ERC FUNDED PROJECTS

Most hereditary diseases in humans are genetically complex, resulting from combinations of mutations in multiple genes. However synthetic interactions between genes are very difficult to identify in population studies because of a lack of statistical power and we fundamentally do not understand how mutations interact to produce phenotypes. C. elegans is a unique animal in which genetic interactions can be rapidly identified in vivo using RNA interference, and we recently used this system to construct the first genetic interaction network for any animal, focused on signal transduction genes. The first objective of this proposal is to extend this work and map a comprehensive genetic interaction network for this model metazoan. This project will provide the first insights into the global properties of animal genetic interaction networks, and a comprehensive view of the functional relationships between genes in an animal. The second objective of the proposal is to use C. elegans to develop and validate experimentally integrated gene networks that connect genes to phenotypes and predict genetic interactions on a genome-wide scale. The methods that we develop and validate in C. elegans will then be applied to predict phenotypes and interactions for human genes. The final objective is to dissect the molecular mechanisms underlying genetic interactions, and to understand how these interactions evolve. The combined aim of these three objectives is to generate a framework for understanding and predicting how mutations interact to produce phenotypes, including in human disease.

1 100 000 €

Start date: 2008-09-01, End date: 2014-04-30

This project aims at creating a multimedia archive of the printed works of Anton Francesco Doni, who was not only an author but also a typographer, a publisher and a member of the Giolito and Marcolini’s editorial staff. The analysis of Doni’s work may be a good way to investigate appropriation, text rewriting and image reusing practices which are typical of several authors of the 16th Century, as clearly shown by the critics in the last decades. This project intends to bring to light the wide range of impulses from which Doni’s texts are generated, with a great emphasis on the figurative aspect. The encoding of these texts will be carried out using the TEI (Text Encoding Initiative) guidelines, which will enable any single text to interact with a range of intertextual references both at a local level (inside the same text) and at a macrostructural level (references to other texts by Doni or to other authors). The elements that will emerge from the textual encoding concern: A) The use of images Real images: the complex relation between Doni’s writing and the xylographies available in Marcolini’s printing-house or belonging to other collections. Mental images: the remarkable presence of verbal images, as descriptions, ekphràseis, figurative visions, dreams and iconographic allusions not accompanied by illustrations, but related to a recognizable visual repertoire or to real images that will be reproduced. B) The use of sources A parallel archive of the texts most used by Doni will be created. Digital anastatic reproductions of the 16th-Century editions known by Doni will be provided whenever available. The various forms of intertextuality will be divided into the following typologies: allusions; citations; rewritings; plagiarisms; self-quotations. Finally, the different forms of narrative (tales, short stories, anecdotes, lyrics) and the different idiomatic expressions (proverbial forms and wellerisms) will also be encoded.

559 200 €

Start date: 2008-08-01, End date: 2012-07-31

"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

To successfully complete secondary education, persistent learning behavior is essential. Why are some adolescents more resilient to setbacks at school than others? In addition to actual ability, students’ implicit beliefs about the nature of their abilities have major impact on their motivation and achievements. Ability beliefs range from viewing abilities as “entities” that cannot be improved much by effort (entity beliefs), to believing that they are incremental with effort and time (incremental beliefs). Importantly, ability beliefs shape which goals a student pursues at school; proving themselves (performance goals) or improving themselves (learning goals). The central aims of the proposal are to unravel 1) the underlying processing mechanisms of how beliefs and goals shape resilience to setbacks at school and 2) how to influence these mechanisms to stimulate persistent learning behavior. Functional brain research, including my own, has revealed the profound top-down influence of goals on selective information processing. Goals may thus determine which learning-related information is attended. Project 1 jointly investigates the essential psychological and neurobiological processes to unravel the longitudinal effects of beliefs and goals on how the brain prioritizes information during learning, and how this relates to school outcomes. Project 2 reveals how to influence this interplay with the aim to long-lastingly stimulate persistent learning behavior. I will move beyond existing approaches by introducing a novel intervention in which students experience their own learning-related brain activity and its malleability. The results will demonstrate how ability beliefs and goals shape functional brain development and school outcomes during adolescence, and how we can optimally stimulate this interplay. The research has high scientific impact as it bridges multiple disciplines and thereby provides a strong impulse to the emerging field of educational neuroscience.

