclusive and circular productive models, such as the “design global, manufacture local” (DGML) model. DGML describes the processes through which design is developed as a global digital commons, whereas the manufacturing takes place locally, through shared infrastructures and with local biophysical conditions in mind. DGML seems to form economies of scope that promote sustainability and open innovation while celebrating new ways of cooperation. However, such claims rest on thin conceptual and empirical foundations. COSMOLOCALISM is a multiphase, pilot-driven investigation of the DGML phenomenon that seeks to understand relevant organisational models, their evolution, and their broader political economy/ecology and policy implications. Through the lens of diverse case studies and participatory action research, the conditions under which the DGML model thrives will be explored. COSMOLOCALISM has three concurrent streams: practices; innovation; and sustainability. First, DGML practices will be studied, patterns will be recognised and their form, function, cultural values, and governance structure will be determined. Second, the relevant open innovation ecosystems and their potential to reorient design and manufacturing practices will be examined. Third, selected DGML products will be evaluated from an environmental sustainability perspective, involving both qualitative and quantitative methods. The interdisciplinary nature of COSMOLOCALISM will explore new horizons to substantively improve our understanding of how we could do “more” and “better” with less.

1 017 275 €

Start date: 2019-01-01, End date: 2022-12-31

Von Neumann's concept of quantization goes back to the foundations of quantum mechanics and provides a noncommutative model of integration. Over the years, von Neumann algebras have shown a profound structure and set the right framework for quantizing portions of algebra, analysis, geometry and probability. A fundamental part of my research is devoted to develop a very much expected Calderón-Zygmund theory for von Neumann algebras. The lack of natural metrics partly justifies this long standing gap in the theory. Key new ingredients come from recent results on noncommutative martingale inequalities, operator space theory and quantum probability. This is an ambitious research project and applications include new estimates for noncommutative Riesz transforms, Fourier and Schur multipliers on arbitrary discrete groups or noncommutative ergodic theorems. Other related objectives of this project include Rubio de Francia's conjecture on the almost everywhere convergence of Fourier series for matrix valued functions or a formulation of Fefferman-Stein's maximal inequality for noncommutative martingales. Reciprocally, I will also apply new techniques from quantum probability in noncommutative Lp embedding theory and the local theory of operator spaces. I have already obtained major results in this field, which might be useful towards a noncommutative form of weighted harmonic analysis and new challenging results on quantum information theory.

1 090 925 €

Start date: 2010-10-01, End date: 2015-09-30

Over many years, our research group has explored the complex relationship between cancer and ageing. As part of this work, we have generated mouse models of protease deficiency which are protected from cancer but exhibit accelerated ageing. Further studies with these mice have allowed us to unveil novel mechanisms of both normal and pathological ageing, to discover two new human progeroid syndromes, and to develop therapies for the Hutchinson-Gilford progeria syndrome, now in clinical trials. We have also integrated data from many laboratories to first define The hallmarks of ageing and the current possibilities for Metabolic control of longevity. Now, we propose to leverage our extensive experience in this field to further explore the relative relevance of cell-intrinsic and -extrinsic mechanisms of ageing. Our central hypothesis is that ageing derives from the combination of both systemic and cell-autonomous deficiencies which lead to the characteristic loss of fitness associated with this process. Accordingly, it is necessary to integrate multiple approaches to understand the mechanisms underlying ageing. This integrative and multidisciplinary project is organized around three major aims: 1) to characterize critical cell-intrinsic alterations which drive ageing; 2) to investigate ageing as a systemic process; and 3) to design intervention strategies aimed at expanding longevity. To fully address these objectives, we will use both hypothesis-driven and unbiased approaches, including next-generation sequencing, genome editing, and cell reprogramming. We will also perform in vivo experiments with mouse models of premature ageing, genomic and metagenomic studies with short- and long-lived organisms, and functional analyses with human samples from both progeria patients and centenarians. The information derived from this project will provide new insights into the molecular mechanisms of ageing and may lead to discover new opportunities to extend human healthspan.

