ERC FUNDED PROJECTS

"Background: Osteoarthritis (OA) is a common musculoskeletal disease occurring worldwide. Despite extensive research, etiology of OA is still poorly understood. Histopathological grading (HPG) of 2D tissue sections is the gold standard reference method for determination of OA stage. However, traditional 2D-HPG is destructive and based only on subjective visual evaluation. These limitations induce bias to clinical in vitro OA diagnostics and basic research that both rely strongly on HPG. Objectives: 1) To establish and validate the very first 3D-HPG of OA based on cutting-edge nano/micro-CT (Computed Tomography) technologies in vitro; 2) To use the established method to clarify the beginning phases of OA; and 3) To validate 3D-HPG of OA for in vivo use. Methods: Several hundreds of human osteochondral samples from patients undergoing total knee arthroplasty will be collected. The samples will be imaged in vitro with nano/micro-CT and clinical high-end extremity CT devices using specific contrast-agents to quantify tissue constituents and structure in 3D in large volume. From this information, a novel 3D-HPG is developed with statistical classification algorithms. Finally, the developed novel 3D-HPG of OA will be applied clinically in vivo. Significance: This is the very first study to establish 3D-HPG of OA pathology in vitro and in vivo. Furthermore, the developed technique hugely improves the understanding of the beginning phases of OA. Ultimately, the study will contribute for improving OA patients’ quality of life by slowing the disease progression, and for providing powerful tools to develop new OA therapies."

1 500 000 €

Start date: 2014-02-01, End date: 2019-01-31

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

Integrins are transmembrane cell adhesion receptors controlling cell proliferation and migration. Our objective is to gain fundamentally novel mechanistic insight into the emerging new roles of integrins in cancer and to generate a road map of integrin dependent pathways critical in mammary gland development and integrin signalling thus opening new targets for therapeutic interventions. We will combine an in vivo based translational approach with cell and molecular biological studies aiming to identify entirely novel concepts in integrin function using cutting edge techniques and synthetic-biology tools. The specific objectives are: 1) Integrin inactivation in branching morphogenesis and cancer invasion. Integrins regulate mammary gland development and cancer invasion but the role of integrin inactivating proteins in these processes is currently completely unknown. We will investigate this using genetically modified mice, ex-vivo organoid models and human tissues with the aim to identify beneficial combinational treatments against cancer invasion. 2) Endosomal adhesomes – cross-talk between integrin activity and integrin “inside-in signaling”. We hypothesize that endocytosed active integrins engage in specialized endosomal signaling that governs cell survival especially in cancer. RNAi cell arrays, super-resolution STED imaging and endosomal proteomics will be used to investigate integrin signaling in endosomes. 3) Spatio-temporal co-ordination of adhesion and endocytosis. Several cytosolic proteins compete for integrin binding to regulate activation, endocytosis and recycling. Photoactivatable protein-traps and predefined matrix micropatterns will be employed to mechanistically dissect the spatio-temporal dynamics and hierarchy of their recruitment. We will employ innovative and unconventional techniques to address three major unanswered questions in the field and significantly advance our understanding of integrin function in development and cancer.

1 887 910 €

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

Our tissues are constantly renewed by stem cells. Over time, stem cells accumulate cellular damage that will compromise renewal and results in aging. As stem cells can divide asymmetrically, segregation of harmful factors to the differentiating daughter cell could be one possible mechanism for slowing damage accumulation in the stem cell. However, current evidence for such mechanisms comes mainly from analogous findings in yeast, and studies have concentrated only on few types of cellular damage. I hypothesize that the chronological age of a subcellular component is a proxy for all the damage it has sustained. In order to secure regeneration, mammalian stem cells may therefore specifically sort old cellular material asymmetrically. To study this, I have developed a novel strategy and tools to address the age-selective segregation of any protein in stem cell division. Using this approach, I have already discovered that stem-like cells of the human mammary epithelium indeed apportion chronologically old mitochondria asymmetrically in cell division, and enrich old mitochondria to the differentiating daughter cell. We will investigate the mechanisms underlying this novel phenomenon, and its relevance for mammalian aging. We will first identify how old and young mitochondria differ, and how stem cells recognize them to facilitate the asymmetric segregation. Next, we will analyze the extent of asymmetric age-selective segregation by targeting several other subcellular compartments in a stem cell division. Finally, we will determine whether the discovered age-selective segregation is a general property of stem cell in vivo, and it's functional relevance for maintenance of stem cells and tissue regeneration. Our discoveries may open new possibilities to target aging associated functional decline by induction of asymmetric age-selective organelle segregation.

1 500 000 €

Start date: 2016-05-01, End date: 2021-04-30

This project focuses on one of the most fascinating events of the long history of the human species: the origins and spread of agriculture. Research over the past 40 years has provided an invaluable dataset on crop domestication and the spread of agriculture into Europe. However, despite the enormous advances in research there are important areas that remain almost unexplored, some of immense interest. This is the case of the western Mediterranean region from where our knowledge is still limited (Iberian Peninsula) or almost inexistent (northern Morocco). The last few years have witnessed a considerable increase in archaeobotany and the effort of a group of Spanish researchers working together in different aspects of agriculture has started to produce the first results. My proposal will approach the study of the arrival of agriculture to the western Mediterranean by exploring different interrelated research areas. The project involves the application of different techniques (analysis of charred plant remains, pollen and non-pollen microfossils, phytoliths, micro-wear analyses, isotopes, soil micromorphology, genetics, and ethnoarchaeology) which will help to define the emergence and spread of agriculture in the area, its likely place of origin, its main technological attributes as well as the range crop husbandry practices carried out. The interaction between the different approaches and the methodologies involved will allow achieving a greater understanding of the type of agriculture that characterized the first farming communities in the most south-western part of Europe.

1 545 169 €

Start date: 2009-04-01, End date: 2013-03-31

"When I asked my seven-year-old daughter ""Who is the boy in your class who was also new in school last year, like you?"", she instantly replied ""Daniel"", using the descriptive content in my utterance to identify an entity in the real world and refer to it. The ability to use language to refer to reality is crucial for humans, and yet it is very difficult to model. AMORE breaks new ground in Computational Linguistics, Linguistics, and Artificial Intelligence by developing a model of linguistic reference to entities implemented as a computational system that can learn its own representations from data. This interdisciplinary project builds on two complementary semantic traditions: 1) Formal semantics, a symbolic approach that can delimit and track linguistic referents, but does not adequately match them with the descriptive content of linguistic expressions; 2) Distributional semantics, which can handle descriptive content but does not associate it to individuated referents. AMORE synthesizes the two approaches into a unified, scalable model of reference that operates with individuated referents and links them to referential expressions characterized by rich descriptive content. The model is a distributed (neural network) version of a formal semantic framework that is furthermore able to integrate perceptual (visual) and linguistic information about entities. We test it extensively in referential tasks that require matching noun phrases (“the Medicine student”, “the white cat”) with entity representations extracted from text and images. AMORE advances our scientific understanding of language and its computational modeling, and contributes to the far-reaching debate between symbolic and distributed approaches to cognition with an integrative proposal. I am in a privileged position to carry out this integration, since I have contributed top research in both distributional and formal semantics. "