1 597 291 €

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

This project focuses on the appropriation of the Old Testament by early Christian interpreters of the Bible. A historical approach, not commonly adopted in the study of biblical interpretation, will enable us to study how this process contributed to the formation of distinctive Christian identities within the multicultural society of the late Roman principate and early Byzantine rule. The exegetes of this period were to a great extent responsible for the creation of a distinctive, sophisticated, and uncompromising discourse—a ‘totalising Christian discourse’, which determines Christian identities up to this day. In two projects, carried out by three researchers, we will make cross sections of the relevant material. It was allegorizing interpretation that enabled exegetes belonging to the so-called School of Alexandria to recognize Christ everywhere in the Old Testament, and thus to appropriate it and make it useful to the Church. Thus the Song of Songs was no longer considered an earthly love song, but was said to describe Christ’s love for the Church. Exegetes associated with the School of Antioch opposed to this kind of approach. They are often described as literalists. The traditional understanding of the distinctions between the two schools needs to be broadened and corrected by a picture of the actual practice of their hermeneutics. In my view the Antiochene opposition was brought about by the fact that pagan and ‘heretic’ critics did not accept the Alexandrian use of allegory. My innovative hypothesis is related to the central role played by the letters of the apostle Paul in the Antiochene reaction against Alexandria. For the Antiochenes, the use of Paul became an alternative means to bridge the gap between the two Testaments. Instead of a book in which every jot and tittle referred to Christ through allegory, the Antiochenes came to view the Old Testament as an amalgamation of moral lessons that agreed with Paul's teaching.

655 309 €

Start date: 2008-09-01, End date: 2013-12-31

The metabolism of cancer cells is altered to meet cellular requirements for growth, providing novel means to selectively target tumorigenesis. While extensively studied, our current view of cancer cellular metabolism is fundamentally limited by lack of information on variability in metabolic activity between distinct subcellular compartments and cells. We propose to develop a spatio-temporal fluxomics approach for quantifying metabolic fluxes in the cytoplasm vs. mitochondria as well as their cell-cycle dynamics, combining mass-spectrometry based isotope tracing with cell synchronization, rapid cellular fractionation, and computational metabolic network modelling. Spatio-temporal fluxomics will be used to revisit and challenge our current understanding of central metabolism and its induced adaptation to oncogenic events – an important endeavour considering that mitochondrial bioenergetics and biosynthesis are required for tumorigenesis and accumulating evidences for metabolic alterations throughout the cell-cycle. Our preliminary results show intriguing oscillations between oxidative and reductive TCA cycle flux throughout the cell-cycle. We will explore the extent to which cells adapt their metabolism to fulfil the changing energetic and anabolic demands throughout the cell-cycle, how metabolic oscillations are regulated, and their benefit to cells in terms of thermodynamic efficiency. Spatial flux analysis will be instrumental for investigating glutaminolysis - a ‘hallmark’ metabolic adaptation in cancer involving shuttling of metabolic intermediates and cofactors between mitochondria and cytoplasm. On a clinical front, our spatio-temporal fluxomics analysis will enable to disentangle oncogene-induced flux alterations, having an important tumorigenic role, from artefacts originating from population averaging. A comprehensive view of how cells adapt their metabolism due to oncogenic mutations will reveal novel targets for anti-cancer drugs.

1 481 250 €

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

Understanding how values of different options that lead to choice are represented in the brain is a basic scientific question with far reaching implications. I recently showed that by the mere-association of a cue and a button press we could influence preferences of snack food items up to two months following a single training session lasting less than an hour. This novel behavioural change manipulation cannot be explained by any of the current learning theories, as external reinforcement was not used in the process, nor was the context of the decision changed. Current choice theories focus on goal directed behaviours where the value of the outcome guides choice, versus habit-based behaviours where an action is repeated up to the point that the value of the outcome no longer guides choice. However, in this novel task training via the involvement of low-level visual, auditory and motor mechanisms influenced high-level choice behaviour. Thus, the far-reaching goal of this project is to study the mechanism, by which low-level sensory, perceptual and motor neural processes underlie value representation and change in the human brain even in the absence of external reinforcement. I will use behavioural, eye-gaze and functional MRI experiments to test how low-level features influence the neural representation of value. I will then test how they interact with the known striatal representation of reinforced behavioural change, which has been the main focus of research thus far. Finally, I will address the basic question of dynamic neural plasticity and if neural signatures during training predict long term success of sustained behavioural change. This research aims at a paradigmatic shift in the field of learning and decision-making, leading to the development of novel interventions with potential societal impact of helping those suffering from health-injuring behaviours such as addictions, eating or mood disorders, all in need of a long lasting behavioural change.