2 456 250 €

Start date: 2017-09-01, End date: 2022-08-31

The belief that ‘the end of music is to move human affections’ (Descartes, Compendium musicae) has been a central issue in European musical thought since Plato. Opera was invented to recover the power of Ancient music to move the human heart, and its history is a permanent exploration of the capacity of action, words and music to convey emotions. In the eighteenth century a new type of opera consolidated with the chief concern of expressing the character’s emotions as they changed throughout the drama, inspired by Descartes’ theory of human passions. The key expressive medium was the aria col da capo, where a single, distinct passion was represented, like a concentrated pill of emotional meaning. The ideal corpus to study this issue are the 900 operas set to music by 300 composers on the 27 dramas by Pietro Metastasio (1698-1782). It contains a comprehensive catalogue of emotions in music, a unique window of opportunity to scrutinize conventions that defined music expression and meaning for over a century, paving the way for the emergence of ‘absolute’ instrumental music, autonomous from any other art form. DIDONE presents an innovative approach to unveil these conventions: the creation of a corpus of 4,000 digitized arias from 200 opera scores based on Metastasio’s eight most popular dramas, to be analysed using traditional methods and big data computer technology. The comparative scrutiny of dozens of different musical settings of the same librettos will reveal how composers correlate specific dramatic circumstances and emotions with distinct poetic and musical features. The results will be applicable to three main fields: (i) opera performance; (ii) analysis and interpretation of other types of music; and (iii) composition in several scenarios, from film soundtracks to creation by Artificial Intelligence. An opera festival will be designed to recover and disseminate this hitherto ignored repertoire, which was essential to define the European musical identity.

2 498 690 €

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

Understanding how organisms adapt to their environments is a long-standing problem in Biology with far-reaching implications: adaptation affects the ability of species to survive in changing environments, host-pathogen interactions, and resistance to pesticides and drugs. Despite recent progress, adaptation is to date a poorly understood process largely due to limitations of current approaches that focus (i) on a priori candidate genes, (ii) on signals of selection at the DNA level without functional validation of the identified candidates, and (iii) on small sets of adaptive mutations that do not represent the variability present in natural populations. As a result, major questions such as what is the relative importance of different types of mutations in adaptation?, and what is the importance of epigenetic changes in adaptive evolution?, remain largely unanswered. To gain a deep understanding of adaptation, we need to systematically identify adaptive mutations across space and time, pinpoint their molecular mechanisms and discover their fitness effects. To this end, Drosophila melanogaster has proven to be an ideal organism. Besides the battery of genetic tools and resources available, D. melanogaster has recently adapted to live in out of Africa environments. We and others have already shown that transposable elements (TEs) have substantially contributed to the adaptation of D. melanogaster to different environmental challenges. Here, we propose to use state-of-the-art techniques, such as Illumina TruSeq sequencing and CRISPR/Cas9 genome editing, to systematically identify and characterize in detail adaptive TE insertions in D. melanogaster natural populations. Only by moving from gathering anecdotic evidence to applying global approaches, we will be able to start constructing a quantitative and predictive theory of adaptation that will be relevant for other species as well.

2 392 521 €

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

This project aims at making a breakthrough contribution in the broad area of Control of Partial Differential Equations (PDE) and their numerical approximation methods by addressing key unsolved issues appearing systematically in real-life applications. To this end, we pursue three objectives: 1) to contribute with new key theoretical methods and results, 2) to develop the corresponding numerical tools, and 3) to build up new computational software, the DYCON-COMP computational platform, thereby bridging the gap to applications. The field of PDEs, together with numerical approximation and simulation methods and control theory, have evolved significantly in the last decades in a cross-fertilization process, to address the challenging demands of industrial and cross-disciplinary applications such as, for instance, the management of natural resources, meteorology, aeronautics, oil industry, biomedicine, human and animal collective behaviour, etc. Despite these efforts, some of the key issues still remain unsolved, either because of a lack of analytical understanding, of the absence of efficient numerical solvers, or of a combination of both. This project identifies and focuses on six key topics that play a central role in most of the processes arising in applications, but which are still poorly understood: control of parameter dependent problems; long time horizon control; control under constraints; inverse design of time-irreversible models; memory models and hybrid PDE/ODE models, and finite versus infinite-dimensional dynamical systems. These topics cannot be handled by superposing the state of the art in the various disciplines, due to the unexpected interactive phenomena that may emerge, for instance, in the fine numerical approximation of control problems. The coordinated and focused effort that we aim at developing is timely and much needed in order to solve these issues and bridge the gap from modelling to control, computer simulations and applications.