1 499 805 €

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

Blood and lymphatic vessels have been the subject of intense investigation due to their important role in cancer development and in cardiovascular diseases. The significant advance in the methods used to modify and analyse gene function have allowed us to obtain a much better understanding of the molecular mechanisms involved in the regulation of the biology of blood vessels. However, there are two key aspects that significantly diminish our capacity to understand the function of gene networks and their intersections in vivo. One is the long time that is usually required to generate a given double mutant vertebrate tissue, and the other is the lack of single-cell genetic and phenotypic resolution. We have recently performed an in vivo comparative transcriptome analysis of highly angiogenic endothelial cells experiencing different VEGF and Notch signalling levels. These are two of the most important molecular mechanisms required for the adequate differentiation, proliferation and sprouting of endothelial cells. Using the information generated from this analysis, the overall aim of the proposed project is to characterize the vascular function of some of the previously identified genes and determine how they functionally interact with these two signalling pathways. We propose to use novel inducible genetic tools that will allow us to generate a spatially and temporally regulated fluorescent cell mosaic matrix for quantitative analysis. This will enable us to analyse with unprecedented speed and resolution the function of several different genes simultaneously, during vascular development, homeostasis or associated diseases. Understanding the genetic epistatic interactions that control the differentiation and behaviour of endothelial cells, in different contexts, and with high cellular definition, has the potential to unveil new mechanisms with high biological and therapeutic relevance.

1 481 375 €

Start date: 2015-03-01, End date: 2020-02-29

Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.

1 999 770 €

Start date: 2018-05-01, End date: 2023-04-30

"A conventional assumption in dynamic models is that agents form their expectations in a very sophisticated manner. In particular, that they have Rational Expectations (RE). We develop some tools to relax this assumption while retaining fully optimal behaviour by agents. We study implications for asset pricing and macro policy. We assume that agents have a consistent set of beliefs that is close, but not equal, to RE. Agents are ""Internally Rational"", that is, they behave rationally given their system of beliefs. Thus, it is conceptually a small deviation from RE. It provides microfoundations for models of adaptive learning, since the learning algorithm is determined by agents’ optimal behaviour. In previous work we have shown that this framework can match stock price and housing price fluctuations, and that policy implications are quite different. In this project we intend to: i) develop further the foundations of internally rational (IR) learning, ii) apply this to explain observed asset price price behavior, such as stock prices, bond prices, inflation, commodity derivatives, and exchange rates, iii) extend the IR framework to the case when agents entertain various models, iv) optimal policy under IR learning and under private information when some hidden shocks are not revealed ex-post. Along the way we will address policy issues such as: effects of creating derivative markets, sovereign spread as a signal of sovereign default risk, tests of fiscal sustainability, fiscal policy when agents learn, monetary policy (more specifically, QE measures and interest rate policy), and the role of credibility in macro policy."

1 970 260 €

Start date: 2013-06-01, End date: 2018-08-31

The objective of this project is to overcome current limitations for antibody production that are inherent to the extant immune system of vertebrates. This will be done by creating an all-in-one artificial/synthetic counterpart based exclusively on prokaryotic parts, devices and modules. To this end, ARISYS will exploit design concepts, construction hierarchies and standardization notions that stem from contemporary Synthetic Biology for the assembly and validation of (what we believe is) the most complex artificial biological system ventured thus far. This all-bacterial immune-like system will not only simplify and make affordable the manipulations necessary for antibody generation, but will also permit the application of such binders by themselves or displayed on bacterial cells to biotechnological challenges well beyond therapeutic and health-related uses. The work plan involves the assembly and validation of autonomous functional modules for [i] displaying antibody/affibody (AB) scaffolds attached to the surface of bacterial cells, [ii] conditional diversification of target-binding sequences of the ABs, [iii] contact-dependent activation of gene expression, [iv] reversible bi-stable switches, and [v] clonal selection and amplification of improved binders. These modules composed of stand-alone parts and bearing well defined input/output functions, will be assembled in the genomic chassis of streamlined Escherichia coli and Pseudomonas putida strains. The resulting molecular network will make the ABs expressed and displayed on the cell surface to proceed spontaneously (or at the user's decision) through subsequent cycles of affinity and specificity maturation towards antigens or other targets presented to the bacterial population. In this way, a single, easy-to-handle (albeit heavily engineered) strain will govern all operations that are typically scattered in a multitude of separate methods and apparatuses for AB production.

2 422 271 €

Start date: 2013-05-01, End date: 2019-04-30

The ARTSOUNDSCAPES project deals with sound, rock art and sacred landscapes among past hunter-gatherers and early agricultural societies around the world. The potential of sound to stimulate powerful emotions makes it a common medium for conferring places with extraordinary agency. Ethnographic and ethnohistorical sources indicate that these sites are often endowed with a sacred significance and, in many cases, they also receive special treatment, including the production of rock paintings. Despite the aural experience being an integral component of the human condition and a key element in ritual, archaeology has largely been unable to study it systematically. Rock art landscapes are no exception and, although some studies have been made, they have largely been reproached for their lack of scientific rigour and subjectivity. ARTSOUNDSCAPES will fully address this weakness by investigating the perception of sound in rock art landscapes from an interdisciplinary approach. Borrowing methods developed in acoustic engineering, the project will assess, from an objective and quantitative perspective, the acoustic properties of rock art landscapes in selected areas around the world: the Western/Central Mediterranean in Europe, Siberia in Asia, and Baja California in North America. Human experiences associated with altered or mystical states invoked by the identified special sonic characteristics of these landscapes will be further tested by exploring the psychoacoustic effects these soundscapes have on people and their neural correlate to brain activity. The project will also thoroughly survey ethnographic attitudes to sacred soundscapes based on both current premodern societies and ethnohistorical sources. The groundbreaking combination of this array of interdisciplinary approaches will facilitate the ultimate aim of the project: to propose a phenomenological understanding of sacred soundscapes among late hunter-gatherers and early agriculturalists around the world.

2 239 375 €

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

The long-term goal of this proposal is to explore a novel immune pathway that involves an unexpected interplay between marginal zone (MZ) B cells and neutrophils. MZ B cells are strategically positioned at the interface between the immune system and the circulation and rapidly produce protective antibodies to blood-borne pathogens through a T cell-independent pathway that remains poorly understood. We recently found that the human spleen contains a novel subset of B cell helper neutrophils (NBH cells) with a phenotype and gene expression profile distinct from those of conventional circulating neutrophils (NC cells). In this proposal, we hypothesize that NC cells undergo splenic reprogramming into NBH cells through an IL-10-dependent pathway involving perifollicular sinusoidal endothelial cells. We contend that these unique endothelial cells release NC cell-attracting chemokines and IL-10 upon sensing blood-borne bacteria through Toll-like receptors. We also argue that IL-10 from sinusoidal endothelial cells stimulates NC cells to differentiate into NBH cells equipped with powerful MZ B cell-stimulating activity. The following three aims will be pursued. Aim 1 is to determine the mechanisms by which splenic sinusoidal endothelial cells induce reprogramming of NC cells into NBH cells upon sensing bacteria through Toll-like receptors. Aim 2 is to elucidate the mechanisms by which NBH cells induce IgM production, IgG and IgA class switching, and plasma cell differentiation in MZ B cells. Aim 3 is to evaluate the mechanisms by which NBH cells induce V(D)J gene somatic hypermutation and high-affinity antibody production in MZ B cells. These studies will uncover previously unknown facets of the immunological function of neutrophils by taking advantage of unique cells and tissues from patients with rare primary immunodeficiencies and by making use of selected mouse models. Results from these studies may also lead to the identification of novel vaccine strategies.

