ERC FUNDED PROJECTS

Adaptive behaviour is typically attributed to an executive-control system that allows people to regulate impulsive actions and to fulfil long-term goals instead. Failures to regulate impulsive actions have been associated with a variety of clinical and behavioural disorders. Therefore, establishing a good understanding of impulse-control mechanisms and how to improve them could be hugely beneficial for both individuals and society at large. Yet many fundamental questions remain unanswered. This stems from a narrow focus on reactive inhibitory control and well-practiced actions. To make significant progress, we need to develop new models that integrate different aspects of impulsive action and executive control. The proposed research program aims to answer five fundamental questions. (1) Can novel impulsive actions arise during task-preparation stages?; (2) What is the role of negative emotions in the origin and control of impulsive actions?; (3) How does learning modulate impulsive behaviour?; (4) When are impulsive actions (dys)functional?; and (5) How is variation in state impulsivity associated with trait impulsivity? To answer these questions, we will use carefully designed behavioural paradigms, cognitive neuroscience techniques (TMS & EEG), physiological measures (e.g. facial EMG), and mathematical modelling of decision-making to specify the origin and control of impulsive actions. Our ultimate goal is to transform the impulsive action field by replacing the currently dominant ‘inhibitory control’ models of impulsive action with detailed multifaceted models that can explain impulsivity and control across time and space. Developing a new behavioural model of impulsive action will also contribute to a better understanding of the causes of individual differences in impulsivity and the many disorders associated with impulse-control deficits.

1 998 438 €

Start date: 2018-06-01, End date: 2023-11-30

Forecasting is a fundamental tool in Economics, Statistics, Business and other sciences. Judging whether forecasts are good and robust is of great importance since forecasts are used everyday to guide policymakers' and practitioners' decisions. The proposal aims at addressing four important issues that researchers encounter in practice. A first issue is how to assess whether forecasts are optimal in the presence of instabilities. Optimality is an important property of models’ forecasts: if forecasts are not optimal, then the model can be improved. Existing methods to assess forecast optimality are not robust to the presence of instabilities, which are widespread in the data. How to obtain such robust methods and what they tell us about widely used economic models’ forecasts is the first task of this project. A second problem faced by forecasters in practice is to evaluate density forecasts. Density forecasts are important tools for policymakers since they quantify uncertainty around forecasts. However, existing methodologies focus on a null hypothesis that is not necessarily the one of interest to the forecaster. The second task is to develop tests for forecast density evaluation that address forecasters’ needs. A third, important question is “Why Do We Use Forecast Tests To Evaluate Models’ Performance?”. The third task of this project is to understand the relationship between traditional in-sample and forecast evaluation tests, and develop a framework that helps to understand under which circumstances forecast tests are more useful than typical in-sample tests. A final question is how researchers can improve models that do not forecast well. Model misspecification is widespread, still economists are often left wondering exactly which parts of their models are misspecified. The fourth task is to propose an empirical framework for addressing this issue. By estimating time-varying wedges, we assess where misspecification is located, and how important it is.

501 860 €

Start date: 2014-07-01, End date: 2019-06-30

Thoracic aortic aneurysm and dissection (TAAD) is an important cause of morbidity and mortality in the western world. As 20% of all affected individuals have a positive family history, the genetic contribution to the development of TAAD is significant. Over the last decade dozens of genes were identified underlying syndromic and non-syndromic forms of TAAD. Although mutations in these disease culprits do not yet explain all cases, their identification and functional characterization were essential in deciphering three key aortic aneurysm/dissection patho-mechanisms: disturbed extracellular matrix homeostasis, dysregulated TGFbeta signaling and altered aortic smooth muscle cell contractility. Owing to the recent advent of next-generation sequencing technologies, I anticipate that the identification of additional genetic TAAD causes will remain quite straightforward in the coming years. Importantly, in many syndromic and non-syndromic families, significant non-penetrance and both inter- and intra-familial clinical variation are observed. So, although the primary genetic underlying mutation is identical in all these family members, the clinical spectrum varies widely from completely asymptomatic to sudden death due to aortic dissection at young age. The precise mechanisms underlying this variability remain largely elusive. Consequently, a better understanding of the functional effects of the primary mutation is highly needed and the identification of genetic variation that modifies these effects is becoming increasingly important. In this project, I carefully selected four different innovative strategies to discover mother nature’s own modifying capabilities in human and mouse aortopathy. The identification of these genetic modifiers will advance the knowledge significantly beyond the current understanding, individualize current treatment protocols to deliver true precision medicine and offer promising new leads to novel therapeutic strategies.