2 065 125 €

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

City growth is driven by a combination of systematic determinants and shocks. Random growth models predict realistic city size distributions but ignore, for instance, the strong empirical association between human capital and city growth. Models with systematic determinants predict degenerate size distributions. We will develop an integrated model that combines systematic and random determinants to explain the link between human capital, entrepreneurship and growth, while generating relevant city size distributions. We will calibrate the model to quantify the contribution of cities to aggregate growth. Urban growth also has a poorly understood spatial component. Combining gridded data of land use, population, businesses and roads for 3 decennial periods we will track the evolution of land use in the US with an unprecedented level of spatial detail. We will pay particular attention to the magnitude and causes of “slash-and-burn” development: instances when built-up land stops meeting needs in terms of use and intensity and, instead of being redeveloped, it is abandoned while previously open space is built up. Job-to-job flows across cities matter for efficiency and during the recent crisis they have plummeted. We will study them with individual social security data. Even if there have only been small changes in mismatch between unemployed workers and vacancies during the crisis, if workers shy away from moving to take a job in another city, misallocation can increase substantially. We will also study commuting flows for Spain and the UK based on anonymized cell phone location records. We will identify urban areas by iteratively aggregating municipalities if more than a given share of transit flows end in the rest of the urban area. We will also measure the extent to which people cross paths with others opening the possibility of personal interactions, and assess the extent to which this generates productivity-enhancing agglomeration economies.

1 292 586 €

Start date: 2016-08-01, End date: 2021-07-31

This project aims to reformulate and generalize standard theories of human health and mortality. It proposes new formal models and a systematic agenda to empirically test hypotheses that link developmental biology, epigenetics and adult human illness, disability and mortality. We seek to break new ground developing innovative formal models for illnesses and mortality, testing new hypotheses about the evolution of human health and, to the extent permitted by findings, reformulating standard theories to make them applicable to a less restrictive segment of populations than they are now. Over the past two decades there has been massive growth of research on the nature of delayed adult effects of conditions experienced in early life. This field of research is known as the Developmental Origins of Adult Health and Disease (DOHaD). Increasing evidence suggests that the mechanisms that are implicated are epigenetic and constitute an evolved adaptation selected over thousands of years to improve fitness in changing landscapes. The emergence of DOHaD is as close as we will ever come to a paradigmatic shift in the study of human health, disability and mortality. The most tantalizing possibility is that advances in our understanding of epigenetic mechanisms will shed light on pathways linking early exposures and delayed adult health thus fundamentally transforming our understanding of human illnesses and, in one fell swoop, bridge population health, epigenetics, and developmental and evolutionary biology. The overarching goal of this project is to contribute to this nascent area of study by (a) proposing new formal demographic models of health, disability and mortality; (b) empirically testing DOHaD predictions with population data; (c) testing a microsimulation model to verify DOHaD predictions about two conditions, obesity and Type 2 Diabetes, and (d) assessing the adult health, disability and mortality toll implicated by relations between early conditions, obesity and T2D.

2 852 655 €

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

DSGE models are the standard tool of quantitative macroeconomics. We use them to measure economics phenomena and to provide policy advice. However, since Kydland and Prescott s 1982, the profession has fought about how to take these models to the data. Kydland and Prescott proposed to calibrate their model. Why? Macroeconomists could not compute their models efficiently. Moreover, the techniques required for estimating DSGE models using the likelihood did not exist. Finally, models were ranked very badly by likelihood ratio tests. Calibration offered a temporary solution. By focusing only on a very limited set of moments of the model, researchers could claim partial success and keep developing their theory. The landscape changed in the 1990s. There were developments along three fronts. First, macroeconomists learned how to efficiently compute equilibrium models with rich dynamics. Second, statisticians developed simulation techniques like Markov chain Monte Carlo (MCMC), which we require to estimate DSGE models. Third, and perhaps most important, computer power has become so cheap that we can now do things that were unthinkable 20 years ago. This proposal tries to estimate non-linear and/or non-normal DSGE models using a likelihood approach. Why non-linear models? Previous research has proved that second order approximation errors in the policy function have first order effects on the likelihood function. Why non-normal models? Time-varying volatility is key to understanding the Great Moderation. Kim and Nelson (1999), McConnell and Pérez-Quirós (2000), and Stock and Watson (2002) have documented a decline in the variance of output growth since the mid 1980s. Only DSGE models with richer structure than normal innovations can account for this.