2 214 035 €

Start date: 2012-04-01, End date: 2017-09-30

Membranes of eukaryotic cells organize signal transduction proteins into microdomains or lipid rafts whose integrity is essential for numerous cellular processes. Lipid rafts has been considered a fundamental step to define the cellular complexity of eukaryotes, assuming that bacteria do not require such a sophisticated organization of their signaling networks. However, I have discovered that bacteria organize many signaling pathways in membrane microdomains similar to the eukaryotic lipid rafts. Perturbation of bacterial lipid rafts leads to a potent and simultaneous impairment of all raft-harbored signaling pathways. Consequently, the disassembly of lipid rafts in pathogens like Staphylococcus aureus generates a simultaneous inhibition of numerous infection-related processes that can be further explored to control bacterial infections. This unexpected sophistication in membrane organization is unprecedented in bacteria and hence, this proposal will explore the molecular basis of the assembly of bacterial lipid rafts and their role in the infection-related processes. These questions will be addressed in three main goals: First, I will elucidate the molecular components and the mechanism of assembly of bacterial lipid rafts using S. aureus as model organism. Second, I will dissect the molecular basis that links the functionality of the infection-related processes to the integrity of bacterial lipid rafts. Third, my collection of anti-raft small molecules that are able to disrupt lipid rafts will be tested as antimicrobial agents to prevent hospital-acquired infections, abrogate pre-existing infections and develop bacteria-free materials that can be used in clinical settings. I will use a number of molecular approaches in combination with cutting-edge techniques in flow cytometry, cell-imaging and transcriptomics to clarify the architecture and functionality of lipid rafts and demonstrate the feasibility of targeting lipid a new strategy for anti-microbial therapy.

1 493 126 €

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

Most of the lymphomas diagnosed in the western world are originated from mature B cells. The hallmark of these malignancies is the presence of recurrent chromosome translocations that usually involve the immunoglobulin loci and a proto-oncogene. As a result of the translocation event the proto-oncogene becomes deregulated under the influence of immunoglobulin cis sequences thus playing an important role in the etiology of the disease. Upon antigen encounter mature B cells engage in the germinal center reaction, a complex differentiation program of critical importance to the development of the secondary immune response. The germinal center reaction entails the somatic remodelling of immunoglobulin genes by the somatic hypermutation and class switch recombination reactions, both of which are triggered by Activation Induced Deaminase (AID). We have previously shown that AID also initiates lymphoma-associated c-myc/IgH chromosome translocations. In addition, the germinal center reaction involves a fine-tuned balance between intense B cell proliferation and program cell death. This environment seems to render B cells particularly vulnerable to malignant transformation. We aim at studying the molecular events responsible for B cell susceptibility to lymphomagenesis from two perspectives. First, we will address the role of AID in the generation of lymphomagenic lesions in the context of AID specificity and transcriptional activation. Second, we will approach the regulatory function of microRNAs of AID-dependent, germinal center events. The proposal aims at the molecular understanding of a process that lies in the interface of immune regulation and oncogenic transformation and therefore the results will have profound implications both to basic and clinical understanding of lymphomagenesis.

1 596 000 €

Start date: 2008-12-01, End date: 2014-11-30

Learning to read is probably one of the most exciting discoveries in our life. Using a longitudinal approach, the research proposed examines how the human brain responds to two major challenges: (a) the instantiation a complex cognitive function for which there is no genetic blueprint (learning to read in a first language, L1), and (b) the accommodation to new statistical regularities when learning to read in a second language (L2). The aim of the present research project is to identify the neural substrates of the reading process and its constituent cognitive components, with specific attention to individual differences and reading disabilities; as well as to investigate the relationship between specific cognitive functions and the changes in neural activity that take place in the course of learning to read in L1 and in L2. The project will employ a longitudinal design. We will recruit children before they learn to read in L1 and in L2 and track reading development with both cognitive and neuroimaging measures over 24 months. The findings from this project will provide a deeper understanding of (a) how general neurocognitive factors and language specific factors underlie individual differences – and reading disabilities– in reading acquisition in L1 and in L2; (b) how the neuro-cognitive circuitry changes and brain mechanisms synchronize while instantiating reading in L1 and in L2; (c) what the limitations and the extent of brain plasticity are in young readers. An interdisciplinary and multi-methodological approach is one of the keys to success of the present project, along with strong theory-driven investigation. By combining both we will generate breakthroughs to advance our understanding of how literacy in L1 and in L2 is acquired and mastered. The research proposed will also lay the foundations for more applied investigations of best practice in teaching reading in first and subsequent languages, and devising intervention methods for reading disabilities.

2 487 000 €

Start date: 2012-05-01, End date: 2017-04-30

The linguistic capacity to express and comprehend an unlimited number of ideas when combining a limited number of elements has only been observed in humans. Nevertheless, research has not fully identified the components of language that make it uniquely human and that allow infants to grasp the complexity of linguistic structure in an apparently effortless manner. Research on comparative cognition suggests humans and other species share powerful learning mechanisms and basic perceptual abilities we use for language processing. But humans display remarkable linguistic abilities that other animals do not possess. Understanding the interplay between general mechanisms shared across species and more specialized ones dedicated to the speech signal is at the heart of current debates in human language acquisition. This is a highly relevant issue for researchers in the fields of Psychology, Linguistics, Biology, Philosophy and Cognitive Neuroscience. By conducting experiments across several populations (human adults and infants) and species (human and nonhuman animals), and using a wide array of experimental techniques, the present proposal hopes to shed some light on the origins of shared biological constraints that guide more specialized mechanisms in the search for linguistic structure. More specifically, we hope to understand how general perceptual and cognitive mechanisms likely present in other animals constrain the way humans tackle the task of language acquisition. Our hypothesis is that differences between humans and other species are not the result of humans being able to process increasingly complex structures that are the hallmark of language. Rather, differences might be due to humans and other animals focusing on different cues present in the signal to extract relevant information. This research will hint at what is uniquely human and what is shared across different animals species.

