Project acronym 3DCellPhase-
Project In situ Structural Analysis of Molecular Crowding and Phase Separation
Researcher (PI) Julia MAHAMID
Host Institution (HI) EUROPEAN MOLECULAR BIOLOGY LABORATORY
Call Details Starting Grant (StG), LS1, ERC-2017-STG
Summary This proposal brings together two fields in biology, namely the emerging field of phase-separated assemblies in cell biology and state-of-the-art cellular cryo-electron tomography, to advance our understanding on a fundamental, yet illusive, question: the molecular organization of the cytoplasm.
Eukaryotes organize their biochemical reactions into functionally distinct compartments. Intriguingly, many, if not most, cellular compartments are not membrane enclosed. Rather, they assemble dynamically by phase separation, typically triggered upon a specific event. Despite significant progress on reconstituting such liquid-like assemblies in vitro, we lack information as to whether these compartments in vivo are indeed amorphous liquids, or whether they exhibit structural features such as gels or fibers. My recent work on sample preparation of cells for cryo-electron tomography, including cryo-focused ion beam thinning, guided by 3D correlative fluorescence microscopy, shows that we can now prepare site-specific ‘electron-transparent windows’ in suitable eukaryotic systems, which allow direct examination of structural features of cellular compartments in their cellular context. Here, we will use these techniques to elucidate the structural principles and cytoplasmic environment driving the dynamic assembly of two phase-separated compartments: Stress granules, which are RNA bodies that form rapidly in the cytoplasm upon cellular stress, and centrosomes, which are sites of microtubule nucleation. We will combine these studies with a quantitative description of the crowded nature of cytoplasm and of its local variations, to provide a direct readout of the impact of excluded volume on molecular assembly in living cells. Taken together, these studies will provide fundamental insights into the structural basis by which cells form biochemical compartments.
Summary
This proposal brings together two fields in biology, namely the emerging field of phase-separated assemblies in cell biology and state-of-the-art cellular cryo-electron tomography, to advance our understanding on a fundamental, yet illusive, question: the molecular organization of the cytoplasm.
Eukaryotes organize their biochemical reactions into functionally distinct compartments. Intriguingly, many, if not most, cellular compartments are not membrane enclosed. Rather, they assemble dynamically by phase separation, typically triggered upon a specific event. Despite significant progress on reconstituting such liquid-like assemblies in vitro, we lack information as to whether these compartments in vivo are indeed amorphous liquids, or whether they exhibit structural features such as gels or fibers. My recent work on sample preparation of cells for cryo-electron tomography, including cryo-focused ion beam thinning, guided by 3D correlative fluorescence microscopy, shows that we can now prepare site-specific ‘electron-transparent windows’ in suitable eukaryotic systems, which allow direct examination of structural features of cellular compartments in their cellular context. Here, we will use these techniques to elucidate the structural principles and cytoplasmic environment driving the dynamic assembly of two phase-separated compartments: Stress granules, which are RNA bodies that form rapidly in the cytoplasm upon cellular stress, and centrosomes, which are sites of microtubule nucleation. We will combine these studies with a quantitative description of the crowded nature of cytoplasm and of its local variations, to provide a direct readout of the impact of excluded volume on molecular assembly in living cells. Taken together, these studies will provide fundamental insights into the structural basis by which cells form biochemical compartments.
Max ERC Funding
1 228 125 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym AMBH
Project Ancient Music Beyond Hellenisation
Researcher (PI) Stefan HAGEL
Host Institution (HI) OESTERREICHISCHE AKADEMIE DER WISSENSCHAFTEN
Call Details Advanced Grant (AdG), SH5, ERC-2017-ADG
Summary From medieval times, Arabic as well as European music was analysed in terms that were inherited from Classical Antiquity and had thus developed in a very different music culture. In spite of recent breakthroughs in the understanding of the latter, whose technicalities we access not only through texts and iconography, but also through instrument finds and surviving notated melodies, its relation to music traditions known from later periods and different places is almost uncharted territory.
The present project explores relations between Hellenic/Hellenistic music as pervaded the theatres and concert halls throughout and beyond the Roman empire, Near Eastern traditions – from the diatonic system emerging from cuneiform sources to the flourishing musical world of the caliphates – and, as far as possible, African musical life south of Egypt as well – a region that maintained close ties both with the Hellenised culture of its northern neighbours and with the Arabian Peninsula.
On the one hand, this demands collaboration between Classical Philology and Arabic Studies, extending methods recently developed within music archaeological research related to the Classical Mediterranean. Arabic writings need to be examined in close reading, using recent insights into the interplay between ancient music theory and practice, in order to segregate the influence of Greek thinking from ideas and facts that must relate to contemporaneous ‘Arabic’ music-making. In this way we hope better to define the relation of this tradition to the ‘Classical world’, potentially breaking free of Orientalising bias informing modern views. On the other hand, the study and reconstruction, virtual and material, of wind instruments of Hellenistic pedigree but found outside the confinements of the Hellenistic ‘heartlands’ may provide evidence of ‘foreign’ tonality employed in those regions – specifically the royal city of Meroë in modern Sudan and the Oxus Temple in modern Tajikistan.
Summary
From medieval times, Arabic as well as European music was analysed in terms that were inherited from Classical Antiquity and had thus developed in a very different music culture. In spite of recent breakthroughs in the understanding of the latter, whose technicalities we access not only through texts and iconography, but also through instrument finds and surviving notated melodies, its relation to music traditions known from later periods and different places is almost uncharted territory.