1 500 000 €

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

Internal models are fundamental to our understanding of how the mind constructs percepts, makes decisions, controls movements, and interacts with others. Yet, we lack principled quantitative methods to systematically estimate internal models from observable behaviour, and current approaches for discovering their mental representations remain heuristic and piecemeal. I propose to develop a set of novel 'doubly Bayesian' data analytical methods, using state-of-the-art Bayesian statistical and machine learning techniques to infer humans' internal models formalised as prior distributions in Bayesian models of cognition. This approach, cognitive tomography, takes a series of behavioural observations, each of which in itself may have very limited information content, and accumulates a detailed reconstruction of the internal model based on these observations. I also propose a set of stringent, quantifiable criteria which will be systematically applied at each step of the proposed work to rigorously assess the success of our approach. These methodological advances will allow us to track how the structured, task-general internal models that are so fundamental to humans' superior cognitive abilities, change over time as a result of decay, interference, and learning. We will apply cognitive tomography to a variety of experimental data sets, collected by our collaborators, in paradigms ranging from perceptual learning, through visual and motor structure learning, to social and concept learning. These analyses will allow us to conclusively and quantitatively test our central hypothesis that, rather than simply changing along a single 'memory strength' dimension, internal models typically change via complex and consistent patterns of transformations along multiple dimensions simultaneously. To facilitate the widespread use of our methods, we will release and support off-the-shelf usable implementations of our algorithms together with synthetic and real test data sets.

1 179 462 €

Start date: 2017-05-01, End date: 2022-04-30

For decades the cognitive neuroscience community has expended significant effort identifying system-level neural correlates of human consciousness, broad neural signatures that distinguish conscious from unconscious processes at the level of whole brain regions. Meanwhile, within the field of neurobiology, rapid progress has been made in understanding the neurotransmitter systems underlying basic sensory processes (e.g. in mice, monkeys). This research has, however, been performed in relative isolation from studies of human consciousness, and clear opportunities to link the two levels of description remain largely unexplored. Here I will establish this link by combining state-of-the-art neuroimaging techniques with pharmacological interventions. First, I will validate and refine existing theories of consciousness by isolating system-level neural correlates of consciousness that are invariant across experimental tasks and manipulations. Second, I will test the hypothesis that NMDA receptors play a crucial role in recurrent processing, the dynamic information exchange between brain regions, thought to give rise to consciousness. I will also test the hypothesis that rapid fluctuations in spontaneous network activity (modulating arousal levels), which are controlled by noradrenaline and acetylcholine neuromodulatory systems, determine the likelihood of sensory evoked recurrent processing, and hence consciousness, to occur. Third, I will test the hypothesis that recurrent processing provides the possibility for prolonged and flexible information processing, which could represent a potential function of consciousness. In summary, the proposed research has the potential to gain fundamental insights in the neural causes, rather than simply correlates, of human consciousness, as has been the focus of most previous work. In so doing, the work will advance scientific understanding of the long-debated functional significance of consciousness for human cognition and behavior.