1 305 973 €

Start date: 2013-01-01, End date: 2018-12-31

BIOFORCE has a highly ambitious applied objective: to create transgenic cereal plants that will provide a near-complete micronutrient complement (vitamins A, C, E, folate and essential minerals Ca, Fe, Se and Zn) for malnourished people in the developing world, as well as built-in resistance to insects and parasitic weeds. This in itself represents a striking advance over current efforts to address food insecurity using applied biotechnology in the developing world. We will also address fundamental mechanistic aspects of multi-gene/pathway engineering through transcriptome and metabolome profiling. Fundamental science and applied objectives will be achieved through the application of an exciting novel technology (combinatorial genetic transformation) developed and patented by my research group. This allows the simultaneous transfer of an unlimited number of transgenes into plants followed by library-based selection of plants with appropriate genotypes and phenotypes. All transgenes integrate into one locus ensuring expression stability over multiple generations. This proposal represents a new line of research in my laboratory, founded on incremental advances in the elucidation of transgene integration mechanisms in plants over the past two and a half decades. In addition to scientific issues, BIOFORCE address challenges such as intellectual property, regulatory and biosafety issues and crucially how the fruits of our work will be taken up through philanthropic initiatives in the developing world while creating exploitable opportunities elsewhere. BIOFORCE is comprehensive and it provides a complete package that stands to make an unprecedented contribution to food security in the developing world, while at the same time generating new knowledge to streamline and simplify multiplex gene transfer and the simultaneous modification of multiple complex plant metabolic pathways

2 290 046 €

Start date: 2009-04-01, End date: 2014-03-31

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

Humans interact with other people throughout their lives. This project aims to demonstrate that the complex social shaping of the human brain can be adequately tackled only by taking a leap from the conven-tional single-person neuroscience to two-person neuroscience. We will (1) develop a conceptual framework and experimental setups for two-person neuroscience, (2) apply time-sensitive methods for studies of two interacting persons, monitoring both brain and autonomic nervous activity to also cover the brain body connection, (3) use gaze as an index of subject s attention to simplify signal analysis in natural environments, and (4) apply insights from two-person neuroscience into disorders of social interaction. Brain activity will be recorded with millisecond-accurate whole-scalp (306-channel) magnetoencepha-lography (MEG), associated with EEG, and with the millimeter-accurate 3-tesla functional magnetic reso-nance imaging (fMRI). Heart rate, respiration, galvanic skin response, and pupil diameter inform about body function. A new psychophysiological interaction setting will be built, comprising a two-person eye-tracking system. Novel analysis methods will be developed to follow the interaction and possible synchronization of the two persons signals. This uncoventional approach crosses borders of neuroscience, social psychology, psychophysiology, psychiatry, medical imaging, and signal analysis, with intriguing connections to old philosophical questions, such as intersubjectivity and emphatic attunement. The results could open an unprecedented window into human human, instead of just brain brain, interactions, helping to understand also social disorders, such as autism and schizophrenia. Further applications include master apprentice and patient therapist relationships. Advancing from studies of single persons towards two-person neuroscience shows promise of a break-through in understanding the dynamic social shaping of human brain and mind.

2 489 643 €

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

Traffic-related air pollution is an important environmental problem that may affect neurodevelopment. Ultrafine particles (UFP) translocate to the brains of experimental animals resulting in local proinflammatory overexpression. As the basic elements for thinking are acquired by developing brains during infancy and childhood, susceptibility may be elevated in early life. We postulate that traffic-related air pollution (particularly UFPs and metals/hydrocarbons content) impairs neurodevelopment in part via effects on frontal lobe maturation, likely increasing attention-deficit/hyperactivity disorder (ADHD). BREATHE objectives are to develop valid methods to measure children's personal UFP exposure and to develop valid neuroimaging methods to assess correlations between neurobehavior, neurostructural alterations and particle deposition in order to reveal how traffic pollution affects children¿s exposure to key contaminants and brain development, and identify susceptible subgroups. We have conducted general population birth cohort studies providing preliminary evidence of residential air pollution effects on prenatal growth and mental development. We aim to demonstrate short and long-term effects on neurodevelopment using innovative epidemiological methods interfaced with environmental chemistry and neuroimaging following 4000 children from 40 schools with contrasting high/low traffic exposure in six linked components involving: repeated psychometric tests, UFP exposure assessment using personal, school and home measurements, gene-environment interactions on inflammation, detoxification pathways and ADHD genome-wide-associated genes, neuroimaging (magnetic resonance imaging/spectroscopy) in ADHD/non-ADHD children, integrative causal modeling using mathematics, and replication in 2900 children with neurodevelopment followed from pregnancy. We believe the expected results will have worldwide global planning and policy implications.

2 499 230 €

Start date: 2011-08-01, End date: 2016-07-31

"The proposed research project seeks to further our understanding on two important questions for the design of monetary policy: (a) What are the effects of monetary policy interventions on asset price bubbles? (b) How should monetary policy be conducted in the presence of asset price bubbles? The first part of the project will focus on the development of a theoretical framework that can be used to analyze rigorously the implications of alternative monetary policy rules in the presence of asset price bubbles, and to characterize the optimal monetary policy. In particular, I plan to use such a framework to assess the merits of a “leaning against the wind” strategy, which calls for a systematic rise in interest rates in response to the development of a bubble. The second part of the project will seek to produce evidence, both empirical and experimental, regarding the effects of monetary policy on asset price bubbles. The empirical evidence will seek to identify and estimate the sign and response of asset price bubbles to interest rate changes, exploiting the potential differences in the joint behavior of interest rates and asset prices during “bubbly” episodes, in comparison to “normal” times. In addition, I plan to conduct some lab experiments in order to shed some light on the link between monetary policy and bubbles. Participants will trade two assets, a one-period riskless asset and a long-lived stock, in an environment consistent with the existence of asset price bubbles in equilibrium. Monetary policy interventions will take the form of changes in the short-term interest rate, engineered by the experimenter. The experiments will allow us to evaluate some of the predictions of the theoretical models regarding the impact of monetary policy on the dynamics of bubbles, as well as the effectiveness of “leaning against the wind” policies."

799 200 €

Start date: 2014-01-01, End date: 2017-12-31

Cancer progression, characterized by uncontrolled proliferation and motility of cells, is a complex and deadly process. Integrins, a major cell surface adhesion receptor family, are transmembrane proteins known to regulate cell behaviour by transducing extracellular signals to cytoplasmic protein complexes. We and others have shown that recruitment of specific protein complexes by the cytoplasmic domains of integrins is important in tumorigenesis. Here our aim is to study three interrelated processes in cancer progression which involve integrin signalling, but which have not been elucidated earlier at all. 1) Integrins in cell division (cytokinesis). Since coordinated action of the cytoskeleton and membranes is needed both for cell division and motility, shared integrin functions can regulate both events. 2) Dynamic integrin signalosomes at the leading edge of invading cells. Spatially and temporally regulated, integrin-protein complexes at the front of infiltrating cells are likely to dictate the movement of cancer cells in tissues. 3) Transmembrane segments of integrins as scaffolds for integrin signalling. In addition to cytosolic proteins, integrins most likely interact with proteins within the membrane resulting into new signalling modalities. In this proposal we will use innovative, modern and even unconventional techniques (such as RNAi and live-cell arrays detecting integrin traffic, cell motility and multiplication, laser-microdissection, proteomics and bacterial-two-hybrid screens) to unravel these new integrin functions, for which we have preliminary evidence. Each project will give fundamentally novel mechanistic insight into the role of integrins in cancer. Moreover, these interdisciplinary new openings will increase our understanding in cancer progression in general and will open new possibilities for therapeutic intervention targeting both cancer proliferation and dissemination in the body.