The present project explores relations between Hellenic/Hellenistic music as pervaded the theatres and concert halls throughout and beyond the Roman empire, Near Eastern traditions – from the diatonic system emerging from cuneiform sources to the flourishing musical world of the caliphates – and, as far as possible, African musical life south of Egypt as well – a region that maintained close ties both with the Hellenised culture of its northern neighbours and with the Arabian Peninsula.
On the one hand, this demands collaboration between Classical Philology and Arabic Studies, extending methods recently developed within music archaeological research related to the Classical Mediterranean. Arabic writings need to be examined in close reading, using recent insights into the interplay between ancient music theory and practice, in order to segregate the influence of Greek thinking from ideas and facts that must relate to contemporaneous ‘Arabic’ music-making. In this way we hope better to define the relation of this tradition to the ‘Classical world’, potentially breaking free of Orientalising bias informing modern views. On the other hand, the study and reconstruction, virtual and material, of wind instruments of Hellenistic pedigree but found outside the confinements of the Hellenistic ‘heartlands’ may provide evidence of ‘foreign’ tonality employed in those regions – specifically the royal city of Meroë in modern Sudan and the Oxus Temple in modern Tajikistan.
Max ERC Funding
775 959 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym ArsNova
Project European Ars Nova: Multilingual Poetry and Polyphonic Song in the Late Middle Ages
Researcher (PI) Maria Sofia LANNUTTI
Host Institution (HI) UNIVERSITA DEGLI STUDI DI FIRENZE
Call Details Advanced Grant (AdG), SH5, ERC-2017-ADG
Summary Dante Alighieri at the dawn of the 1300s, as well as Eustache Deschamps almost a century later, conceived poetry as music in itself. But what happens with poetry when it is involved in the complex architecture of polyphony? The aim of this project is to study for the first time the corpus of 14th- and early 15th-century poetry set to music by Ars Nova polyphonists (more than 1200 texts). This repertoire gathers different poetic and musical traditions, as shown by the multilingual anthologies copied during the last years of the Schism. The choice of this corpus is motivated by two primary goals: a) to offer a new interpretation of its meaning and function in the cultural and historical context, one that may be then applied to the rest of coeval European lyric poetry; b) to overcome current disciplinary divisions in order to generate a new methodological balance between the project’s two main fields of interest (Comparative Literature / Musicology). Most Ars Nova polyphonists were directly associated with religious institutions. In many texts, the language of courtly love expresses the values of caritas, the theological virtue that guides wise rulers and leads them to desire the common good. Thus, the poetic figure of the lover becomes a metaphor for the political man, and love poetry can be used as a device for diplomacy, as well as for personal and institutional propaganda. From this unprecedented point of view, the project will develop three research lines in response to the following questions: 1) How is the relationship between poetry and music, and how is the dialogue between the different poetic and musical traditions viewed in relation to each context of production? 2) To what extent does Ars Nova poetry take part in the ‘soft power’ strategies exercised by the entire European political class of the time? 3) Is there a connection between the multilingualism of the manuscript tradition and the perception of the Ars Nova as a European, intercultural repertoire?
Summary
Dante Alighieri at the dawn of the 1300s, as well as Eustache Deschamps almost a century later, conceived poetry as music in itself. But what happens with poetry when it is involved in the complex architecture of polyphony? The aim of this project is to study for the first time the corpus of 14th- and early 15th-century poetry set to music by Ars Nova polyphonists (more than 1200 texts). This repertoire gathers different poetic and musical traditions, as shown by the multilingual anthologies copied during the last years of the Schism. The choice of this corpus is motivated by two primary goals: a) to offer a new interpretation of its meaning and function in the cultural and historical context, one that may be then applied to the rest of coeval European lyric poetry; b) to overcome current disciplinary divisions in order to generate a new methodological balance between the project’s two main fields of interest (Comparative Literature / Musicology). Most Ars Nova polyphonists were directly associated with religious institutions. In many texts, the language of courtly love expresses the values of caritas, the theological virtue that guides wise rulers and leads them to desire the common good. Thus, the poetic figure of the lover becomes a metaphor for the political man, and love poetry can be used as a device for diplomacy, as well as for personal and institutional propaganda. From this unprecedented point of view, the project will develop three research lines in response to the following questions: 1) How is the relationship between poetry and music, and how is the dialogue between the different poetic and musical traditions viewed in relation to each context of production? 2) To what extent does Ars Nova poetry take part in the ‘soft power’ strategies exercised by the entire European political class of the time? 3) Is there a connection between the multilingualism of the manuscript tradition and the perception of the Ars Nova as a European, intercultural repertoire?