909 942 €

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

This project aims to understand the role of effort in the reproduction of social inequality. While large-scale test programs like PISA have produced impressive amounts of data on the determinants of cognitive abilities, there is scant evidence on socio-economic differences in cognitive effort. Better understanding the social origins of effort pushes the frontier of knowledge on intergenerational mobility and allows improving equality of opportunity. Specifically, the aim of the project is to answer three research questions: 1. To what extent do children’s effort levels differ by parental socioeconomic background? (descriptive component). 2. Can existing disparities in effort by social background be explained by (a) the intergenerational transmission of effort from parents to children, and (b) varying motivations and differential susceptibility to incentives? (analytical component). 3. What are the best techniques to measure cognitive effort and what are the strengths and weaknesses of measures routinely used in different scientific disciplines? (methodological component). The project will develop and exploit cutting-edge methods of effort measurement such as real-effort tasks and psychophysiological techniques like pupillometry. Their immense potential has remained untapped in inequality research thus far. Experimental data will be collected for a large sample of school-age children and their parents in Spain and Germany. Subjective effort dispositions will be further analyzed using (inter)national surveys. The triangulation of carefully chosen methodologies will provide the first reliable evidence on socioeconomic differences in effort and stimulate new research (e.g. on gender or ethnic differentials in effort). Cross-validation analysis will detect possible biases of commonly used effort measures. The research findings will provide valuable insights for educational practitioners and decisive evidence for normative debates about social inequality and policy design.

1 499 572 €

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

In contrast to human or rodent embryos, ungulate embryos do not implant into the uterus right after blastocyst hatching. Before implantation, the hatched ungulate blastocyst must undergo dramatic morphological changes characterized by cell differentiation, proliferation and migration processes leading to the development of extra-embryonic membranes, the appearance of a flat embryonic disc and gastrulation. This prolonged preimplantation development is termed conceptus elongation and deficiencies on this process constitute the most frequent cause of reproductive failures in ungulates, including the 4 most relevant mammalian livestock species in Europe. The purpose of this project is to elucidate the factors involved in conceptus elongation by gene editing and in vitro culture approaches. A first objective will be to identify key genes involved in differentiation processes by RNA-seq analysis of different embryo derivatives from bovine conceptuses at different developmental stages. Subsequently, the function of some of the genes identified as well as others known to play a crucial role in mouse development or putatively involved in embryo-maternal interactions will be assessed. For this aim, bovine embryos in which a candidate gene has been ablated (KO) will be generated by CRISPR and transferred to recipient females to assess in vivo the function of such particular gene on conceptus development. A second set of experiments pursue the development of an in vitro system for conceptus elongation that would bypass the requirement for in vivo experiments. For this aim we will perform metabolomics and proteomics analyses of bovine uterine fluid at different stages and will use these data to rationally develop a culture system able to sustain conceptus development. The knowledge generated by this project will serve to develop strategies to enhance farming profitability by reducing embryonic loss and to understand Developmental Biology questions unanswered by the mouse model.

1 480 880 €

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

For many years, mitochondria were viewed as semiautonomous organelles, required only for cellular energetics. This view has been displaced by the concept that mitochondria are fully integrated into the life of the cell and that mitochondrial function and stress response rapidly affect other organelles, and even other tissues. A recent discovery from my lab demonstrated that mitochondrial metabolism regulates lysosomal degradation (Cell Metabolism, 2015), thus opening the way to investigate the mechanism behind communication between these organelles and its consequences for homeostasis. With this proposal, we want to assess how mitochondrial crosstalk with endolysosomal compartment controls cellular homeostasis and how mitochondrial dysfunction in certain tissues may account for systemic effects on the rest of the organism. EndoMitTalk will deliver significant breakthroughs on (1) the molecular mediators of endolysosomal-mitochondria communication, and how deregulation of this crosstalk alters cellular (2), and organism homeostasis (3). Our central goals are: 1a,b. To identify metabolic and physical connections mediating endolysosomal-mitochondria crosstalk; 2a. To decode the consequences of altered interorganelle communication in cellular homeostasis 2b. To study the therapeutic potential of improving lysosomal function in respiration-deficient cells; 3a. To assess how unresolved organelle dysfunction and metabolic stresses exclusively in immune cells affects organism homeostasis and lifespan. 3b. To decipher the molecular mediators by which organelle dysfunction in T cells contributes to age-associated diseases, with special focus in cardiorenal and metabolic syndromes. In sum, EndoMitTalk puts forward an ambitious and multidisciplinary but feasible program with the wide purpose of understanding and improving clinical interventions in mitochondrial diseases and age-related pathologies.