1 529 369 €

Start date: 2008-08-01, End date: 2013-07-31

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

1 999 882 €

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

The actual view of cellular transformation and cancer progression supports the notion that cancer cells must undergo metabolic reprogramming in order to survive in a hostile environment. This field has experienced a renaissance in recent years, with the discovery of cancer genes regulating metabolic homeostasis, in turn being accepted as an emergent hallmark of cancer. Prostate cancer presents one of the highest incidences in men mostly in developed societies and exhibits a significant association with lifestyle environmental factors. Prostate cancer recurrence is thought to rely on a subpopulation of cancer cells with low-androgen requirements, high self-renewal potential and multidrug resistance, defined as cancer-initiating cells. However, whether this cancer cell fraction presents genuine metabolic properties that can be therapeutically relevant remains undefined. In CancerMetab, we aim to understand the potential benefit of monitoring and manipulating metabolism for prostate cancer prevention, detection and therapy. My group will carry out a multidisciplinary strategy, comprising cellular systems, genetic mouse models of prostate cancer, human epidemiological and clinical studies and bioinformatic analysis. The singularity of this proposal stems from the approach to the three key aspects that we propose to study. For prostate cancer prevention, we will use our faithful mouse model of prostate cancer to shed light on the contribution of obesity to prostate cancer. For prostate cancer detection, we will overcome the consistency issues of previously reported metabolic biomarkers by adding robustness to the human studies with mouse data integration. For prostate cancer therapy, we will focus on a cell population for which the metabolic requirements and the potential of targeting them for therapy have been overlooked to date, that is the prostate cancer-initiating cell compartment.

1 498 686 €

Start date: 2013-11-01, End date: 2019-10-31

"Understanding the nature of consciousness is one of the grand outstanding scientific challenges and two of its features stand out: consciousness is defined as the construction of one coherent scene but this scene is experienced with a delay relative to the action of the agent and not necessarily the cause of actions and thoughts. Did evolution render solutions to the challenge of survival that includes epiphenomenal processes? The Conscious Distributed Adaptive Control (CDAC) project aims at resolving this paradox by using a multi-disciplinary approach to show the functional role of consciousness in adaptive behaviour, to identify its underlying neuronal principles and to construct a neuromorphic robot based real-time conscious architecture. CDAC proposes that the shift from surviving in a physical world to one that is dominated by intentional agents requires radically different control architectures combining parallel and distributed control loops to assure real-time operation together with a second level of control that assures coherence through sequential coherent representation of self and the task domain, i.e. consciousness. This conscious scene is driving dedicated credit assignment and planning beyond the immediately given information. CDAC advances a comprehensive framework progressing beyond the state of the art and will be realized using system level models of a conscious architecture, detailed computational studies of its underlying neuronal substrate focusing, empirical validation with a humanoid robot and stroke patients and the advancement of beyond state of the art tools appropriate to the complexity of its objectives. The CDAC project directly addresses one of the main outstanding questions in science: the function and genesis of consciousness and will advance our understanding of mind and brain, provide radically new neurorehabilitation technologies and contribute to realizing a new generation of robots with advanced social competence."

2 469 268 €

Start date: 2014-02-01, End date: 2019-01-31

The relentless rise in diabetes is one of the greatest global health emergencies of the 21st century. The increase is most pronounced in low and middle income countries where today three quarters of people with diabetes live and over 80% of the deaths attributed to non-communicable diseases occur. In light of the wealth of knowledge already available about how to tackle the problem, most major international organizations call for the adoption healthy public policies and initiatives to strengthening health systems. However, implementation of recommended action remains limited in many settings. Most evidence comes from high-income settings and may generate recommendations that cannot be successfully implemented in other settings without careful consideration and contextualization. I propose here that this “know-do” gap can be reduced by revealing the barriers to implementing evidence-based recommendations, engaging local stakeholders in developing context-led innovations and developing a tool-kit for contextualizing and implementing diabetes recommendations in low-resource settings. I plan the research in two carefully selected settings in Ecuador, with mixed-methods combining quantitative epidemiological research and qualitative methodology to generate the rich and varied knowledge that is required to trigger policy action and/or changes in care models. Furthermore, I will engage patients, community members, health workers and decision makers in the process of knowledge generation, interpretation and use. The overarching objective is hence, to explore the process by which global recommendations can be translated into context-specific, evidence-informed action for diabetes prevention in low-resource settings. The findings will support the global endeavour to bridge the global “know-do” gap, one of the most important public health challenges this century and a great opportunity for strengthening health systems and achieving health equity.

1 475 334 €

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

"Our research group has worked over the years at the interface between cancer and ageing, with a strong emphasis on mouse models. More recently, we became interested in cellular reprogramming because we hypothesized that understanding cellular plasticity could yield new insights into cancer and ageing. Indeed, during the previous ERC Advanced Grant, we made relevant contributions to the fields of cellular reprogramming (Nature 2013), cellular senescence (Cell 2013), cancer (Cancer Cell 2012), and ageing (Cell Metabolism 2012). Now, we take advantage of our diverse background and integrate the above processes. Our unifying hypothesis is that cellular plasticity lies at the basis of tissue regeneration (“adaptive cellular plasticity”), as well as at the origin of cancer (“maladaptive gain of cellular plasticity”) and ageing (“maladaptive loss of cellular plasticity”). A key experimental system will be our “reprogrammable mice” (with inducible expression of the four Yamanaka factors), which we regard as a tool to induce cellular plasticity in vivo. The project is divided as follows: Objective #1 – Cellular plasticity and cancer: role of tumour suppressors in in vivo de-differentiation and reprogramming / impact of transient de-differentiation on tumour initiation / lineage tracing of Oct4 to determine whether a transient pluripotent-state occurs during cancer. Objective #2 – Cellular plasticity in tissue regeneration and ageing: impact of transient de-differentiation on tissue regeneration / contribution of the damage-induced microenvironment to tissue regeneration / impact of transient de-differentiation on ageing. Objective #3: New frontiers in cellular plasticity: chemical manipulation of cellular plasticity in vivo / new states of pluripotency / characterization of in vivo induced pluripotency and its unique properties. We anticipate that the completion of this project will yield new fundamental insights into cancer, regeneration and ageing."

2 488 850 €

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

The household and family structure in every major industrialized country changed in a fundamental way during the last couple of decades. First, marriage is less important today, as divorce, cohabitation, and single-motherhood are much more common. Second, female labor force participation has increased dramatically. As a result of these changes, today s households are very far from traditional breadwinner husband and housekeeper wife paradigm. These dramatic changes generated significant public interest and a large body of literature that tries to understand causes and consequences of these changes. This project has two main goals. First, it studies changes in household and family structure. The particular questions that it tries to answer are: 1) What are economic factors behind the rise in premarital sex and its destigmatization? What determines parents incentives to socialize their children and affect their attitudes? 2) What are the causes and consequences of the recent rise in assortative mating and diverging marriage patterns by different educational groups? 3) Why are marriage patterns among blacks so different than whites in the U.S.? The second aim of this project is to improve our understanding of income risk, the role of social insurance policies and labor market dynamics by building models that explicitly considers two-earner households. In particular, we ask the following set of questions: 1) What is the role of social insurance policies (income maintenance programs or progressive taxation) in an economy populated by two-earner households facing uninsurable idiosyncratic risk? 2) How does marriage and labor market dynamics interact and how important this interaction for our understanding of labor supply and marriage decisions?