Max ERC Funding
2 193 375 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym ATG9_SOLVES_IT
Project In vitro high resolution reconstitution of autophagosome nucleation and expansion catalyzed byATG9
Researcher (PI) Sharon TOOZE
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Advanced Grant (AdG), LS1, ERC-2017-ADG
Summary Autophagy is a conserved, lysosomal-mediated pathway required for cell homeostasis and survival. It is controlled by the master regulators of energy (AMPK) and growth (TORC1) and mediated by the ATG (autophagy) proteins. Deregulation of autophagy is implicated in cancer, immunity, infection, aging and neurodegeneration. Autophagosomes form and expand using membranes from the secretory and endocytic pathways but how this occurs is not understood. ATG9, the only transmembrane ATG protein traffics through the cell in vesicles, and is essential for rapid initiation and expansion of the membranes which form the autophagosome. Crucially, how ATG9 functions is unknown. I will determine how ATG9 initiates the formation and expansion of the autophagosome by amino acid starvation through a molecular dissection of proteins resident in ATG9 vesicles which modulate the composition and property of the initiating membrane. I will employ high resolution light and electron microscopy to characterize the nucleation of the autophagosome, proximity-specific biotinylation and quantitative Mass Spectrometry to uncover the proteome required for the function of the ATG9, and optogenetic tools to acutely regulate signaling lipids. Lastly, with our tools and knowledge I will develop an in vitro reconstitution system to define at a molecular level how ATG9 vesicle proteins, membranes that interact with ATG9 vesicles, and other accessory ATG components nucleate and form an autophagosome. In vitro reconstitution of autophagosomes will be assayed biochemically, and by correlative light and cryo-EM and cryo-EM tomography, while functional reconstitution of autophagy will be tested by selective cargo recruitment. The development of a reconstituted system and identification proteins and lipids which are key components for autophagosome formation will provide a means to identify a new generation of targets for translational work leading to manipulation of autophagy for disease related therapies.
Summary
Autophagy is a conserved, lysosomal-mediated pathway required for cell homeostasis and survival. It is controlled by the master regulators of energy (AMPK) and growth (TORC1) and mediated by the ATG (autophagy) proteins. Deregulation of autophagy is implicated in cancer, immunity, infection, aging and neurodegeneration. Autophagosomes form and expand using membranes from the secretory and endocytic pathways but how this occurs is not understood. ATG9, the only transmembrane ATG protein traffics through the cell in vesicles, and is essential for rapid initiation and expansion of the membranes which form the autophagosome. Crucially, how ATG9 functions is unknown. I will determine how ATG9 initiates the formation and expansion of the autophagosome by amino acid starvation through a molecular dissection of proteins resident in ATG9 vesicles which modulate the composition and property of the initiating membrane. I will employ high resolution light and electron microscopy to characterize the nucleation of the autophagosome, proximity-specific biotinylation and quantitative Mass Spectrometry to uncover the proteome required for the function of the ATG9, and optogenetic tools to acutely regulate signaling lipids. Lastly, with our tools and knowledge I will develop an in vitro reconstitution system to define at a molecular level how ATG9 vesicle proteins, membranes that interact with ATG9 vesicles, and other accessory ATG components nucleate and form an autophagosome. In vitro reconstitution of autophagosomes will be assayed biochemically, and by correlative light and cryo-EM and cryo-EM tomography, while functional reconstitution of autophagy will be tested by selective cargo recruitment. The development of a reconstituted system and identification proteins and lipids which are key components for autophagosome formation will provide a means to identify a new generation of targets for translational work leading to manipulation of autophagy for disease related therapies.
Max ERC Funding
2 121 055 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym ATTACK
Project Pressured to Attack: How Carrying-Capacity Stress Creates and Shapes Intergroup Conflict
Researcher (PI) Carsten DE DREU
Host Institution (HI) UNIVERSITEIT LEIDEN
Call Details Advanced Grant (AdG), SH3, ERC-2017-ADG
Summary Throughout history, what has been causing tremendous suffering is groups of people fighting each other. While behavioral science research has advanced our understanding of such intergroup conflict, it has exclusively focused on micro-level processes within and between groups at conflict. Disciplines that employ a more historical perspective like climate studies or political geography report that macro-level pressures due to changes in climate or economic scarcity can go along with social unrest and wars. How do these macro-level pressures relate to micro-level processes? Do they both occur independently, or do macro-level pressures trigger micro-level processes that cause intergroup conflict? And if so, which micro-level processes are triggered, and how?
With unavoidable signs of climate change and increasing resource scarcities, answers to these questions are urgently needed. Here I propose carrying-capacity stress (CCS) as the missing link between macro-level pressures and micro-level processes. A group experiences CCS when its resources do not suffice to maintain its functionality. CCS is a function of macro-level pressures and creates intergroup conflict because it impacts micro-level motivation to contribute to one’s group’s fighting capacity and shapes the coordination of individual contributions to out-group aggression through emergent norms, communication and leadership.
To test these propositions I develop a parametric model of CCS that is amenable to measurement and experimentation, and use techniques used in my work on conflict and cooperation: Meta-analyses and time-series analysis of macro-level historical data; experiments on intergroup conflict; and measurement of neuro-hormonal correlates of cooperation and conflict. In combination, this project provides novel multi-level conflict theory that integrates macro-level discoveries in climate research and political geography with micro-level processes uncovered in the biobehavioral sciences
Summary
Throughout history, what has been causing tremendous suffering is groups of people fighting each other. While behavioral science research has advanced our understanding of such intergroup conflict, it has exclusively focused on micro-level processes within and between groups at conflict. Disciplines that employ a more historical perspective like climate studies or political geography report that macro-level pressures due to changes in climate or economic scarcity can go along with social unrest and wars. How do these macro-level pressures relate to micro-level processes? Do they both occur independently, or do macro-level pressures trigger micro-level processes that cause intergroup conflict? And if so, which micro-level processes are triggered, and how?
With unavoidable signs of climate change and increasing resource scarcities, answers to these questions are urgently needed. Here I propose carrying-capacity stress (CCS) as the missing link between macro-level pressures and micro-level processes. A group experiences CCS when its resources do not suffice to maintain its functionality. CCS is a function of macro-level pressures and creates intergroup conflict because it impacts micro-level motivation to contribute to one’s group’s fighting capacity and shapes the coordination of individual contributions to out-group aggression through emergent norms, communication and leadership.