1 499 766 €

Start date: 2017-05-01, End date: 2022-04-30

At the heart of the multi-faceted enterprise of formal semantics lies a simple yet powerful conception of meaning based on truth-conditions: one understands a sentence if one knows under which circumstances the sentence is true. This notion has been extremely fruitful resulting in a wealth of practical applications. But to what extent can it also account for the human linguistic behavior? The past decade has seen the increasing interaction between cognitive science and formal semantics, and the emergence of the new field of experimental semantics. One of its main challenges is the traditional normative take on meaning, which makes semantic theories hard to compare with experimental data. The aim of this project is to advance experimental semantics by building cognitive semantics, that is semantics founded on cognitive representations instead of normative logical abstractions. Numerical information plays a central role in communication. We talk about the number of students in a class, or the proportion of votes for a particular political party. In this project, I will focus on the linguistic expressions of quantities, known as quantifiers. Recent progress in the study of computational constraints on quantifier processing in natural language laid the groundwork for extending semantic theory with cognitive aspects. In parallel, cognitive science has furthered the study of non-linguistic quantity representations. This project will integrate formal models of quantifier semantics with cognitive quantity representations in order to obtain cognitive semantics of quantifiers, which is both logically precise and psychologically plausible. The theory will have significant repercussions, not only in the immediately related disciplines as semantics and psycholinguistics, but also beyond, e.g., in philosophy and in language technology.

1 457 063 €

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

Inhibitory control refers to the ability to control behavioural impulses and is critical for cognitive development. It has been traditionally thought of as a stable trait across the lifespan but recent insights from cognitive neuroscience show prolonged changes in brain regions that support inhibitory control indicating greater malleability than previously believed. Because childhood inhibitory control predicts well-being later in life this suggests exciting opportunities for enhancing inhibitory control. I build on highly promising pilot results and draw on a recent neurocognitive model of inhibitory control to test 1) if inhibitory control can be enhanced during childhood, 2) if this transfers onto other domains important for healthy psychological development such as prosocial- and patient decision-making and academic achievement and 3) which factors predict training success. Children aged 5 to 10 years will undergo 8 weeks of inhibitory control training, which is a critical duration for observing prolonged training effects and be compared to a group undergoing active sham-training of comparable stimuli and duration but without inhibition. I will assess training effects on the brain and look at transfer effects onto other domains such as other executive functions, prosocial- and patient decision-making and academic achievement, both immediately and 1 year after training. I expect training to 1) improve inhibitory control, 2) transfer onto performance on above-mentioned domains and 3) elicit neural changes indicating the effectiveness of training for re- and proactive control. I also expect that individual differences in inhibitory control ability and associated brain regions prior to training will predict training success. The proposed research has the potential to generate a new and ground-breaking framework on early malleability of inhibitory control with implications for interventions at the time point of greatest likely impact.

1 500 000 €

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

The DNA within our cells is constantly being damaged by both environmental and endogenous agents; of the many forms of DNA damage, the DNA double-strand break (DSB) is considered to be most dangerous. Correct processing of DSBs is not only essential for maintaining genomic integrity but is also required in specific biological processes, such as meiotic recombination and V(D)J recombination, in which DNA breaks are deliberately generated. In animals, defects in the proper response to DSBs can thus have different outcomes: cancer predisposition, embryonic lethality, or compromised immunity. Many genes that play a role in the processing of DSBs have been identified over the past decades, mainly by cloning genes that are responsible for specific human genomic instability or immune deficiency syndromes, and by genetic approaches using unicellular eukaryotes and rodent cell lines. It is, however, evident that many components required in higher eukaryotes are not yet known and the identification of those will be a major challenge for future research. Here, we will for the first time systematically test all genes encoded by an animals genome directly for their involvement in the cellular response to DSB in both somatic and germline tissues: we will use our recently developed transgenic animal models (C. elegans) that visualizes repair of a single localized genomic DNA break in genome wide RNAi screenings to identify (and then characterize) the complement of genes that are required to keep our genome stable, and when mutated can predispose humans to cancer. In parallel, we will study the cellular response to single DNA breaks that are artificially generated during different stages of gametogenesis, as well as address the developmental consequences of DSB induction during the earliest stages of embryonic development – an almost completely unexplored area in the field of genome instability and DNA damage responses.