1 037 000 €

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

Research on the role played by women as actors and by gender as a cultural category has crucially contributed to historiographical revision of the Enlightenment and its legacy to the modern world. However, the perspective adopted has been national or, if comparative, mostly radial. A leap forward is urgent because current circulationist approaches to the Enlightenment tend to forget its key gender dimension and to underplay contributions from Southern Europe. This projects offers, for the first time in the field, a systematic,truly transnational and transatlantic approach, which knits together cultural, intellectual, gender and postcolonial history, literary, philosophical and visual studies. It looks at the cultural transfer of gender notions in global perspective around five axes: translation, learned sociability, travel, reading and sensibility, to be explored through textual and iconographic analysis and archival research. Adopting the vantage point of Spain and its empire will allow to question approaches based either on the “national context” or the centre-periphery dichotomy, to reassess the role of the Catholic Enlightenment in the making of modernity and to highlight the mediating roles played by local actors, male and female, in processes of sociocultural change. CIRGEN’s specific objectives are: to challenge dichotomous visions of Enlightenment discourses of gender by stressing their plural (and often conflictive) contribution to modernity; to decenter customary radial perspectives by stressing multilateral dialogues both within Europe and beyond; to better understand the role played by gender in the cultural geography of Enlightenment, particularly in the construction of the South/North symbolic divide; to produce empirically grounded evidence of the practical and iconic role of women in the making of modern reading publics; to foster innovative scholarship on the gendering of emotions in defining national identities and moral standards of civilization.

2 499 415 €

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

Background: Therapeutic angiogenesis with vascular endothelial growth factors (VEGFs) has great potential to become a novel, minimally invasive new treatment for a large number of patients with severe myocardial ischemia. However, this requires development of new technology. Advancing state-of-the-art: We propose a paradigm shift in gene therapy for chronic ischemia by activating endogenous VEGF-A,-B and -C genes and angiogenic transcription programs from the native promoters instead of gene transfer of exogenous cDNA to target tissues. We will develop a new platform technology (endogenetherapy) based on our novel concept of the release of promoter pausing and new promoter-targeted upregulating short hairpinRNAs, tissue-specific superenhancerRNAs activating specific transcription centers involving gene clusters in different chromosomal regions, small circularRNAs formed from self-splicing exons-introns that can be regulated with oligonucleotides and small molecules such as metabolites, nuclear RNAi vectors and specific CRISPR/gRNAmutatedCas9-VP16 technology with an ability to target integration into genomic safe harbor sites. After preclinical studies in mice and in a newly developed chronic cardiac ischemia model in pigs with special emphasis on the analysis of clinically relevant blood flow, metabolic and functional outcomes based on MRI, ultrasound, photoacoustic and PET imaging, the best construct will be taken to a phase I clinical study in patients with severe myocardial ischemia. Since endogenetherapy also involves epigenetic changes, which are reversible and long-lasting, we expect to efficiently activate natural angiogenic programs. Significance: If successful, this approach will begin a new era in gene therapy. Since there is a clear lack of technology capable of targeted upregulation of endogenous genes, the novel endogenetherapy approach may become widely applicable beyond cardiovascular diseases also in other areas of medicine and biomedical research.

2 437 500 €

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

Management of marine fisheries is still far from incorporating adaptation to climate change, even though global stocks are heavily overexploited and climate change is adding additional pressure to the resource. In fact, there is growing evidence that current fisheries management systems may no longer be effective under climate change, and this will translate into both ecological and socioeconomic impacts. This research project argues that the combination of fisheries management science and socio-ecological systems thinking is necessary in order to advance in fisheries adaptation to climate change. To this end, the main objectives are set to: 1) Identify and understand the new challenges raised by climate change for current sustainable fisheries management; 2) Develop a novel approach to fisheries adaptation within a socio-ecological framework; 3) Provide empirical evidence on potential solutions for the adaptation of fisheries management systems; and 4) Help introduce fisheries adaptation at the top of the regional and international adaptation policy agendas. To do this, I will combine model and simulation approaches to fisheries with specific case studies where both biophysical and economic variables will be studied an modelled, but also individuals will be given the opportunity to participate in an active way, learning from participatory methods their preferences towards adaptation and the consequences of the new scenarios climate change poses. Three potential case studies are identified for property rights over stocks, property rights over space, and Marine Reserves in two European and one international case study areas. As a result, I expect to develop a new Adaptation Framework for fisheries management that can be scalable, transferable and easily operationalized, and a set of case study examples on how to integrate theory and participatory processes with the aim of increasing social, ecological and institutional resilience to climate change.

1 184 931 €

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

Resilience and recovery ability are key determinants of species persistence and viability in a changing world. Populations exposed to rapid environmental changes and human-induced alterations are often affected by both ecological and evolutionary processes and their interactions, that is, eco-evolutionary dynamics. The integrated perspective offered by eco-evolutionary dynamics is vital for understanding drivers of resilience and recovery of natural populations undergoing rapid changes and exposed to multiple stressors. However, the feedback mechanisms, and the ways in which evolution and phenotypic changes scale up to interacting species, communities, and ecosystems, remains poorly understood. The objective of my proposal is to bridge and close this gap by merging the fields of ecology and evolution into two interfaces of complex biological dynamics. I will do this in the context of conservation and sustainable harvesting of aquatic ecosystems. I will develop a novel mechanistic theory of eco-evolutionary ecosystem dynamics, by coupling the theory of allometric trophic networks with the theory of life-history evolution. I will analyse the eco-evolutionary dynamics of aquatic ecosystems to identify mechanisms responsible for species and ecosystem resilience and recovery ability. This will be done through systematic simulation studies and detailed analyses of three aquatic ecosystems. The project delves into the mechanisms through which anthropogenic and environmental drivers alter the eco-evolutionary dynamics of aquatic ecosystems. Mechanistic understanding of these dynamics, and their consequences to species and ecosystems, has great potential to resolve fundamental yet puzzling patterns observed in natural populations and to identify species and ecosystem properties regulating resilience and recovery ability. This will drastically change our ability to assess the risks related to current and future anthropogenic and environmental influences on aquatic ecosystems.

1 999 391 €

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

Growth originates from meristems, where stem cells are located. Lateral meristems, which provide thickness to tree stems and other plant organs, include vascular cambium (produces xylem [wood] and phloem); and cork cambium (forms cork, a tough protective layer). We recently identified the molecular mechanism that specifies stem cells of vascular cambium. Unexpectedly, this same set of experiments revealed also novel aspects of the regulation of cork cambium, a meristem whose development has remained unknown. CORKtheCAMBIA aims to identify the stem cells of cork cambium and reveal how they mechanistically regulate plant organ thickening. Thus, stemming from these novel unpublished findings and my matching expertise on plant stem cells and lateral growth, the timing is perfect to discover the molecular mechanism underlying specification of stem cells of cork cambium. To identify the origin of stem cells of cork cambium, 1st-we will combine lineage tracing with a detailed molecular marker analysis. To deduce the cell dynamics of cork cambium, 2nd-we will follow regeneration of the stem cells after ablation of this meristem. To discover the molecular factors regulating the stem cell specification of cork cambium, 3rd-we will utilize molecular genetics and a novel method (inducible CRISPR/Cas9 mutant targeting) being developed in my lab. Since the lateral growth is orchestrated by two adjacent, nested meristems, cork and vascular cambia, the growth process must be tightly co-regulated. Thus, 4th-an in silico model of the intertwined growth process will be generated. By combining modelling with experimentation, we will uncover mechanistically how cork and vascular cambium coordinate lateral growth. CORKtheCAMBIA will thus provide long-awaited insight into the regulatory mechanisms specifying the stem cells of lateral meristem as whole, lay the foundation for studies on radial thickening and facilitate rational manipulation of lateral meristems of crop plants and trees.