To test these propositions I develop a parametric model of CCS that is amenable to measurement and experimentation, and use techniques used in my work on conflict and cooperation: Meta-analyses and time-series analysis of macro-level historical data; experiments on intergroup conflict; and measurement of neuro-hormonal correlates of cooperation and conflict. In combination, this project provides novel multi-level conflict theory that integrates macro-level discoveries in climate research and political geography with micro-level processes uncovered in the biobehavioral sciences
Max ERC Funding
2 490 383 €
Duration
Start date: 2018-08-01, End date: 2023-07-31
Project acronym AutoClean
Project Cell-free reconstitution of autophagy to dissect molecular mechanisms
Researcher (PI) Claudine Simone Kraft
Host Institution (HI) UNIVERSITAETSKLINIKUM FREIBURG
Call Details Consolidator Grant (CoG), LS1, ERC-2017-COG
Summary Autophagy, a lysosomal degradation pathway in which the cell digests its own components, is an essential biological pathway that promotes organismal health and longevity and helps combat cancer and neurodegenerative diseases. Accordingly, the 2016 Nobel Prize in Physiology or Medicine was awarded for research in autophagy. Although autophagy has been extensively studied from yeast to mammals, the molecular events that underlie its induction and progression remain elusive. A highly conserved protein kinase, Atg1, plays a unique and essential role in initiating autophagy, yet despite this pivotal importance it has taken over twenty years for its first downstream target to be discovered. However, whilst our identification of the autophagy related membrane protein Atg9 as the first Atg1 substrate is an important advance, the molecular mechanisms that enable the extensive remodelling of cellular membranes that occurs during autophagy is still completely undefined. A detailed knowledge of the inputs and outputs of the Atg1 kinase will enable us to provide a definitive mechanistic understanding of autophagy. We have devised a novel permeabilized cell assay that reconstitutes the pathway in vitro, allowing us to recapitulate key steps in the autophagic process and thereby determine how the individual steps that lead up to autophagy are controlled. We will use this system to dissect the functional role of Atg1 kinase in autophagosome-vacuole fusion (Objective 1), and to determine the origin of the autophagic membrane and the role of Atg1 in expanding these (Objective 2). To reveal how Atg1/ULK1 kinase is activated in mammalian cells, we will apply the unique and carefully tailored synthetic in vivo approaches that we have recently developed (Objective 3). By focusing on the activation of the Atg1 kinase and the molecular events that it executes, we will be able to explain its central role in regulating the autophagic process and define the mechanistic steps in the pathway.
Summary
Autophagy, a lysosomal degradation pathway in which the cell digests its own components, is an essential biological pathway that promotes organismal health and longevity and helps combat cancer and neurodegenerative diseases. Accordingly, the 2016 Nobel Prize in Physiology or Medicine was awarded for research in autophagy. Although autophagy has been extensively studied from yeast to mammals, the molecular events that underlie its induction and progression remain elusive. A highly conserved protein kinase, Atg1, plays a unique and essential role in initiating autophagy, yet despite this pivotal importance it has taken over twenty years for its first downstream target to be discovered. However, whilst our identification of the autophagy related membrane protein Atg9 as the first Atg1 substrate is an important advance, the molecular mechanisms that enable the extensive remodelling of cellular membranes that occurs during autophagy is still completely undefined. A detailed knowledge of the inputs and outputs of the Atg1 kinase will enable us to provide a definitive mechanistic understanding of autophagy. We have devised a novel permeabilized cell assay that reconstitutes the pathway in vitro, allowing us to recapitulate key steps in the autophagic process and thereby determine how the individual steps that lead up to autophagy are controlled. We will use this system to dissect the functional role of Atg1 kinase in autophagosome-vacuole fusion (Objective 1), and to determine the origin of the autophagic membrane and the role of Atg1 in expanding these (Objective 2). To reveal how Atg1/ULK1 kinase is activated in mammalian cells, we will apply the unique and carefully tailored synthetic in vivo approaches that we have recently developed (Objective 3). By focusing on the activation of the Atg1 kinase and the molecular events that it executes, we will be able to explain its central role in regulating the autophagic process and define the mechanistic steps in the pathway.
Max ERC Funding
1 955 666 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym BETLIV
Project Returning to a Better Place: The (Re)assessment of the ‘Good Life’ in Times of Crisis
Researcher (PI) Valerio SIMONI RIBA
Host Institution (HI) FONDATION POUR L INSTITUT DE HAUTES ETUDES INTERNATIONALES ET DU DEVELOPPEMENT
Call Details Starting Grant (StG), SH5, ERC-2017-STG
Summary What makes for a valuable and good life is a question that many people in the contemporary world ask themselves, yet it is one that social science research has seldom addressed. Only recently have scholars started undertaking inductive comparative research on different notions of the ‘good life’, highlighting socio-cultural variations and calling for a better understanding of the different imaginaries, aspirations and values that guide people in their quest for better living conditions. Research is still lacking, however, on how people themselves evaluate, compare, and put into perspective different visions of good living and their socio-cultural anchorage. This project addresses such questions from an anthropological perspective, proposing an innovative study of how ideals of the good life are articulated, (re)assessed, and related to specific places and contexts as a result of the experience of crisis and migration. The case studies chosen to operationalize these lines of enquiry focus on the phenomenon of return migration, and consist in an analysis of the imaginaries and experience of return by Ecuadorian and Cuban men and women who migrated to Spain, are dissatisfied with their life there, and envisage/carry out the project of going back to their countries of origin (Ecuador and Cuba respectively). The project’s ambition is to bring together and contribute to three main scholarly areas of enquiry: 1) the study of morality, ethics and what counts as ‘good life’, 2) the study of the field of economic practice, its definition, value regimes, and ‘crises’, and 3) the study of migratory aspirations, projects, and trajectories. A multi-sited endeavour, the research is designed in three subprojects carried out in Spain (PhD student), Ecuador (Post-Doc), and Cuba (PI), in which ethnographic methods will be used to provide the first empirically grounded study of the links between notions and experiences of crisis, return migration, and the (re)assessment of good living.