1 498 625 €

Start date: 2017-03-01, End date: 2022-02-28

"The Environmental Justice Atlas (www.ejatlas.org) is a global database built by us, drawing on activist and academic knowledge. It maps 1500 conflicts. To improve geographical and thematic coverage it will grow to 3000 by 2019. It systematizes conflicts across 100+ fields documenting the commodities at stake, the actors involved, impacts, forms of mobilizations and outcomes allowing analyses that will lead to a general theory of ecological distribution conflicts. We shall research the links between changes in social metabolism and resource extraction conflicts at the “commodity frontiers”. Also other questions in political ecology and social movement theory such as the effectiveness of direct action by grassroots protesters compared to institutional forms of contention. Does the involvement of different actors, e.g. indigenous groups, relate to different conflict outcomes? How often does the IUCN ally itself to ""the environmentalism of the poor""? Do mobilizations and outcomes vary across sectors (mining, hydroelectric dams, waste incinerators) according to project differences in economic and biophysical dimensions, environmental and health risks? Are conflicts on point resources (mining, oil extraction) regularly different from conflicts in agriculture? Can we track networked resistances against Western companies, compared to those from China or other countries? Resistance to environmental damage has brought into being many local and some international EJOs pushing for alternative social transformations. We shall study the Vocabulary of Environmental Justice they deploy: climate justice, water justice, food sovereignty, biopiracy, sacrifice zones, and other terms specific to countries: Chinese “cancer villages”, Indian “sand mafias”, Brazilian “green deserts” (eucalyptus plantations). Finally, are there signs of an alliance between the Global Environmental Justice Movement and the small European movement for “prosperity without growth”, décroissance, Post-Wachstum?"

1 910 811 €

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

Almost half of the human genome is made of Transposable Elements (TEs), whose ongoing activity continually impacts our genome. However, little is known about how the host regulates TEs and their genomic and epigenomic impacts. EpiPluriRetro will advance research in a new groundbreaking concept: that TEs are active in our pluripotent genome, and that epigenetic regulation is employed therein to regulate TE activity. LINE-1 retrotransposons comprise approximately 20% of the mammalian genome, and L1 retrotransposition events can create genetic diversity by a variety of mechanisms. From acting as simple insertion mutagens to inducing other complex genomic alterations it is becoming increasingly evident that the activity of TEs is a major force driving human genome evolution. It has been demonstrated that the main mutagenic load associated with TE mobilization occurs during early human embryogenesis (i.e., our pluripotent genome). EpiPluriRetro will examine how epigenetic mechanisms influence LINE-1 retrotransposition in pluripotent cells. To do that, we will combine genetic, biochemical and genomics approaches to identify pluripotent host factors that influence the fate of LINE-1 retrotransposition. In addition, EpiPluriRetro will analyze the impact of LINE-1 insertions in our pluripotent genome and the Epimutagenic impact of new LINE-1 mobilization events in pluripotent cells. To do that, we have developed an innovative approach to analyze the effect of LINE-1 insertions within human genes without biases, including epigenetic alterations induced by a new L1 insertion. EpiPluriRetro will help to understand how the activity of TEs is controlled in our heritable genome, which will directly impact our knowledge in how new genetic diseases are generated in humans. In addition, EpiPluriRetro will allow us to describe a new concept in human biology, as we will analyze how new TE insertions can modify the chromatin status of flanking genomic regions where they insert.

1 453 800 €

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

This project aims to investigate the extent to which current trends in family formation, living arrangements and gender-specific education levels are related to the spatial distribution of welfare and the emergence of jobless households in contemporary societies. Inter alia, we aim to explore whether the welfare disequalizing, impoverishing and polarizing effects that are currently associated with recent patterns in assortative mating, lone parenthood and household composition are offset by an unprecedented phenomenon that is sweeping the world during the last decades: the rapid process education expansion in tandem with a reversal of the gender gap in education. The extent to which these two opposing forces occur and which of them is more influential in shaping the distribution of welfare between and within countries is among the main goals of this project. To this end, we will draw upon a variety of household surveys and the world largest sources of census microdata: the Integrated Public Use Microdata Series (IPUMS) project and the Latin American and Caribbean Demographic Centre. Because of their unparalleled geographical coverage and detail, these sources of data constitute exceptional instruments to study socio-demographic phenomena that have been vastly underutilized by the international research community. Triangulating our analysis at the micro, meso and macro levels, we will establish formal linkages between welfare distributions and its socio-demographic correlates to unveil insightful relationships that have been unsatisfactorily explored so far because of the lack of appropriately harmonized, sufficiently detailed and georeferenced datasets. We will strongly emphasize the spatial distribution of variables to unravel local patterns that might take place at highly disaggregated levels, therefore not being discernible to traditional (not as finely-grained) approaches.