1 999 752 €

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

The mammalian cerebral cortex was subject to a dramatic expansion in surface area during evolution. This process is recapitulated during development and is accompanied by folding of the cortical sheet, which allows fitting a large cortical surface within a limited cranial volume. A loss of cortical folds is linked to severe intellectual impairment in humans, so cortical folding is believed to be crucial for brain function. However, developmental mechanisms responsible for cortical folding, and the influence of this on cortical function, remain largely unknown. The goal of this proposal is to understand the genetic and cellular mechanisms that control the developmental expansion and folding of the cerebral cortex, and what is the impact of these processes on its functional organization. Human studies have identified genes essential for the proper folding of the human cerebral cortex. Genetic manipulations in mice have unraveled specific functions for some of those genes in the development of the cerebral cortex. But because the mouse cerebral cortex does not fold naturally, the mechanisms of cortical expansion and folding in larger brains remain unknown. We will study these mechanisms on ferret, an ideal model with a naturally folded cerebral cortex. We will combine the advantages of ferrets with cell biology, genetics and next-generation transcriptomics, together with state-of-the-art in vivo, in vitro and in silico approaches, including in vivo imaging of functional columnar maps. The successful execution of this project will provide insights into developmental and genetic risk factors for anomalies in human cortical topology, and into mechanisms responsible for the early formation of cortical functional maps.

1 701 116 €

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

The Mediterranean, a key socio-cultural, economic and political crossroads, has shifted its relative position recently, with profound effects for relations between the peoples associated with its diverse parts. Crosslocations is a groundbreaking theoretical approach that goes beyond current borders research to analyse the significance of the changes in relations between places and peoples that this involves. It does this through explaining shifts in the relative positioning of the Mediterranean’s many locations – i.e. the changing values of where people are rather than who they are. Approaches focusing on people’s identities, statecraft or networks do not provide a way to research how the relative value of ‘being somewhere in particular’ is changing and diversifying. The approach builds on the idea that in socio-cultural terms, location is a form of political, social, economic, and technical relative positioning, involving diverse scales that calibrate relative values (here called ‘locating regimes’). This means locations are both multiple and historically variable, so different types of location may overlap in the same geographical space, particularly in crossroads regions such as the Mediterranean. The dynamics between them alter relations between places, significantly affecting people’s daily lives, including their life chances, wellbeing, environmental, social and political conditions and status. The project will first research the locating regimes crossing the Mediterranean region (border regimes, infrastructures; digital technologies; fiscal, financial and trading systems; environmental policies; and social and religious structures); then intensively ethnographically study the socio-cultural dynamics of relative positioning that these regimes generate in selected parts of the Mediterranean region. Through explaining the dynamics of relative location, Crosslocations will transform our understanding of trans-local, socio-cultural relations and separations.

2 433 234 €

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

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

Up to one third of diabetic patients develop nephropathy, a serious complication of diabetes. Microalbuminuria is the earliest sign of the complication, which may ultimately develop to end-stage renal disease requiring dialysis or a kidney transplant. Insulin resistance and metabolic syndrome are associated with an increased risk for diabetic nephropathy. Interestingly, glomerular epithelial cells or podocytes have recently been shown to be insulin responsive. Further, nephrin, a key structural component of podocytes, is essential for insulin action in these cells. Our novel findings show that adaptor protein CD2AP, an interaction partner of nephrin, associates with regulators of insulin signaling and glucose transport in glomeruli. The results suggest that nephrin and CD2AP are involved, by association with these proteins, in the regulation of insulin signaling and glucose transport in podocytes. We hypothesize that podocytes can develop insulin resistance and that disturbances in insulin response affect podocyte function and contribute to the development of diabetic nephropathy. The aim of this project is to clarify the mechanisms leading to development of insulin resistance in podocytes and to study the association between insulin resistance and the development of diabetic nephropathy. For this we will develop transgenic zebrafish and mouse models by overexpressing/knocking down insulin signaling-associated proteins specifically in podocytes. Further, we aim to identify novel drug leads to treat insulin resistance and diabetic nephropathy by performing high-throughput small molecule library screens on the developed transgenic fish models. The ultimate goal is to find a treatment to combat the early stages of diabetic nephropathy in humans.

2 000 000 €

Start date: 2009-11-01, End date: 2014-10-31

Anxiety disorders include different forms of pathological fear and anxiety and rank among the most common health concerns in human medicine. Millions of people become affected every year, and many of them do not respond to treatments. Anxiety disorders are heritable, but genetically complex. As a result, traditional gene mapping methods in the human population with prominent locus and allelic heterogeneity have not succeeded. Similarly, rodents have provided some insights into the circuitry of anxiety, but naturally occurring versions do not exist and gene deletion studies have not provided adequate models. To break through and identify new anxiety genes, I propose a novel and unique approach that resorts to man s best friend, dog. Taking advantage of the exaggerated genetic homogeneity characteristic of purebred dogs, recent genomics tools and the existence of naturally occurring heritable behaviour disorders in dogs can remedy the current lack of a suitable animal model of human psychiatric disorders. I propose to collect and perform a genome-wide association study in four breed-specific anxiety traits in dogs representing the three major forms of human anxiety: compulsive pacing and tail-chasing, noise phobia, and shyness corresponding to human OCD, panic disorder and social phobia, respectively. Canine anxiety disorders respond to human medications and other phenomenological studies suggest a share biological mechanism in both species. The proposed research has the potential to discover new genetic risk factors, which eventually will shed light on the biological basis of common neuropsychiatric disorders in both dog and human, provide insight into etiological mechanisms, enable identification of individuals at high-risk for adverse health outcomes, and facilitate development of tailored treatments.

1 381 807 €

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

Female germ cells, oocytes, are highly specialised cells. They ensure the continuity of species by providing the female genome and mitochondria along with most of the nutrients and housekeeping machinery the early embryo needs after fertilisation. Oocytes are remarkable in their ability to survive for long periods of time, up to 50 years in humans, and retain the ability to give rise to a young organism while other cells age and die. Surprisingly little is known about oocyte dormancy. A key feature of dormant oocytes of virtually all vertebrates is the presence of a Balbiani body, which is a non-membrane bound compartment that contains most of the organelles in dormant oocytes and disappears as the oocyte matures. The goal of this proposal is to combine genetic and biochemical perturbations with imaging and the state of the art proteomics techniques to reveal the mechanisms dormant oocytes employ to remain viable. My previous research has shown that the Balbiani body forms an amyloid-like cage around organelles that could be protective. This has led me to identify the large number of unanswered questions about the cell biology of a dormant oocyte. In this proposal, we will study three of these questions: 1) What is the metabolic nature of organelles in dormant oocytes? 2) How does the Balbiani body disassemble and release the complement of organelles when oocytes start to mature? 3) What is the structure and function of the Balbiani body in mammals? We will use oocytes from two vertebrate species, frogs and mice, which are complementary for their ease of handling and relationship to human physiology. By studying the Balbiani body, this proposal will provide fundamental insights into organisation and function of organelles in oocytes and the regulation of physiological amyloid-like structures. More generally, the proposed experiments open up new avenues into the mechanisms that protect organelles from ageing and how oocytes stay dormant for many decades.