Summary
What makes for a valuable and good life is a question that many people in the contemporary world ask themselves, yet it is one that social science research has seldom addressed. Only recently have scholars started undertaking inductive comparative research on different notions of the ‘good life’, highlighting socio-cultural variations and calling for a better understanding of the different imaginaries, aspirations and values that guide people in their quest for better living conditions. Research is still lacking, however, on how people themselves evaluate, compare, and put into perspective different visions of good living and their socio-cultural anchorage. This project addresses such questions from an anthropological perspective, proposing an innovative study of how ideals of the good life are articulated, (re)assessed, and related to specific places and contexts as a result of the experience of crisis and migration. The case studies chosen to operationalize these lines of enquiry focus on the phenomenon of return migration, and consist in an analysis of the imaginaries and experience of return by Ecuadorian and Cuban men and women who migrated to Spain, are dissatisfied with their life there, and envisage/carry out the project of going back to their countries of origin (Ecuador and Cuba respectively). The project’s ambition is to bring together and contribute to three main scholarly areas of enquiry: 1) the study of morality, ethics and what counts as ‘good life’, 2) the study of the field of economic practice, its definition, value regimes, and ‘crises’, and 3) the study of migratory aspirations, projects, and trajectories. A multi-sited endeavour, the research is designed in three subprojects carried out in Spain (PhD student), Ecuador (Post-Doc), and Cuba (PI), in which ethnographic methods will be used to provide the first empirically grounded study of the links between notions and experiences of crisis, return migration, and the (re)assessment of good living.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym BioMatrix
Project Structural Biology of Exopolysaccharide Secretion in Bacterial Biofilms
Researcher (PI) Petya Violinova KRASTEVA
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Call Details Starting Grant (StG), LS1, ERC-2017-STG
Summary Bacterial biofilm formation is a paramount developmental process in both Gram-positive and Gram-negative species and in many pathogens has been associated with processes of horizontal gene transfer, antibiotic resistance development and pathogen persistence. Bacterial biofilms are collaborative sessile macrocolonies embedded in complex extracellular matrix that secures both mechanical resistance and a medium for intercellular exchange.
Biogenesis platforms for the secretion of biofilm matrix components - many of which controlled directly or indirectly by the intracellular second messenger c-di-GMP - are important determinants for biofilm formation and bacterial disease, and therefore present compelling targets for the development of novel therapeutics. During my Ph.D. and post-doctoral work I studied the structure and function of c-di-GMP-sensing protein factors controling extracellular matrix production by DNA-binding at the transcription initiation level or by inside-out signalling mechanisms at the cell envelope, as well as membrane exporters involved directly in downstream matrix component secretion.
Here, I propose to apply my expertise in microbiology, protein science and structural biology to study the structure and function of exopolysaccharide secretion systems in Gram-negative species. Using Pseudomonas aeruginosa, Vibrio spp. and Escherichia coli as model organisms, my team will aim to reveal the global architecture and individual building components of several expolysaccharide-producing protein megacomplexes. We will combine X-ray crystallography, biophysical and biochemical assays, electron microscopy and in cellulo functional studies to provide a comprehensive view of extracellular matrix production that spans the different resolution levels and presents molecular blueprints for the development of novel anti-infectives. Over the last year I have laid the foundation of these studies and have demonstrated the overall feasibility of the project.
Summary
Bacterial biofilm formation is a paramount developmental process in both Gram-positive and Gram-negative species and in many pathogens has been associated with processes of horizontal gene transfer, antibiotic resistance development and pathogen persistence. Bacterial biofilms are collaborative sessile macrocolonies embedded in complex extracellular matrix that secures both mechanical resistance and a medium for intercellular exchange.
Biogenesis platforms for the secretion of biofilm matrix components - many of which controlled directly or indirectly by the intracellular second messenger c-di-GMP - are important determinants for biofilm formation and bacterial disease, and therefore present compelling targets for the development of novel therapeutics. During my Ph.D. and post-doctoral work I studied the structure and function of c-di-GMP-sensing protein factors controling extracellular matrix production by DNA-binding at the transcription initiation level or by inside-out signalling mechanisms at the cell envelope, as well as membrane exporters involved directly in downstream matrix component secretion.
Here, I propose to apply my expertise in microbiology, protein science and structural biology to study the structure and function of exopolysaccharide secretion systems in Gram-negative species. Using Pseudomonas aeruginosa, Vibrio spp. and Escherichia coli as model organisms, my team will aim to reveal the global architecture and individual building components of several expolysaccharide-producing protein megacomplexes. We will combine X-ray crystallography, biophysical and biochemical assays, electron microscopy and in cellulo functional studies to provide a comprehensive view of extracellular matrix production that spans the different resolution levels and presents molecular blueprints for the development of novel anti-infectives. Over the last year I have laid the foundation of these studies and have demonstrated the overall feasibility of the project.
