Project acronym 4C
Project 4C technology: uncovering the multi-dimensional structure of the genome
Researcher (PI) Wouter Leonard De Laat
Host Institution (HI) KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary The architecture of DNA in the cell nucleus is an emerging epigenetic key contributor to genome function. We recently developed 4C technology, a high-throughput technique that combines state-of-the-art 3C technology with tailored micro-arrays to uniquely allow for an unbiased genome-wide search for DNA loci that interact in the nuclear space. Based on 4C technology, we were the first to provide a comprehensive overview of long-range DNA contacts of selected loci. The data showed that active and inactive chromatin domains contact many distinct regions within and between chromosomes and genes switch long-range DNA contacts in relation to their expression status. 4C technology not only allows investigating the three-dimensional structure of DNA in the nucleus, it also accurately reconstructs at least 10 megabases of the one-dimensional chromosome sequence map around the target sequence. Changes in this physical map as a result of genomic rearrangements are therefore identified by 4C technology. We recently demonstrated that 4C detects deletions, balanced inversions and translocations in patient samples at a resolution (~7kb) that allowed immediate sequencing of the breakpoints. Excitingly, 4C technology therefore offers the first high-resolution genomic approach that can identify both balanced and unbalanced genomic rearrangements. 4C is expected to become an important tool in clinical diagnosis and prognosis. Key objectives of this proposal are: 1. Explore the functional significance of DNA folding in the nucleus by systematically applying 4C technology to differentially expressed gene loci. 2. Adapt 4C technology such that it allows for massive parallel analysis of DNA interactions between regulatory elements and gene promoters. This method would greatly facilitate the identification of functionally relevant DNA elements in the genome. 3. Develop 4C technology into a clinical diagnostic tool for the accurate detection of balanced and unbalanced rearrangements.
Summary
The architecture of DNA in the cell nucleus is an emerging epigenetic key contributor to genome function. We recently developed 4C technology, a high-throughput technique that combines state-of-the-art 3C technology with tailored micro-arrays to uniquely allow for an unbiased genome-wide search for DNA loci that interact in the nuclear space. Based on 4C technology, we were the first to provide a comprehensive overview of long-range DNA contacts of selected loci. The data showed that active and inactive chromatin domains contact many distinct regions within and between chromosomes and genes switch long-range DNA contacts in relation to their expression status. 4C technology not only allows investigating the three-dimensional structure of DNA in the nucleus, it also accurately reconstructs at least 10 megabases of the one-dimensional chromosome sequence map around the target sequence. Changes in this physical map as a result of genomic rearrangements are therefore identified by 4C technology. We recently demonstrated that 4C detects deletions, balanced inversions and translocations in patient samples at a resolution (~7kb) that allowed immediate sequencing of the breakpoints. Excitingly, 4C technology therefore offers the first high-resolution genomic approach that can identify both balanced and unbalanced genomic rearrangements. 4C is expected to become an important tool in clinical diagnosis and prognosis. Key objectives of this proposal are: 1. Explore the functional significance of DNA folding in the nucleus by systematically applying 4C technology to differentially expressed gene loci. 2. Adapt 4C technology such that it allows for massive parallel analysis of DNA interactions between regulatory elements and gene promoters. This method would greatly facilitate the identification of functionally relevant DNA elements in the genome. 3. Develop 4C technology into a clinical diagnostic tool for the accurate detection of balanced and unbalanced rearrangements.
Max ERC Funding
1 225 000 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym ALMP_ECON
Project Effective evaluation of active labour market policies in social insurance programs - improving the interaction between econometric evaluation estimators and economic theory
Researcher (PI) Bas Van Der Klaauw
Host Institution (HI) STICHTING VU
Call Details Starting Grant (StG), SH1, ERC-2007-StG
Summary In most European countries social insurance programs, like welfare, unemployment insurance and disability insurance are characterized by low reemployment rates. Therefore, governments spend huge amounts of money on active labour market programs, which should help individuals in finding work. Recent surveys indicate that programs which aim at intensifying job search behaviour are much more effective than schooling programs for improving human capital. A second conclusion from these surveys is that despite the size of the spendings on these programs, evidence on its effectiveness is limited. This research proposal aims at developing an economic framework that will be used to evaluate the effectiveness of popular programs like offering reemployment bonuses, fraud detection, workfare and job search monitoring. The main innovation is that I will combine economic theory with recently developed econometric techniques and detailed administrative data sets, which have not been explored before. While most of the literature only focuses on short-term outcomes, the available data allow me to also consider the long-term effectiveness of programs. The key advantage of an economic model is that I can compare the effectiveness of the different programs, consider modifications of programs and combinations of programs. Furthermore, using an economic model I can construct profiling measures to improve the targeting of programs to subsamples of the population. This is particularly relevant if the effectiveness of programs differs between individuals or depends on the moment in time the program is offered. Therefore, the results from this research will not only be of scientific interest, but will also be of great value to policymakers.