1 381 286 €

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

Making cancer treatment more personalized and effective is one of the grand challenges in our health care system. However, many drugs have entered clinical trials but so far showed limited efficacy or induced rapid development of resistance. We critically need multi-targeted drug combinations, which shall selectively inhibit the cancer cells and block the emergence of drug resistance. This project will develop mathematical and computational tools to identify drug combinations that can be used to provide personalized and more effective therapeutic strategies that may prevent acquired resistance. Utilizing molecular profiling and pharmacological screening data from patient-derived leukaemia and ovarian cancer samples, I will develop model-based clustering methods for identification of patient subgroups that are differentially responsive to first-line chemotherapy. For patients resistant to chemotherapy, I will develop network modelling approaches to predict the most potential drug combinations by understanding the underlying drug target interactions. The drug combination prediction will be made for each patient and will be validated using a preclinical drug testing platform on patient samples. I will explore the drug combination screen data to identify significant synergy at the therapeutically relevant doses. The drug combination hits will be mapped into signalling networks to infer their mechanisms. Drug combinations with selective efficacy in individual patient samples or in sample subgroups will be further translated into in treatment options by clinical collaborators. This will lead to novel and personalized strategies to treat cancer patients.

1 500 000 €

Start date: 2017-06-01, End date: 2022-05-31

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

Longitudinal omics data hold great promise to improve biomarker detection and enable dynamic individualized predictions. Recent technological advances have made proteomics an increasingly attractive option but clinical longitudinal proteomic datasets are still rare and computational tools for their analysis underdeveloped. The objective of this proposal is to create a roadmap to detect clinically feasible protein markers using longitudinal data and effective computational tools. A biomedical focus is on early detection of Type 1 diabetes (T1D). Specific objectives are: 1) Novel biomarker detector using longitudinal data. DynaOmics introduces novel types of multi-level dynamic markers that are undetectable in conventional single-time cross-sectional studies (e.g. within-individual changes in abundance or associations), develops optimization methods for their robust and reproducible detection within and across individuals, and validates their utility in well-defined samples. 2) Individualized disease risk prediction dynamically. DynaOmics develops dynamic individualized predictive models using the multi-level longitudinal proteome features and novel statistical and machine learning methods that have previously not been used in this context, including joint models of longitudinal and time-to-event data, and one-class classification type techniques. 3) Dynamic prediction of T1D. DynaOmics builds a predictive model of dynamic T1D risk to assist early detection of the disease, which is crucial for developing future therapeutic and preventive strategies. T1D typically involves a relatively long symptom-free period before clinical diagnosis but current tools to predict early T1D risk have restricted power. The objectives involve innovative and unconventional approaches and address major unmet challenges in the field, having high potential to open new avenues for diagnosis and treatment of complex diseases and fundamentally novel insights towards precision medicine.

1 499 869 €

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

"Perceptions, memories, emotions, and everything that makes us human, demand the flexible integration of information represented and computed in a distributed manner. The human brain is structured into a large number of areas in which information and computation are highly segregated. Normal brain functions require the integration of functionally specialized but widely distributed brain areas. Furthermore, human behavior entails a flexible task- dependent interplay between different subsets of these brain areas in order to integrate them according to the corresponding goal-directed requirements. We contend that the functional and encoding roles of diverse neuronal populations across areas are subject to intra- and inter-cortical dynamics. More concretely, we hypothesize that coherent oscillations within frequency-specific large-scale networks and coherent structuring of the underlying fluctuations are crucial mechanisms for the flexible integration of distributed processing and interaction of representations. The project aims to elucidate precisely the interplay and mutual entrainment between local brain area dynamics and global network dynamics and their breakdown in brain diseases. We wish to better understand how segregated distributed information and processing are integrated in a flexible and context-dependent way as required for goal-directed behavior. It will allow us to comprehend the mechanisms underlying brain functions by complementing structural and activation based analyses with dynamics. We expect to gain a full explanation of the mechanisms that mediate the interactions between global and local spatio-temporal patterns of activity revealed at many levels of observations (fMRI, EEG, MEG) in humans under task and resting conditions, complemented and further constrained by using more detailed characterization of brain dynamics via Local Field Potentials and neuronal recording in animals under task and resting conditions."

2 467 530 €

Start date: 2012-07-01, End date: 2017-06-30

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

The ageing population structure of most European countries has major health, economic and social consequences that lead to a need to better understand both the evolutionary limitations of deferring ageing, as well as the mechanisms involved in growing old. Ageing involves reduced fertility, mobility and ability to combat disease, but some individuals cope with growing old better than others. Improving the quality of life at old age and predicting future changes in longevity patterns of societies might depend on our ability to develop indicators of how old we really are and how many healthy years we have ahead, and how those indicators depend on our health history across several decades. Yet, most model species used in biology are short-lived and provide a poor comparison to long-lived mammals such as humans. Further, they do not often inform on the mechanisms of ageing alongside its fitness consequences in natural populations of long-lived mammals. This project integrates different ageing mechanisms with unique data on lifelong disease and reproductive history in the most long-lived non-human mammal studied so far, the Asian elephant. I will examine how different mechanisms of ageing (telomere dynamics, oxidative stress and telomerase activity) interact with lifelong disease and reproductive history, and current endocrinological measures of stress and reproductive status. This will help us to better understand both the mechanisms of ageing and their consequences on senescence rates. To do so, I will combine the most comprehensive demographic data (N~10.000) on Asian elephants in the world with bi-monthly health assessments and disease records across life (N~2500) and with longitudinal markers of ageing and hormonal correlates of stress and reproductive potential (N~240). Understanding changes in health across life and its links to ageing rates, stress levels and life-history in a species as long-lived as humans will be relevant to a large range of end-users.

1 949 316 €

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

The majority of animals show an external bilateral symmetry, precluding the observation of multiple internal left-right (L/R) asymmetries which are fundamental for organ packaging and function. A prominent molecular pathway converging on and downstream of the Pitx2 transcription factor confers left-handed information in the left side of the embryo, with players expressed on the right ensuring that the left determinants are excluded. Therefore, conferring or excluding left identity in left and right hand sides, respectively, drives L/R asymmetry. Some indications suggest that a program actively specifying right–handed information could exist on the right. Our recent findings support this view. In a screening for novel regulators of the epithelial to mesenchymal transition (EMT), we have identified a transcription factor, EMT2, which similarly to well known factor Snail, it is an EMT inducer. The EMT is crucial for the development of tissues during embryonic development and for the progression of carcinomas to the invasive state. Strikingly, again as Snail, in addition to promote EMT, the EMT2 factor is predominantly expressed on the right side and may operate instructing L/R identity on the right-hand side of the embryo. With this background, our knowledge of the EMT and a series of genome-wide high-throughput approaches and a comprehensive functional analysis using the chick, the fish and the mouse as model systems we propose to reveal the putative molecular pathways conveying right-handed information and to reveal commonalities between L/R pathways and the EMT. In the long run, we aim at better understanding human pathologies that involve these morphogenetic and cellular processes, including pathological situs conditions (i.e. altered organ positioning) and cancer progression.

2 460 000 €

Start date: 2013-05-01, End date: 2018-12-31