1 987 860 €

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

The origin of Harmonic Analysis goes back to the study of the heat diffusion, modeled by a differential equation, and the claim made by Fourier that every periodic function can be represented as a series of sines and cosines. In this statement we can find the motivation to many of the advances that have been made in this field. Partial Differential Equations model many phenomena from the natural, economic and social sciences. Existence, uniqueness, convergence to the boundary data, regularity of solutions, a priori estimates, etc., can be studied for a given PDE. Often, Harmonic Analysis plays an important role in such problems and, when the scenarios are not very friendly, Harmonic Analysis turns out to be fundamental. Not very friendly scenarios are those where one lacks of smoothness either in the coefficients of the PDE and/or in the domains where the PDE is solved. Some of these problems lead to obtain the boundedness of certain singular integral operators and this drives one to the classical and modern Calderón-Zygmund theory, the paradigm of Harmonic Analysis. When studying the behavior of the solutions of the given PDE near the boundary, one needs to understand the geometrical features of the domains and then Geometric Measure Theory jumps into the picture. This ambitious project lies between the interface of three areas: Harmonic Analysis, PDE and Geometric Measure theory. It seeks deep results motivated by elliptic PDE using techniques from Harmonic Analysis and Geometric Measure Theory.This project is built upon results obtained by the applicant in these three areas. Some of them are very recent and have gone significantly beyond the state of the art. The methods to be used have been shown to be very robust and therefore they might be useful towards its applicability in other regimes. Crucial to this project is the use of Harmonic Analysis where the applicant has already obtained important contributions.

1 429 790 €

Start date: 2014-01-01, End date: 2018-12-31

Biological systems are robust to perturbations, with many genetic, stochastic and environmental challenges having no or little phenotypic consequence. However, the extent of this robustness varies across individuals, for example the same mutation or treatment may only affect a subset of individuals. The overall objective of this project is to understand the cellular and molecular mechanisms that confer this robustness and why it varies across individuals. We will address three specific questions: 1. Why do inherited mutations have different outcomes in different individuals, even when they are genetically identical and share a common environment? 2. What are the mechanisms during development that confer robustness to mechanical deformation? 3. How can the loss of robustness be exploited to specifically kill cancer cells? To address the first two questions, we will use live imaging procedures that we have developed that make the C. elegans embryo a unique animal system to link early inter-individual variation in gene expression and cellular behaviour to later variation in phenotypes. To address the third question, we will apply our understanding of genetic robustness and genetic interaction networks in model organisms to the comprehensive analysis of cancer genome datasets. The predictions from these hypothesis-driven computational analyses will then be evaluated using wet-lab experiments. Understanding and predicting variation in robustness is both a fundamental challenge for biology and one that is central to the development of personalised and predictive medicine. A patient does not want to know the typical outcome of a mutation or treatment; they want to know what will actually happen to them. The work outlined here will contribute to our basic understanding of robustness and its variation among individuals, and it will also directly tackle the problem of predicting and targeting variation in robustness as a strategy to kill tumour cells.

1 996 812 €

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

Financial markets constitute the backbone of modern economies, intermediating resources from those who have them (i.e., lenders) to those who can put them to productive use (i.e., borrowers). The defining feature of these markets is that they entail the exchange of goods today for a borrower’s promise to deliver goods in the future. These promises are sustained by guarantees, which are akin to the amount of future income that borrowers can credibly pledge to lenders. I refer to this pledgeable income as an economy’s stock of collateral. This stock determines the amount and type of promises that can be traded in an economy and, in turn, this set of promises determines the transactions that can be carried out. Intuitively, when this set of promises is large, resources find their most productive uses and efficiency is high. This raises a general question: what are the key determinants of the set of promises that an economy is able to sustain, and why does it vary? In macroeconomic models, it is commonly assumed that all promises are backed by only one kind of collateral, i.e. usually that of private borrowers, and that this collateral is ‘fundamental’, i.e. it consists of output. Real-world financial markets, however, rely on many types of collateral to guarantee promises. In this proposal, I focus on three such types. First, collateral may be ‘bubbly’, i.e. promises can be backed by nothing else but the income that the sale of new promises is expected to bring in the future. Second, collateral need not be private, as government promises are sustained by pledging public income. Third, collateral need not be homogenous, as it may differ in quality or type across entrepreneurs, and this quality may not be perfectly observed by all. I address the following broad questions. How do economies produce these different types of collateral? How do they interact with one another? Is there a role for policy in maintaining the efficient level and composition of collateral?