Summary
In most European countries social insurance programs, like welfare, unemployment insurance and disability insurance are characterized by low reemployment rates. Therefore, governments spend huge amounts of money on active labour market programs, which should help individuals in finding work. Recent surveys indicate that programs which aim at intensifying job search behaviour are much more effective than schooling programs for improving human capital. A second conclusion from these surveys is that despite the size of the spendings on these programs, evidence on its effectiveness is limited. This research proposal aims at developing an economic framework that will be used to evaluate the effectiveness of popular programs like offering reemployment bonuses, fraud detection, workfare and job search monitoring. The main innovation is that I will combine economic theory with recently developed econometric techniques and detailed administrative data sets, which have not been explored before. While most of the literature only focuses on short-term outcomes, the available data allow me to also consider the long-term effectiveness of programs. The key advantage of an economic model is that I can compare the effectiveness of the different programs, consider modifications of programs and combinations of programs. Furthermore, using an economic model I can construct profiling measures to improve the targeting of programs to subsamples of the population. This is particularly relevant if the effectiveness of programs differs between individuals or depends on the moment in time the program is offered. Therefore, the results from this research will not only be of scientific interest, but will also be of great value to policymakers.
Max ERC Funding
550 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym DSBREPAIR
Project Developmental and Genetic Analysis of DNA Double-Strand Break Repair
Researcher (PI) Marcel Tijsterman
Host Institution (HI) ACADEMISCH ZIEKENHUIS LEIDEN
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary 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.
Summary
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.
Max ERC Funding
1 060 000 €
Duration
Start date: 2008-05-01, End date: 2014-04-30
Project acronym ON THE OTHER HAND
Project On the other hand: the linguistic impact of having two symmetrical articulators in sign language
Researcher (PI) Onno Alex Crasborn
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Starting Grant (StG), SH3, ERC-2007-StG
Summary Deaf people communicate with two hands. Hearing people communicate with only one mouth. What are the implications of this difference for our view of human language? The proposed research aims to approach this central issue by addressing a number of new and concrete questions, using highly innovative methods. Linguistic models are generally based on the fact that spoken language structures are linear and hierarchically structured. The symmetry of the two hands in signed languages makes room for abundant simultaneity, even though our motor system imposes severe constraints on the independent action of the two hands. We know that deaf people rarely utter two different sentences at the same time (one with the left and one with the right hand), but there are indications that from below the level of single signs up to the structuring of discourse, the two hands contribute to communication in a fashion unparalleled in spoken languages. The two hands can be mere copies of each other, but in many well-described cases the second hand is not redundant and both hands can perform independent linguistic functions. This proposal focuses on three questions that target different components in Nederlandse Gebarentaal (NGT, Sign Language of the Netherlands): discourse, syntax, and phonology. 1. What kind of information does a second hand contribute to signed communication in longer utterances (discourse)? 2. Which types of utterances in which a second hand occurs (subordination, coordination, parenthesis, apposition) can be distinguished in signed sentences? 3. What are the constraints on the one-handed articulation of two-handed signs, which is often necessary to create simultaneous constructions? To answer these questions, the most recent technical possibilities will be employed. Our corpus of NGT (Sign Language of the Netherlands), one of the first and largest digital sign language corpora in the world, will serve as the central resource for addressing all questions.
Summary
Deaf people communicate with two hands. Hearing people communicate with only one mouth. What are the implications of this difference for our view of human language? The proposed research aims to approach this central issue by addressing a number of new and concrete questions, using highly innovative methods. Linguistic models are generally based on the fact that spoken language structures are linear and hierarchically structured. The symmetry of the two hands in signed languages makes room for abundant simultaneity, even though our motor system imposes severe constraints on the independent action of the two hands. We know that deaf people rarely utter two different sentences at the same time (one with the left and one with the right hand), but there are indications that from below the level of single signs up to the structuring of discourse, the two hands contribute to communication in a fashion unparalleled in spoken languages. The two hands can be mere copies of each other, but in many well-described cases the second hand is not redundant and both hands can perform independent linguistic functions. This proposal focuses on three questions that target different components in Nederlandse Gebarentaal (NGT, Sign Language of the Netherlands): discourse, syntax, and phonology. 1. What kind of information does a second hand contribute to signed communication in longer utterances (discourse)? 2. Which types of utterances in which a second hand occurs (subordination, coordination, parenthesis, apposition) can be distinguished in signed sentences? 3. What are the constraints on the one-handed articulation of two-handed signs, which is often necessary to create simultaneous constructions? To answer these questions, the most recent technical possibilities will be employed. Our corpus of NGT (Sign Language of the Netherlands), one of the first and largest digital sign language corpora in the world, will serve as the central resource for addressing all questions.