Max ERC Funding
1 499 901 €
Duration
Start date: 2018-08-01, End date: 2023-07-31
Project acronym BLOCKCHAINSOCIETY
Project The Disrupted Society: mapping the societal effects of blockchain technology diffusion
Researcher (PI) Balazs BODO
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Call Details Starting Grant (StG), SH3, ERC-2017-STG
Summary Recent advances in cryptography yielded the blockchain technology, which enables a radically new and decentralized method to maintain authoritative records, without the need of trusted intermediaries. Bitcoin, a cryptocurrency blockchain application has already demonstrated that it is possible to operate a purely cryptography-based, global, distributed, decentralized, anonymous financial network, independent from central and commercial banks, regulators and the state.
The same technology is now being applied to other social domains (e.g. public registries of ownership and deeds, voting systems, the internet domain name registry). But research on the societal impact of blockchain innovation is scant, and we cannot properly assess its risks and promises. In addition, crucial knowledge is missing on how blockchain technologies can and should be regulated by law.
The BlockchainSociety project focuses on three research questions. (1) What internal factors contribute to the success of a blockchain application? (2) How does society adopt blockchain? (3) How to regulate blockchain? It breaks new ground as it (1) maps the most important blockchain projects, their governance, and assesses their disruptive potential; (2) documents and analyses the social diffusion of the technology, and builds scenarios about the potential impact of blockchain diffusion; and (3) it creates an inventory of emerging policy responses, compares and assesses policy tools in terms of efficiency and impact. The project will (1) build the conceptual and methodological bridges between information law, the study of the self-governance of technological systems via Science and Technology Studies, and the study of collective control efforts of complex socio-technological assemblages via Internet Governance studies; (2) address the most pressing blockchain-specific regulatory challenges via the analysis of emerging policies, and the development of new proposals.
Summary
Recent advances in cryptography yielded the blockchain technology, which enables a radically new and decentralized method to maintain authoritative records, without the need of trusted intermediaries. Bitcoin, a cryptocurrency blockchain application has already demonstrated that it is possible to operate a purely cryptography-based, global, distributed, decentralized, anonymous financial network, independent from central and commercial banks, regulators and the state.
The same technology is now being applied to other social domains (e.g. public registries of ownership and deeds, voting systems, the internet domain name registry). But research on the societal impact of blockchain innovation is scant, and we cannot properly assess its risks and promises. In addition, crucial knowledge is missing on how blockchain technologies can and should be regulated by law.
The BlockchainSociety project focuses on three research questions. (1) What internal factors contribute to the success of a blockchain application? (2) How does society adopt blockchain? (3) How to regulate blockchain? It breaks new ground as it (1) maps the most important blockchain projects, their governance, and assesses their disruptive potential; (2) documents and analyses the social diffusion of the technology, and builds scenarios about the potential impact of blockchain diffusion; and (3) it creates an inventory of emerging policy responses, compares and assesses policy tools in terms of efficiency and impact. The project will (1) build the conceptual and methodological bridges between information law, the study of the self-governance of technological systems via Science and Technology Studies, and the study of collective control efforts of complex socio-technological assemblages via Internet Governance studies; (2) address the most pressing blockchain-specific regulatory challenges via the analysis of emerging policies, and the development of new proposals.
Max ERC Funding
1 499 631 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym BSP
Project Belief Systems Project
Researcher (PI) Mark BRANDT
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT BRABANT
Call Details Starting Grant (StG), SH3, ERC-2017-STG
Summary Belief systems research is vital for understanding democratic politics, extremism, and political decision-making. What is the basic structure of belief systems? Clear answers to this fundamental question are not forthcoming. This is due to flaws in the conceptualization of belief systems. The state-of-the-art treats a belief system as a theoretical latent variable that causes people’s responses on attitudes and values relevant to the belief system. This approach cannot assess a belief system because it cannot assess the network of connections between the beliefs–attitudes and values–that make up the system; it collapses across them and the interrelationships are lost.
The Belief Systems Project conceptualizations belief systems as systems of interconnecting attitudes and values. I conceptualize attitudes and values as interactive nodes in a network that are analysed with network analyses. With these conceptual and empirical tools, I can understand the structure and dynamics of the belief system and will be able to avoid theoretical pitfalls common in belief system assessments. This project will move belief systems research beyond the state-of-the-art in four ways by:
1. Mapping the structure of systems of attitudes and values, something that is not possible using current methods.
2. Answering classic questions about central concepts and clustering of belief systems.
3. Modeling within-person belief systems and their variations, so that I can make accurate predictions about partisan motivated reasoning.
4. Testing how external and internal pressures (e.g., feelings of threat) change the underlying structure and dynamics of belief systems.
Using survey data from around the world, longitudinal panel studies, intensive longitudinal designs, experiments, and text analyses, I will triangulate on the structure of political belief systems over time, between countries, and within individuals.
Summary
Belief systems research is vital for understanding democratic politics, extremism, and political decision-making. What is the basic structure of belief systems? Clear answers to this fundamental question are not forthcoming. This is due to flaws in the conceptualization of belief systems. The state-of-the-art treats a belief system as a theoretical latent variable that causes people’s responses on attitudes and values relevant to the belief system. This approach cannot assess a belief system because it cannot assess the network of connections between the beliefs–attitudes and values–that make up the system; it collapses across them and the interrelationships are lost.