1 174 500 €

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

Evolution of animal morphology relies on changes in developmental programs that control body plans and organ shape. Such changes are thought to arise form alteration of the expression of functionally conserved developmental genes and their vast downstream networks. Although this hypothesis has a profound impact on the way we view animal evolution, final proof is still lacking. The hypothesis calls for evolution to take place mainly through modifications of cis-regulatory elements (CREs) controlling gene expression. However, these genomic regions are precisely those that we understand the least and, until recently, basic knowledge on how regulatory information is organized in the 3D genome or how to spatio-temporally assign CREs to their target genes was unknown. The advent of next generation sequencing-based tools has made possible to identify genome-wide CREs and reveal how they are organized in the 3D genome. But this new knowledge has been largely ignored by most hypotheses on the evolution of gene expression, development and animal morphology. These new high-throughput methods have been mainly restricted to selected model organisms, and due to the lack of sequence conservation of CREs across lineages, we still have very limited information about the impact of CREs on animal morphology evolution. By integrating in a systematic and phylogenetically driven manner the contribution of CREs and their 3D organization to animal morphology at different evolutionary scales, we will for the first time link evolution, regulatory information, genome 3D architecture and morphology. We will apply this strategy to study animal morphology along the evolution of deuterostome body plans, the generation of fin morphological diversity in vertebrates, and the recent phenotypic changes in fish adapted to cave environments. Our proposal will make ground-breaking advances in our understanding of the global principles underlying the evolution of cis-regulatory DNA and animal form.

2 499 514 €

Start date: 2017-09-01, End date: 2022-08-31

The project applies a multiple equilibrium framework to understand ongoing transformations in family demography and their consequences for social inequalities. Associated with the changing economic role of women emerge novel family forms that replace the conventional male breadwinner model. The transition is very much in flux, producing multiple equilibria some of which are unstable and associated with inefficient and inequitable couple specialization. Based on long micro panel data for four countries at different stages of the transition, the study will address three parallel issues. One, identifying equilibrium shifts from the traditional towards more gender symmetric family forms, with particular focus on the endogenously driven dynamics that drive populations towards a gender egalitarian equilibrium. Two, analyzing the potentially polarizing demographic correlates of changing family behaviour in particular in terms of marital choice and couple stability. Three, testing hypotheses regarding family polarization with respect to parental investments in children and how these, in turn, influence children’s life chances.

2 098 860 €

Start date: 2011-06-01, End date: 2016-05-31

The popularization of information technology and the Internet has resulted in an unprecedented growth in the scale at which individuals and institutions generate, communicate and access information. In this context, the effective leveraging of the vast amounts of available data to discover and address people's needs is a fundamental problem of modern societies. Since most of this circulating information is in the form of written or spoken human language, natural language processing (NLP) technologies are a key asset for this crucial goal. NLP can be used to break language barriers (machine translation), find required information (search engines, question answering), monitor public opinion (opinion mining), or digest large amounts of unstructured text into more convenient forms (information extraction, summarization), among other applications. These and other NLP technologies rely on accurate syntactic parsing to extract or analyze the meaning of sentences. Unfortunately, current state-of-the-art parsing algorithms have high computational costs, processing less than a hundred sentences per second on standard hardware. While this is acceptable for working on small sets of documents, it is clearly prohibitive for large-scale processing, and thus constitutes a major roadblock for the widespread application of NLP. The goal of this project is to eliminate this bottleneck by developing fast parsers that are suitable for web-scale processing. To do so, FASTPARSE will improve the speed of parsers on several fronts: by avoiding redundant calculations through the reuse of intermediate results from previous sentences; by applying a cognitively-inspired model to compress and recode linguistic information; and by exploiting regularities in human language to find patterns that the parsers can take for granted, avoiding their explicit calculation. The joint application of these techniques will result in much faster parsers that can power all kinds of web-scale NLP applications.