Max ERC Funding
500 000 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym RPPV
Project Representation and Processing of Pitch Variation in Tonal Languages
Researcher (PI) Yiya Chen
Host Institution (HI) UNIVERSITEIT LEIDEN
Call Details Starting Grant (StG), SH3, ERC-2007-StG
Summary In connected speech, spoken words may vary considerably from their forms in isolation. Much of the variation is regular. There have been heated debates on whether and how speakers store regular variants in their long-term memory, and how they process them in speech production and comprehension. Most psycholinguistic work, however, focuses on how listeners cope with segmental variation. I propose instead to examine how speakers store and process regular pitch variation. My empirical focus is on Chinese dialects, where pitch changes (tones) are used to distinguish word meanings in isolation, but tonal realization of words in phrases is determined by domain formation and pitch changes within the domain, together known as tone sandhi. Crucially, both how a tonal domain is formed and how sandhi variants are realized within the domain are influenced by a complex mixture of pragmatic, syntactic, and phonological factors. The pitch variation in these dialects thus manifests at all levels of linguistic organization. I hypothesize that the way pitch variation is stored in the mental lexicon and processed during speech production varies according to the types of tone sandhi changes and the constituent structures of sandhi domains. I take an interdisciplinary approach to test this hypothesis. Cross-dialect speech corpora will be compiled to obtain a comprehensive understanding of how pitch variation is conditioned in linguistic contexts. Acoustic and perceptual experiments will be conducted to understand the categorical vs. gradient nature of pitch variation. Both voice onset latencies and speakers’ eye movements during speech will be monitored to tap into the representation as well as the processing of pitch variation. Results of this project will contribute to debates on representation and processing of regular linguistic variation in general, therefore furthering our understanding of human cognition.
Summary
In connected speech, spoken words may vary considerably from their forms in isolation. Much of the variation is regular. There have been heated debates on whether and how speakers store regular variants in their long-term memory, and how they process them in speech production and comprehension. Most psycholinguistic work, however, focuses on how listeners cope with segmental variation. I propose instead to examine how speakers store and process regular pitch variation. My empirical focus is on Chinese dialects, where pitch changes (tones) are used to distinguish word meanings in isolation, but tonal realization of words in phrases is determined by domain formation and pitch changes within the domain, together known as tone sandhi. Crucially, both how a tonal domain is formed and how sandhi variants are realized within the domain are influenced by a complex mixture of pragmatic, syntactic, and phonological factors. The pitch variation in these dialects thus manifests at all levels of linguistic organization. I hypothesize that the way pitch variation is stored in the mental lexicon and processed during speech production varies according to the types of tone sandhi changes and the constituent structures of sandhi domains. I take an interdisciplinary approach to test this hypothesis. Cross-dialect speech corpora will be compiled to obtain a comprehensive understanding of how pitch variation is conditioned in linguistic contexts. Acoustic and perceptual experiments will be conducted to understand the categorical vs. gradient nature of pitch variation. Both voice onset latencies and speakers’ eye movements during speech will be monitored to tap into the representation as well as the processing of pitch variation. Results of this project will contribute to debates on representation and processing of regular linguistic variation in general, therefore furthering our understanding of human cognition.
Max ERC Funding
600 000 €
Duration
Start date: 2008-11-01, End date: 2014-10-31
Project acronym SPATIAL MEMORY
Project Neural correlates of spatial memory in children and adults
Researcher (PI) Gabriele Janzen
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Starting Grant (StG), SH3, ERC-2007-StG
Summary In everyday life we navigate through known and unknown spatial environments. We have to learn how to find our way back, make a detour around a barrier or find a shortcut. The ability to remember the spatial surroundings and to communicate about space has been crucial to human adaptation and survival. The proposed research project investigates the development of spatial skills, the underlying neural correlates of spatial representations and spatial wayfinding mechanisms, spatial language and their linkage. Recent comparative studies have shown that human infants early in their cognitive development share a spatial memory strategy with all non-human great apes. This strategy preference for spatial cues in young human infants changes during the first years in childhood into a preference for a feature based strategy. Recent functional Magnetic Resonance Imaging (fMRI) studies have shown the enormous importance of spatial cues for successful wayfinding. I will push forward these findings and investigate how spatial cues are learned and represented during child and adulthood and later used for actual navigation. The role of language for spatial strategies to date is entirely unknown. Language could play a key role in spatial strategy switch during childhood as well as affect wayfinding strategies for children and adults. The combination of different methods, FMRI, EEG, measurement of eye-movements, response times as well as navigational behaviour collected during initial and repeated spatial cue learning and wayfinding will provide answers to these questions. In sum, the proposed research provides new insight into the nature of human spatial thinking for children and adults.