1 060 000 €

Start date: 2008-05-01, End date: 2014-04-30

The human brain has evolved the ability to support communication in complex and dynamic environments. In such environments, language is learned, and mostly used in face-to-face contexts in which processing and learning is based on multiple cues: linguistic (such as lexical, syntactic), but also discourse, prosody, face and hands (gestures). Yet, our understanding of how language is learnt and processed, and its associated neural circuitry, comes almost exclusively from reductionist approaches in which the multimodal signal is reduced to speech or text. ECOLANG will pioneer a new way to study language comprehension and learning using a real-world approach in which language is analysed in its rich face-to-face multimodal environment (i.e., language’s ecological niche). Experimental rigour is not compromised by the use of innovative technologies (combining automatic, manual and crowdsourcing methods for annotation; creating avatar stimuli for our experiments) and state-of-the-art modelling and data analysis (probabilistic modelling and network-based analyses). ECOLANG studies how the different cues available in face-to-face communication dynamically contribute to processing and learning in adults, children and aphasic patients in contexts representative of everyday conversation. We collect and annotate a corpus of naturalistic language which is then used to derive quantitative informativeness measures for each cue and their combination using computational models, tested and refined on the basis of behavioural and neuroscientific data. We use converging methodologies (behavioural, EEG, fMRI and lesion-symptom mapping) and we investigate different populations (3-4 years old children, healthy and aphasic adults) in order to develop mechanistic accounts of multimodal communication at the cognitive as well as neural level that can explain processing and learning (by both children and adults) and can have impact on the rehabilitation of language functions after stroke.

2 243 584 €

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

The pioneering enterprise I propose is the study of a particular type of linguistic discontinuity – language revival – inspired by the revival of Hebrew at the end of the 19th century. The historical and sociocultural dimensions the revival have been studied before, but not its linguistic dimensions. My main aim is to construct a model of the linguistic factors which have shaped the revival of Hebrew. I expect this model to provide clues for the understanding of the process of language revival in general. For a language to be revived, a new grammar must be created by its native speakers. I hypothesize that the new grammar is formed by some of the general principles which also govern other better known cases of linguistic discontinuity (creoles, mixed languages, emergent sign languages etc.). The model I will develop will lay the foundation for a new subfield within the study of discontinuity – the study of language revival. I will start with careful work of documenting the development of the grammar of Modern Hebrew, in particular its syntax, something which has not been done systematically before. One product of the project will be a linguistic application for the documentation and annotation of the novel syntactic constructions of Modern Hebrew, their sources in previous stages of Hebrew and in the languages with which Modern Hebrew was in contact at the time of the revival, and the development of these constructions since the beginning of the revival until the present time. The linguistic application will be made available on the web for other linguists to use and to contribute to. The institution of an expanding data-base of the syntactic innovations of Modern Hebrew which comprises both documentation/ annotation and theoretical modeling which could be applied to other languages makes this an extremely ambitious proposal with potentially wide-reaching ramifications for the revival and revitalization of the languages of ethno-linguistic minorities world wide.

2 498 750 €

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

Epigenetic inheritance is the transmission of information, generally in the form of DNA methylation or post-translational modifications on histones that regulate the availability of underlying genetic information for transcription. RNA itself feeds back to contribute to histone modification. Sequence accessibility is both a matter of folding the chromatin fibre to alter access to recognition motifs, and the local concentration of factors needed for efficient transcriptional initiation, elongation, termination or mRNA stability. In heterochromatin we find a subset of regulatory factors in carefully balanced concentrations that are maintained in part by the segregation of active and inactive domains. Histone H3 K9 methylation is key to this compartmentation. C. elegans provides an ideal system in which to study chromatin-based gene repression. We have demonstrated that histone H3 K9 methylation is the essential signal for the sequestration of heterochromatin at the nuclear envelope in C. elegans. The recognition of H3K9me1/2/3 by an inner nuclear envelope-bound chromodomain protein, CEC-4, actively sequesters heterochromatin in embryos, and contributes redundantly in adult tissues. Epiherigans has the ambitious goal to determine definitively what targets H3K9 methylation, and identify its physiological roles. We will examine how this mark contributes to the epigenetic recognition of repeat vs non-repeat sequence, and mediates a stress-induced response to oxidative damage. We will examine the link between these and the spatial clustering of heterochromatic domains. Epiherigans will develop an integrated approach to identify in vivo the factors that distinguish repeats from non-repeats, self from non-self within genomes and will examine how H3K9me contributes to a persistent ROS or DNA damage stress response. It represents a crucial step towards understanding of how our genomes use heterochromatin to modulate, stabilize and transmit chromatin organization.