1 481 747 €

Start date: 2017-02-01, End date: 2022-01-31

The research of this proposal is focused on solving problems that involve the evolution of fluid interfaces. The project will investigate the dynamics of free boundaries arising between incompressible fluids of different nature. The main concern is well-posed scenarios which include the possible formation of singularities in finite time or existence of solutions for all time. These contour dynamics issues are governed by fundamental fluid mechanics equations such as the Euler, Navier-Stokes, Darcy and quasi-geostrophic systems. They model important problems such as water waves, viscous waves, Muskat, interface Hele-Shaw and SQG sharp front evolution. All these contour dynamics frameworks will be studied with emphasis on singularity formation and global existence results, not only for their importance in mathematical physics, but also for their mathematical interest. This presents huge challenges which will in particular require the use of different tools and methods from several areas of mathematics. A new technique, introduced to the field by the Principal Investigator, has already enabled the analysis of several singularity formations for the water waves and Muskat problems, as well as to obtain global existence results for Muskat. The main goal of this proposal is to develop upon this work, going far beyond the state of the art in these contour dynamics problems for incompressible fluids.

1 106 936 €

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

Gadd45 family proteins play a critical role in genomic stability, cell cycle regulation proliferation and apoptosis. Gadd45a is activated by the tumor suppressor gene p53, which is mutated in >50% of human tumors. The lack of GADD45a in mice leads to spontaneous development of an autoimmune disease similar to systemic lupus erythematosus. The molecular mechanisms that cause autoimmunity are poorly understood. Recent evidence suggests that p38 activation is involved in autoimmune development and tumor suppression. We found that Gadd45a negatively regulates p38 activity in T cells by preventing phosphorylation on Tyr323. Inhibition of Tyr323p38 phosphorylation is a potential therapeutic target in several types of leukemia and autoimmune diseases, including lupus and rheumatoid arthritis. The main goals of this project are a) to study the in vivo function of the Gadd45 family and p38 in tumor suppression and autoimmunity, and b) to analyze their molecular mechanisms to identify targets for disease treatment. We will dissect the signaling pathways involved in development of autoimmunity and cancer using a multidisciplinary approach that combines mouse genetic, human epigenetic, biochemical, molecular biological and immunological techniques. Our project involves the characterization of murine models deficient in each member of the Gadd45 family (Gadd45a, Gadd45b, Gadd45g), as well as double- and triple-knockout mice, development of a knock-in model for p38a, in vivo and in vitro analysis of T cell activation, proliferation, apoptosis and differentiation, epigenetic studies of potential targets, and finally, validation of these results in autoimmune disease and cancer patients. The results of this project will help identify new therapeutic targets for autoimmune diseases and/or cancer.

1 755 805 €

Start date: 2008-09-01, End date: 2014-08-31

In the last decade the approaches of the global history have been emphasized in order to visualize the progress, form and method which historians have undertaken when carrying out ambitious research projects to analyse and compare diverse geographical and cultural areas of Asia and Europe. But when dealing with comparisons and cross-cultural studies in Europe and Asia, some scholarly works have exceeded of ambiguities when defining geographical units as well as chronology. In this project I examine perceptions and dialogues between China and Europe by analysing strategic geopolitical sites which fostered commerce, consumption and socioeconomic networks between China and Europe through a particular case study: Macau, connecting with South China, and Marseille in Mediterranean Europe. How did foreign merchant networks and trans-national communities of Macau and Marseille operate during the eighteenth century and contribute to somehow transfer respectively European and Chinese socio-cultural habits and forms in local population? What was the degree and channels of consumption of European goods in China and Chinese goods in Europe? These are the main questions to answer during my research to explore the bilateral Sino-European trade relations and how the trans-national dimension of exotic commodities changed tastes by creating a new type of global consumerism. Such concrete comparison can help to narrow the gap that some researchers have created when widely analysing differences between Asia and Europe without a specific geographical and chronological delineation. The major novelty of this project is based on the use of Chinese and European sources to study changes in consumer behaviour. The principal investigator of the project works in China which is and added value for the achievement of outstanding results. So the expected results will bring an obvious breakthrough by adding the specific part of the project in which each team member will work.