The Belief Systems Project conceptualizations belief systems as systems of interconnecting attitudes and values. I conceptualize attitudes and values as interactive nodes in a network that are analysed with network analyses. With these conceptual and empirical tools, I can understand the structure and dynamics of the belief system and will be able to avoid theoretical pitfalls common in belief system assessments. This project will move belief systems research beyond the state-of-the-art in four ways by:
1. Mapping the structure of systems of attitudes and values, something that is not possible using current methods.
2. Answering classic questions about central concepts and clustering of belief systems.
3. Modeling within-person belief systems and their variations, so that I can make accurate predictions about partisan motivated reasoning.
4. Testing how external and internal pressures (e.g., feelings of threat) change the underlying structure and dynamics of belief systems.
Using survey data from around the world, longitudinal panel studies, intensive longitudinal designs, experiments, and text analyses, I will triangulate on the structure of political belief systems over time, between countries, and within individuals.
Max ERC Funding
1 496 944 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym BURSTREG
Project Single-molecule visualization of transcription dynamics to understand regulatory mechanisms of transcriptional bursting and its effects on cellular fitness
Researcher (PI) Tineke LENSTRA
Host Institution (HI) STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Call Details Starting Grant (StG), LS1, ERC-2017-STG
Summary Transcription in single cells is a stochastic process that arises from the random collision of molecules, resulting in heterogeneity in gene expression in cell populations. This heterogeneity in gene expression influences cell fate decisions and disease progression. Interestingly, gene expression variability is not the same for every gene: noise can vary by several orders of magnitude across transcriptomes. The reason for this transcript-specific behavior is that genes are not transcribed in a continuous fashion, but can show transcriptional bursting, with periods of gene activity followed by periods of inactivity. The noisiness of a gene can be tuned by changing the duration and the rate of switching between periods of activity and inactivity. Even though transcriptional bursting is conserved from bacteria to yeast to human cells, the origin and regulators of bursting remain largely unknown. Here, I will use cutting-edge single-molecule RNA imaging techniques to directly observe and measure transcriptional bursting in living yeast cells. First, bursting properties will be quantified at different endogenous and mutated genes to evaluate the contribution of cis-regulatory promoter elements on bursting. Second, the role of trans-regulatory complexes will be characterized by dynamic depletion or gene-specific targeting of transcription regulatory proteins and observing changes in RNA synthesis in real-time. Third, I will develop a new technology to visualize the binding dynamics of single transcription factor molecules at the transcription site, so that the stability of upstream regulatory factors and the RNA output can directly be compared in the same cell. Finally, I will examine the phenotypic effect of different bursting patterns on organismal fitness. Overall, these approaches will reveal how bursting is regulated at the molecular level and how different bursting patterns affect the heterogeneity and fitness of the organism.
Summary
Transcription in single cells is a stochastic process that arises from the random collision of molecules, resulting in heterogeneity in gene expression in cell populations. This heterogeneity in gene expression influences cell fate decisions and disease progression. Interestingly, gene expression variability is not the same for every gene: noise can vary by several orders of magnitude across transcriptomes. The reason for this transcript-specific behavior is that genes are not transcribed in a continuous fashion, but can show transcriptional bursting, with periods of gene activity followed by periods of inactivity. The noisiness of a gene can be tuned by changing the duration and the rate of switching between periods of activity and inactivity. Even though transcriptional bursting is conserved from bacteria to yeast to human cells, the origin and regulators of bursting remain largely unknown. Here, I will use cutting-edge single-molecule RNA imaging techniques to directly observe and measure transcriptional bursting in living yeast cells. First, bursting properties will be quantified at different endogenous and mutated genes to evaluate the contribution of cis-regulatory promoter elements on bursting. Second, the role of trans-regulatory complexes will be characterized by dynamic depletion or gene-specific targeting of transcription regulatory proteins and observing changes in RNA synthesis in real-time. Third, I will develop a new technology to visualize the binding dynamics of single transcription factor molecules at the transcription site, so that the stability of upstream regulatory factors and the RNA output can directly be compared in the same cell. Finally, I will examine the phenotypic effect of different bursting patterns on organismal fitness. Overall, these approaches will reveal how bursting is regulated at the molecular level and how different bursting patterns affect the heterogeneity and fitness of the organism.
Max ERC Funding
1 950 775 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym C-CLEAR
Project Complement: to clear or not to clear
Researcher (PI) Piet Gros
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Advanced Grant (AdG), LS1, ERC-2017-ADG
Summary Mammalian complement recognizes a variety of cell-surface danger and damage signals to clear invading microbes and injured host cells, while protecting healthy host cells. Improper complement responses contribute to diverse pathologies, ranging from bacterial infections up to paralyzing Guillain-Barré syndrome and schizophrenia. What determines the balance between complement attack reactions and host-cell defense measures and, thus, what drives cell fate is unclear.
My lab has a long-standing track record in elucidating molecular mechanisms underlying key complement reactions. We have revealed, for example, how the interplay between assembly and proteolysis of these large multi-domain protein complexes achieves elementary regulatory functions, such as localization, amplification and inhibition, in the central (so-called alternative) pathway of complement. Results from my lab underpin research programs for the development of novel therapeutic approaches in academia and industry.
Here the goal is to understand how the molecular mechanisms of complement attack and defense on cell membranes determine clearance of a cell. Enabled by new mechanistic insights and preliminary data we can now address both long-standing and novel questions. In particular, we will address the role of membrane organization and dynamics in complement attack and defense. Facilitated by recent technological developments, we will combine crystallography, cryo-EM, cryo-ET and high-resolution microscopy to resolve complement complex formations and reactions on membranes.