2 500 000 €

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

In Eukaryotes, cellular identity and tissue-specific functions are linked to the epigenetic landscape and the multi-scale architecture of the genome. The packing of DNA into nucleosomes at the ~100 bp scale and the organization of whole chromosomes into functional territories within the nucleus are well documented. At an intermediate scale, chromosomes are organised in megabase to sub-megabase structures called Topologically Associating Domains (TADs). Critically, TADs are highly correlated to patterns of epigenetic marks determining the transcriptional state of the genes they encompass. Until now, the lack of efficient technologies to map chromosome architecture and epigenetic marks at the single-cell level have limited our understanding of the molecular actors and mechanisms implicated in the establishment and maintenance of the multi-scale architecture of chromosomes and epigenetic states, and the interplay between this architecture and other nuclear functions such as transcription. The overall aim of EpiScope is to unveil the functional, multi-scale, 3D architecture of chromatin at the single-cell level while preserving cellular context, with a toolbox of groundbreaking high-performance microscopies (Hi-M). Hi-M will use unique combinations of multi-focus and single-molecule localization microscopies with novel DNA labeling methods and microfluidics. Hi-M will enable the study of structure-function relationships within TADs of different chromatin types and correlate single-cell variations in epigenomic patterns to 3D conformations with genomic specificity and at the nanoscale. Finally, Hi-M will be used to develop a novel high-throughput, high-content method to unveil the full pairwise distance distribution between thousands of genomic loci at the single cell level and at multiple length-scales. Our findings and technologies will shed new light into the mechanisms responsible for cellular memory, identity and differentiation.

1 999 780 €

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

"Gene expression in living cells is a most intricate molecular process, occurring in stages, each of which is regulated by a diversity of mechanisms. Among the various stages leading to gene expression, only transcription is relatively well understood, thanks to Genomics and bioinformatics. In contrast to the vast amounts of genome-wide data and a growing understanding of the structure of networks controlling transcription, we still lack quantitative, genome-wide knowledge of the mechanisms underlying regulation of mRNA degradation and translation. Among the unknowns are the identity of the regulators, their kinetic modes of action, and their means of interaction with the sequence features that make-up their targets; how these target combine to produce a higher level ""grammar"" is also unknown. An important part of the project is dedicated to generating genome-wide experimental data that will form the basis for quantitative and more comprehensive analysis of gene expression. Specifically, the primary objectives of our proposed research plan are: 1) to advance our understanding of the transcriptome, by deciphering the code regulating mRNA decay 2) to break the code which controls protein translation efficiency 3) to understand how mRNA degradation and translation efficiency determine noise in protein expression levels. The proposed strategy is based on an innovative combination of computational prediction, synthetic gene design, and genome-wide data acquisition, all culminating in extensive data analysis, mathematical modeling and focused experiments. This highly challenging, multidisciplinary project is likely to greatly enhance our knowledge of the various modes by which organisms regulate expression of their genomes, how these regulatory mechanisms are interrelated, how they generate precise response to environmental challenges and how they have evolved over time."

1 320 000 €

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

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

1 481 747 €

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

In human cells, two meters of DNA sequence are compressed into a nucleus whose linear size is five orders of magnitude smaller. Deciphering how this amazing structural organization is achieved and how DNA functions can ensue in the environment of a cell’s nucleus represent central questions for contemporary biology. Here, I embrace this challenge by establishing a comprehensive framework of microscopy and sequencing technologies coupled with advanced analytical approaches, aimed at addressing three fundamental highly-interconnected questions: 1) What are the design principles that govern DNA compaction? 2) How does genome structure vary between different cell types as well as among cells of the same type? 3) What is the link between genome structure and function? In preliminary experiments, we have devised a powerful method for Genomic loci Positioning by Sequencing (GPSeq) in fixed cells with optimally preserved nuclear morphology. In parallel, we are developing high-end microscopy tools for simultaneous localization of dozens of genomic locations at high resolution in thousands of single cells. We will obtain first-ever genome-wide maps of radial positioning of DNA loci in the nucleus, and combine them with available DNA contact probability maps in order to build 3D models of the human genome structure in different cell types. Using microscopy, we will visualize chromosomal shapes at unprecedented resolution, and use these rich datasets to discover general DNA folding principles. Finally, by combining high-resolution chromosome visualization with gene expression profiling in single cells, we will explore the link between DNA structure and function. Our study shall illuminate the design principles that dictate how genetic information is packed and read in the human nucleus, while providing a comprehensive repertoire of tools for studying genome organization.