Summary
In everyday life we navigate through known and unknown spatial environments. We have to learn how to find our way back, make a detour around a barrier or find a shortcut. The ability to remember the spatial surroundings and to communicate about space has been crucial to human adaptation and survival. The proposed research project investigates the development of spatial skills, the underlying neural correlates of spatial representations and spatial wayfinding mechanisms, spatial language and their linkage. Recent comparative studies have shown that human infants early in their cognitive development share a spatial memory strategy with all non-human great apes. This strategy preference for spatial cues in young human infants changes during the first years in childhood into a preference for a feature based strategy. Recent functional Magnetic Resonance Imaging (fMRI) studies have shown the enormous importance of spatial cues for successful wayfinding. I will push forward these findings and investigate how spatial cues are learned and represented during child and adulthood and later used for actual navigation. The role of language for spatial strategies to date is entirely unknown. Language could play a key role in spatial strategy switch during childhood as well as affect wayfinding strategies for children and adults. The combination of different methods, FMRI, EEG, measurement of eye-movements, response times as well as navigational behaviour collected during initial and repeated spatial cue learning and wayfinding will provide answers to these questions. In sum, the proposed research provides new insight into the nature of human spatial thinking for children and adults.
Max ERC Funding
873 476 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym TRANH
Project Tarski’s Revolution: A New History. Semantics and Axiomatics from Bolzano to Tarski against the background of the Classical Model of Science
Researcher (PI) Arianna Betti
Host Institution (HI) STICHTING VU
Call Details Starting Grant (StG), SH3, ERC-2007-StG
Summary This project aims at rewriting the history of Tarski’s revolution in semantics by taking into account the development of axiomatics from Bolzano to Tarski. Bolzano’s extraordinary work in semantics has been especially significant for the Polish tradition to which Tarski belongs, and Tarski’s ideas in turn changed the course of contemporary analytic philosophy. Tarski’s work represents a crucial turn in the history of semantics and related fields. The research project aims to establish that the turn at issue must be interpreted in connection with the development of axiomatics in Poland. In particular, the project proposes to interpret Tarski’s turn on the basis of a new framework, the Classical Model of Science, which systematises a general axiomatic ideal of scientific knowledge. The ideal goes back to Aristotle’s “Analytica Posteriora” and has been highly influential for more than two millennia. The interpretation proposed is radically new with respect to existing ones. It is also the only one to offer a convincing account of elements of both continuity and discontinuity in the historical tradition under investigation. The project divides into three subprojects: (I) 'Semantics and Axiomatics in Bolzano against the background of the Classical Model of Science'; (II) 'Semantics and Axiomatics in Tarski against the background of the Classical Model of Science'; (III) 'Semantics and Axiomatics from Bolzano to Tarski against the background of the Classical Model of Science'. The research will be carried out on the basis of original Polish and German sources by a team formed by myself (Project III) and two new members to be appointed, one at PhD level (Project I) and one at Postdoc level (Project II). The project will set a new course in the fragmented field of research on Tarski’s work and its roots and open new perspectives for neighbouring fields. It will also bring to the spotlight the Eastern European analytic tradition, still largely unexplored today.
Summary
This project aims at rewriting the history of Tarski’s revolution in semantics by taking into account the development of axiomatics from Bolzano to Tarski. Bolzano’s extraordinary work in semantics has been especially significant for the Polish tradition to which Tarski belongs, and Tarski’s ideas in turn changed the course of contemporary analytic philosophy. Tarski’s work represents a crucial turn in the history of semantics and related fields. The research project aims to establish that the turn at issue must be interpreted in connection with the development of axiomatics in Poland. In particular, the project proposes to interpret Tarski’s turn on the basis of a new framework, the Classical Model of Science, which systematises a general axiomatic ideal of scientific knowledge. The ideal goes back to Aristotle’s “Analytica Posteriora” and has been highly influential for more than two millennia. The interpretation proposed is radically new with respect to existing ones. It is also the only one to offer a convincing account of elements of both continuity and discontinuity in the historical tradition under investigation. The project divides into three subprojects: (I) 'Semantics and Axiomatics in Bolzano against the background of the Classical Model of Science'; (II) 'Semantics and Axiomatics in Tarski against the background of the Classical Model of Science'; (III) 'Semantics and Axiomatics from Bolzano to Tarski against the background of the Classical Model of Science'. The research will be carried out on the basis of original Polish and German sources by a team formed by myself (Project III) and two new members to be appointed, one at PhD level (Project I) and one at Postdoc level (Project II). The project will set a new course in the fragmented field of research on Tarski’s work and its roots and open new perspectives for neighbouring fields. It will also bring to the spotlight the Eastern European analytic tradition, still largely unexplored today.
Max ERC Funding
897 472 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