1 499 625 €

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

"Cell-cell synapses are an exquisitely evolved means of communication between cells. During the formation of the immune synapse (IS), diverse transmembrane and membrane associated molecules are reorganized into a highly segregated structure at the T cell–Antigen-Presenting Cell (APC) contact site. As part of this process, the tubulin cytoskeleton is vectorially directed toward the center of the IS, where the microtubule-organizing center (MTOC) localizes. MTOC translocation is an early event in IS formation that brings the secretory apparatus into close apposition with the APC, thus providing the basis for polarized secretion. The proposal aims to define how the MTOC controls cytoskeletal rearrangement and communication at the IS, as a mechanism for macromolecule transport and nucleation of signalling molecules during synaptic contact. We will study the mechanisms of MTOC-mediated polarization of multivesicular bodies (MVB) and exosome delivery during IS formation, and will assess the role in these processes of MTOC translocation regulators (HDAC6) and microtubule (MT) polymerization promoters (Plk1 and EB1). MTOC-dependent mitochondrial polarization to the IS will be assessed as a bioenergetic source for cytoskeletal rearrangements, IS maturation and polarized exosomal delivery. In particular, our proposed study of the possible horizontal transfer of miRNAs during cognate interactions between immune cells has the potential to reveal how miRNAs can control the early initiation of immunity. We will investigate the mechanism of directional transfer of RNA-harbouring exosomes at the IS from T cell to APC, and will examine the functional consequences of this transfer on APC biology and on the immune response. These studies will open avenues for the treatment of immune-related diseases."

2 011 200 €

Start date: 2012-02-01, End date: 2017-01-31

Globalization is expanding economic borders rapidly. Barriers to trade are now lower than ever and this has led to the creation of many truly global goods and asset markets. And yet globalization is changing political borders only slowly. The second wave of globalization that started after WWII found the world organized into a set of states or centralized jurisdictions that often go beyond cultural borders but that clearly fall short of economic borders. These centralized jurisdictions still hold most of the political and decision-making power. This growing mismatch between markets and states lowers the quality of economic policymaking. Since constituencies are located inside the state, governments tend to disregard effects of economic policies that are felt beyond the political border. The result is a worsening in policymaking that could seriously mitigate the gains from globalization and even turn them into losses. The goal of this project is to improve our understanding of how this growing mismatch between economic and political borders affects economic policy and political structure. In particular, it focuses on the inefficiencies this mismatch creates and on how should we (“the citizens of the world”) handle them. The project is organized around two themes. The first one is the handling of enforcement externalities. One of the key roles of governments is to enforce contracts. When these contracts involve domestic and foreign residents, governments have the temptation to enforce selectively so as to shift income to domestic residents at the expense of foreigners. The second theme is the evolution of political structure. The world is currently organized into state or centralized jurisdictions. This project studies the hypothesis that globalization leads to an alternative political structure based on a set of overlapping jurisdictions.

1 080 000 €

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

Glioma is the most common and aggressive tumour of the brain and its most malignant form, glioblastoma multiforme, is nowadays virtually not curable. Very little is known about glioma genesis and progression at the molecular level and not much progress has been achieved in the treatment of this disease during the last years. The understanding of the molecular mechanisms involved in the biology of glioma is essential for the development of successful and rational therapeutic strategies. Our project aims to: 1- Study the role of the TGF-beta, Shh, Notch, and Wnt signal transduction pathways in glioma. These pathways have been implicated in glioma but still not much is known about their specific mechanisms of action. 2- Study of a cell population within the tumour mass that has stem-cell-like characteristics, the glioma stem cells, and how the four mentioned pathways regulate their biology. 3- Study the role of a transcription factor, FoxG1, that has an important oncogenic role in some gliomas and that it is regulated by the four mentioned pathways interconnecting some of them. Our approach will be based on a tight collaboration with clinical researchers of our hospital and the study of patient-derived tumours. We will analyse human biopsies, generate primary cultures of human tumour cells, isolate the stem-cell-like population of patient-derived gliomas and generate mouse models for glioma based on the orthotopical inoculation of human glioma stem cells in the mouse brain to generate tumours with the same characteristics as the original human tumour. In addition, we will also study genetically modified mouse models and established cell lines. We expect that our results will help understand the biology of glioma and cancer, and we aspire to translate our discoveries to a more clinical ambit identifying molecular markers of diagnosis and prognosis, markers of response to therapies, and unveil new therapeutic targets against this deadly disease.

1 566 000 €

Start date: 2008-08-01, End date: 2014-07-31