1 499 808 €

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

Through smart technology, we are overwhelmed with new information. Does this unlimited access to knowledge make us smarter? One of the key challenges for modern societies is to understand how the brain assembles our rich inventory of knowledge. Here, I will test the hypothesis that newly acquired knowledge is represented in the hippocampal formation in neural concept spaces, which are based on the coding principles and representational structures of the neural machinery involved in spatial navigation. The key idea is that the brain’s navigation system provides the building blocks of a neural metric for knowledge. In this groundbreaking cognitive neuroscience framework, I will bridge and integrate principles from Nobel Prize awarded neurophysiology and concepts from cognitive science and philosophy. Partly building on my ERC-StG project in which I discovered the core neural mechanisms underlying reconfiguration, integration and scaling of memory networks, the aim of my proposal is two-fold: 1. I seek to decipher neural concept spaces and unravel the neural codes of a cognitive geometry for knowledge and its deformations. 2. I will provide a proof-of-principle framework for next-generation neurocognitive technology and neural user models for cognitive enhancement to edit memories and engineer knowledge. Novel ‘Wikipedia’ learning tasks will be combined with state-of-the-art pattern analyses of space-resolved fMRI and time-resolved MEG to map and quantify representational structures. I will further develop AI-inspired analyses and closed loop brain-computer interfaces to perturb and edit neural concept space. The integrative mission of my program, from cells to systems-level involvement in cognition and to technology, opens up the exciting possibility to lay the ground for redefining cognitive neuroscience of knowledge by unravelling the fundamental neural principles of a cognitive topography and to make critical translations to empower smart brains in a smart society.

2 000 000 €

Start date: 2017-05-01, End date: 2022-04-30

Most of language functions are under the left brain control in both left- and right-handers and involve structural asymmetries between the two hemispheres. While this asymmetry was considered as associated with handedness, such a relation has been recently questioned. Considering the strong language/gesture links in humans and the continuities between the gestural system in apes and monkeys and some language properties, we recently suggested the hypothesis of a continuity between language lateralization and asymmetry of communicative gestures in both human and nonhuman primates. Given the phylogenetical proximity between those species, comparative research on brain specialization between a non-linguistic gestural system (i.e., in monkeys) versus a linguistic gestural systems in humans (i.e., sign language in deaf) might help evaluating the gestural continuities with language lateralization in term of manual asymmetries, structural and functional lateralization of the brain. To this purpose, a first objective is to evaluate the continuities of manual and brain asymmetries between (1) a linguistic gestural system in humans using MRI in 100 adult native deaf French signers, and (2) a non-linguistic gestural system of adult baboons Papio anubis using 106 MRI brain images. A second objective is to explore the functional brain lateralization of gestures production in baboons (versus manipulation) using non-invasive wireless Infrared Spectroscopy in 8 trained subjects within interactions with humans. A last innovative objective is to investigate, through the first non-invasive longitudinal MRI study conducted from birth to sexual maturity in primates, the development and heritability of brain structural asymmetries and their correlates with gesture asymmetries in 30 baboons. At both evolutionary and developmental levels, the project will thus ultimately contribute to enhance our understanding on the role of gestures in the origins of brain specialization for language.