979 800 €

Start date: 2014-09-01, End date: 2019-08-31

What was the role played by courtly musicians and poets in fostering a performative dimension of cultural life in the late Middle Ages? How did this contribute to the social value of the poet and musician as an artist? In the late medieval period the Crown of Aragon was a political and cultural crossroads, a coveted destination for artists of various kinds who attended the refined court of the Catalan kings. Musicians and performing entertainers with skills in the verbal and non-verbal domains were among the most sought after. This project will review and expand the corpus of documentary evidence informing us about musical activity and performing artists at the court of Aragon in the late medieval period, with the aim to analyse what this tells us about similar activity at other European courts. Thus, it will examine the professional profiles, cultural backgrounds and networks of patronage behind the minstrels who thrived in the Catalan court between 1235 and 1435. The main source of information will be the Archive of the Crown of Aragon in Barcelona and the Archive of Valencia. The project will also consider the debt of Catalan poetry to foreign musicians, with the aim to establish whether any intertextuality exists between Catalan poetry and the poetry produced in the regions adjacent to the territories of the Crown of Aragon that was specifically mediated by the presence of foreign musicians at the Catalan court. Specific objectives of the project will be: 1) to establish whether the ideas of minstrelsy passed down to us by literature and scholarship fit the real profiles of minstrels provided by medieval documents; 2) to evaluate the impact, where appropriate, of contacts between religious and ethnic communities in the profession of minstrelsy in late medieval Iberia; 3) to assess the role of queenship in musical and poetic patronage; 4) to clarify the influence of foreign musical traditions on Catalan poetry.

1 341 869 €

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

"This project is centred in Singularity Theory and its interactions and applications to Complex and Algebraic Geometry, Differential/symplectic/Contact Topology, Hodge Theory and Algebraic Topology. This subject is still at the core of various developments (Mori's Theory, Symplectic and Contact Geometry, algebro-geometric Donaldson-Thomas Theory, Hodge Theory and D-modules,...) In the present project we propose several directions of development in singularity theory, designed in order to approach the solution of several classical conjectures, and explore new interactions with the latest developments in nearby areas. New problems and conjectures are formulated, which are interesting bottlenecks whose solution would open new development perspectives in the theory, and whose study will need significantly new ideas. We have taken care of finding feasible starting points and interesting classes of singularities where the initial development is less steep. And to find links among the seemingly difernt techniques and problems which we propose. We deal with the following specific topics: vanishing cohomology of isolated and non-isolated singularities. Rational homotopy generalisations of Hodge Theory and rational vanishing homotopy. Applications to Equisingularity questions. Disentanglement theory and its relation with vanishing homology and homotopy. Symplectic and contact geometry of milnor fibrations. A vast programme in topological equisingularity including a multifaceted attack to Lê-Ramanujan problem. Generalisations of McKay correspondence. Banagl Intersection spaces. Topological and analytic invariants of normal surface singularities. Arc spaces and Nash correspondence. Compactified Jacobians."

1 140 601 €

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

A major shift in our conception of genome regulation has emerged in recent years. It is now obvious that the majority of cellular transcripts do not code for proteins, and a significant subset of them are long RNAs (lncRNAs). My lab and others have shown that lncRNAs regulate genome function and gene expression, and that alterations in lncRNAs are inherent to disease, including cancer. However, our understanding of the roles of lncRNAs and their underlying molecular mechanisms are still extremely poor. Among all the mechanisms reported, the evident connection between lncRNAs and the chromatin places them at the center of cell biology. During their cycle, cells must undergo faithful DNA replication to ensure that an exact copy of their genetic content is passed on to their daughters. Throughout this tightly regulated process chromatin must be disrupted and reconstituted, and it determines where and when replication takes place. If replication is deregulated, cells can proliferate uncontrollably and suffer loss of genome integrity. Our recent findings implicate lncRNA in the process of DNA replication, representing a novel aspect of genome regulation that places lncRNAs at the focal point of cancer biology. To delve deeper into these findings I aim to: 1. Identify the role of lncRNAs in the replication of the chromatin 2. Dissect the molecular mechanism by which lncRNAs function in this process and 3. Explore the role of these lncRNAs as cancer drivers and their potential as therapeutic targets. I will apply tools that we have generated in recent years, as well as new ones, including approaches to identify lncRNAs associated with replicating chromatin, novel lncRNA-tailored CRISPR applications, and the latest methodology for functional study and targeting of long noncoding transcripts in cancer. I am confident that we are in a unique position to address these life-essential and yet pending questions, setting up a basis for future lncRNA-based therapies.