1 499 192 €

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

Hematopoiesis is an important model for stem cell differentiation with great medical significance. Heterogeneity within hematopoietic progenitor populations has considerably limited characterization and molecular understanding of lineage commitment in both health and disease. Advances in single-cell genomic technologies provide an extraordinary opportunity for unbiased and high resolution mapping of biological function and regulation. Recently we have developed an experimental and analytical method, termed massively parallel single-cell RNA-Seq (MARS-Seq), for unbiased classification of individual cells from their native context and successfully applied it for characterization of immune and hematopoietic progenitors. Here, we propose to uncover the hierarchy and regulatory mechanisms controlling hematopoiesis by combining comprehensive single-cell RNA-Seq analyses, modelling approaches, advanced functional assays, single-cell CRISPR screens, knockout models and epigenetic profiling. Exciting preliminary result show that indeed our approach is starting to uncover the complexity of hematopoietic progenitors and the regulatory circuits driving hematopoietic decisions. We will pursue the following aims: (i) Generate a refined model of hematopoiesis by comprehensive single-cell RNA-Seq profiling of hematopoietic progenitors, (ii) validate the predicted model by in vivo functional developmental assays and then (iii) test candidate transcription and chromatin factors uncovered by our model for their role in controlling progression towards various lineages using single-cell measurements combined with CRISPR screens. Together, our study is expected to generate a revised and high-resolution hematopoietic model and decipher the regulatory networks that control hematopoiesis. Our methods and models may provide a platform for future medical advancements including a large-scale European collaborative project to discover a comprehensive human hematopoietic tree.

2 000 000 €

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

The European Late Middle Ages, before the Reformation in the 16th century, were witness to a cultural revolution. The ‘traditional’ dichotomy between the categories ‘religious’ and ‘lay’ and ‘Latin’ and ‘vernacular’ dissolved into a more diffuse situation and led to ‘lay emancipation’ characterised by a dramatic increase in the production of vernacular religious texts and, more specifically, by the production and distribution of vernacular Bibles. However, the diffusion of Bible translations across Europe was not homogeneous. Some regions enjoyed several vernacular translations, counting on lenience and even incentives from religious and worldly authorities, while in other translation activities, production and distribution were at some point strictly forbidden. This disparity and the patchwork distribution of vernacular Bibles raise questions about the conditions of this late medieval cultural revolution, a key to the understanding of the transition from the medieval to modern world. What were the ‘cultural dynamics’ behind this revolution? Who were the agents of this transformation process? How can the tension be analysed between the desire of the Church to control the distribution of translations and the hunger for direct access to biblical texts by generally literate lay people? The main objective of Holy Writ & Lay Readers is to map out this late medieval cultural revolution by concentrating on one of its most relevant manifestations and to reconstruct its social context by using an experimental research method which combines extensive codicological and bibliographical textual research with a socio-historical approach. The central question will be addressed by focusing on the interaction of social and cultural elements, such as a high degree of urbanisation and susceptibility to the influence of religious movements which, as preliminary research has shown, were strictly connected to the diffusion of religious vernacular texts.

683 688 €

Start date: 2008-10-01, End date: 2012-09-30

In daily social interactions, we constantly attribute mental states, such as beliefs or intentions, to other humans – to understand and predict their behaviour. Today we also routinely interact with artificial agents: from Apple’s Siri to GPS navigation systems. In the near future, we will casually interact with robots. However, since we consider artificial agents to have no mental states, we tend to not attune socially with them in the sense of activating our mechanisms of social cognition. This is because it seems pointless to socially attune to something that does not carry social meaning (mental content) under the surface of an observed behaviour. INSTANCE will break new ground in social cognition research by identifying factors that influence attribution of mental states to others and social attunement with humans or artificial agents. The objectives of INSTANCE are to (1) determine parameters of others’ behaviour that make us attribute mental states to them, (2) explore parameters relevant for social attunement, (3) elucidate further factors – culture and experience – that influence attribution of mental states to agents and, thereby social attunement. INSTANCE’s objectives are highly relevant not only for fundamental research in social cognition, but also for the applied field of social robotics, where robots are expected to become humans’ social companions. Indeed, if we do not attune socially to artificial agents viewed as mindless machines, then robots may end up not working well enough in contexts where interaction is paramount. INSTANCE’s unique approach combining cognitive neuroscience methods with real-time human-robot interaction will address the challenge of social attunement between humans and artificial agents. Subtle features of robot behaviour (e.g., timing or pattern of eye movements) will be manipulated. The impact of such features on social attunement (e.g., joint attention) will be examined with behavioural, neural and physiological measures.

1 499 937 €

Start date: 2017-05-01, End date: 2022-04-30