2 000 000 €

Start date: 2018-04-01, End date: 2023-03-31

"The last decades are characterized by an upsurge of research on the impacts of global environmental changes on forests. Climate warming, atmospheric deposition of acidifying and eutrophying pollutants and land-use change are three of the most important threats to biodiversity in temperate forests. However, most studies focused on the effects of single factors over short time periods, such that our ability to predict the combined effects of multiple global change drivers over longer time periods remains rudimentary. The lack of knowledge on effects of global change drivers on forest herb layer communities is particularly striking, since the herb layer contains the largest part of vascular plant diversity in temperate forests and provides key ecosystem services. Therefore PASTFORWARD will build an integrative understanding of the interactive effects of land-use change, atmospheric deposition and climate warming on forest herb layer communities, starting from the insight that changes in herb layer communities are driven primarily by past land use, but can be modulated by atmospheric deposition, climate warming and forest management. Indeed, it is still largely ignored that sensible predictions of herb layer development trajectories under global change can only be made by taking the forest’s land-use history into account, as legacies of past land use can leave century-long imprints on forest herb layer communities. Three complementary data sources (a database with resurveyed vegetation plots, field measurements in a pan-European network of resurvey plots, and a multi-factor experiment) combined with an ecosystem model will be used. Furthermore, concepts and tools from different disciplines, ranging from history over sylviculture to community and ecosystem ecology will be applied. The results of PASTFORWARD will help forest managers and policy makers in taking more informed decisions on how to combine resource extraction with biodiversity conservation."

1 887 780 €

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

"Sorin Popa's deformation/rigidity theory has lead to an enormous progress in our understanding of von Neumann algebras coming from discrete groups and their actions on probability spaces. In a five year long collaboration with Sorin Popa, we solved many long-standing open problems in this area, including superrigidity theorems for group measure space II_1 factors, results on the possible fundamental groups of II_1 factors, and uniqueness theorems for Cartan subalgebras. In the first part of the project, we want to establish new unique Cartan decomposition theorems for II_1 factors coming from hitherto intractable groups. Using methods coming from Lie groups, ergodic theory and geometric group theory, we want to reach such results for lattices in higher rank simple Lie groups, and for countable groups with nonvanishing L^2-Betti numbers. An important intermediate step will be the unique Cartan decomposition of Bernoulli crossed products. Secondly we want to prove classification theorems for type III factors that are equally strong as the existing results for the type II_1 case. This includes a complete classification of the noncommutative Bernoulli shifts of the free groups and will require an intricate combination of Tomita/Takesaki and deformation/rigidity theory. The methods developed so far bring within reach an attack on two of the most important open problems in operator algebras and functional analysis: the free group factor problem and Connes's rigidity conjecture. The exact progress on these problems is of course unforeseeable, but it is sure that the research on these problems will lead to an even deeper interaction between diverse areas of mathematics as operator algebras, group theory, functional analysis, ergodic theory, and descriptive set theory. Intermediate goals are the classification of natural classes of group von Neumann algebras, including those coming from Baumslag-Solitar groups, wreath product groups, and other families of discrete groups."

1 446 660 €

Start date: 2014-07-01, End date: 2019-06-30

Alzheimer´s disease (AD) is the most common form of dementia, with over 35 million people suffering from it worldwide, and it constitutes a personal and societal tragedy of immense proportions. Fifty years of intense research have revealed many key elements of the biology of this neurodegenerative disorder. However, our understanding of the molecular bases of the disease is still very limited, and the available medical treatments for AD are purely symptomatic and hardly effective. It is now clear that the modulation of a single target is unlikely to yield the desired outcome, and we should move from gene-centric to network-centric therapeutic strategies. In addition, we should focus on early (asymptomatic) phases of AD, before the brain damage is irreversible, and the identification of molecular biomarkers to monitor the response of patients is paramount. Accordingly, the main objective of our proposal is the identification of novel biomarkers in AD to monitor the onset and progression of the pathology from very early stages, and to discover combinations of drug targets and chemical compounds able to modify the biology of the disease. We will first run proteomics and transcriptomics experiments, in AD mouse models, to reveal the organization of proteins and genes that are up- or down-regulated at different ages and AD stages, and their potential translocation into/out of mitochondria. We will then construct the AD-associated network, incorporating clinical data, which we will use as a framework for the integration and analyses of the –omics data collected. We will transform the static data snapshots, corresponding to the different AD stages, into a dynamic model able to explain the progression of the disease, providing hints as to the best strategies to monitor and modulate AD evolution. We will finally design and validate a systems pharmacology strategy, based on concerted multi-target perturbations with small molecules, to modify the biology of the disease.

1 296 000 €

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