Thus, this project aims to provide an integrative understanding of the molecular complement mechanisms that determine cell fate. Results will likely be of immediate importance for novel therapeutic approaches for a range of complement-related diseases. Furthermore, it will provide clarity into the general, and possibly fundamental, role of complement in tissue maintenance in mammals.
Summary
Mammalian complement recognizes a variety of cell-surface danger and damage signals to clear invading microbes and injured host cells, while protecting healthy host cells. Improper complement responses contribute to diverse pathologies, ranging from bacterial infections up to paralyzing Guillain-Barré syndrome and schizophrenia. What determines the balance between complement attack reactions and host-cell defense measures and, thus, what drives cell fate is unclear.
My lab has a long-standing track record in elucidating molecular mechanisms underlying key complement reactions. We have revealed, for example, how the interplay between assembly and proteolysis of these large multi-domain protein complexes achieves elementary regulatory functions, such as localization, amplification and inhibition, in the central (so-called alternative) pathway of complement. Results from my lab underpin research programs for the development of novel therapeutic approaches in academia and industry.
Here the goal is to understand how the molecular mechanisms of complement attack and defense on cell membranes determine clearance of a cell. Enabled by new mechanistic insights and preliminary data we can now address both long-standing and novel questions. In particular, we will address the role of membrane organization and dynamics in complement attack and defense. Facilitated by recent technological developments, we will combine crystallography, cryo-EM, cryo-ET and high-resolution microscopy to resolve complement complex formations and reactions on membranes.
Thus, this project aims to provide an integrative understanding of the molecular complement mechanisms that determine cell fate. Results will likely be of immediate importance for novel therapeutic approaches for a range of complement-related diseases. Furthermore, it will provide clarity into the general, and possibly fundamental, role of complement in tissue maintenance in mammals.
Max ERC Funding
2 332 500 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym CALLIOPE
Project voCAL articuLations Of Parliamentary Identity and Empire
Researcher (PI) Josephine HOEGAERTS
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), SH5, ERC-2017-STG
Summary What did politicians sound like before they were on the radio and television? The fascination with politicians’ vocal characteristics and quirks is often connected to the rise of audio-visual media. But in the age of the printed press, political representatives also had to ‘speak well’ – without recourse to amplification.
Historians and linguists have provided sophisticated understandings of the discursive and aesthetic aspects of politicians’ language, but have largely ignored the importance of the acoustic character of their speech. CALLIOPE studies how vocal performances in parliament have influenced the course of political careers and political decision making in the 19th century. It shows how politicians’ voices helped to define the diverse identities they articulated. In viewing parliament through the lens of audibility, the project offers a new perspective on political representation by reframing how authority was embodied (through performances that were heard, rather than seen). It does so for the Second Chamber in Britain and France, and in dialogue with ‘colonial’ modes of speech in Kolkata and Algiers, which, we argue, exerted considerable influence on European vocal culture.
The project devises an innovative methodological approach to include the sound of the human voice in studies of the past that precede acoustic recording. Adapting methods developed in sound studies and combining them with the tools of political history, the project proposes a new way to analyse parliamentary reporting, while also drawing on a variety of sources that are rarely connected to the history of politics.
The main source material for the study comprise transcripts of parliamentary speech (official reports and renditions by journalists). However, the project also mobilizes educational, satirical and fictional sources to elucidate the convoluted processes that led to the cultivation, exertion, reception and evaluation of a voice ‘fit’ for nineteenth-century politics.
Summary
What did politicians sound like before they were on the radio and television? The fascination with politicians’ vocal characteristics and quirks is often connected to the rise of audio-visual media. But in the age of the printed press, political representatives also had to ‘speak well’ – without recourse to amplification.
Historians and linguists have provided sophisticated understandings of the discursive and aesthetic aspects of politicians’ language, but have largely ignored the importance of the acoustic character of their speech. CALLIOPE studies how vocal performances in parliament have influenced the course of political careers and political decision making in the 19th century. It shows how politicians’ voices helped to define the diverse identities they articulated. In viewing parliament through the lens of audibility, the project offers a new perspective on political representation by reframing how authority was embodied (through performances that were heard, rather than seen). It does so for the Second Chamber in Britain and France, and in dialogue with ‘colonial’ modes of speech in Kolkata and Algiers, which, we argue, exerted considerable influence on European vocal culture.
The project devises an innovative methodological approach to include the sound of the human voice in studies of the past that precede acoustic recording. Adapting methods developed in sound studies and combining them with the tools of political history, the project proposes a new way to analyse parliamentary reporting, while also drawing on a variety of sources that are rarely connected to the history of politics.
The main source material for the study comprise transcripts of parliamentary speech (official reports and renditions by journalists). However, the project also mobilizes educational, satirical and fictional sources to elucidate the convoluted processes that led to the cultivation, exertion, reception and evaluation of a voice ‘fit’ for nineteenth-century politics.
Max ERC Funding
1 499 905 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym CAPABLE
Project Enhancing Capabilities? Rethinking Work-life Policies and their Impact from a New Perspective
Researcher (PI) Mara YERKES
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Consolidator Grant (CoG), SH3, ERC-2017-COG
Summary We have witnessed significant work-life policy advancements designed to help men and women more equally combine employment with other spheres of life in recent decades, yet gender inequality persists. Improving gender equality in work-life balance is therefore high on policy agendas throughout Europe. Decades of research in this area have produced key insights but work-family theories fail to sufficiently explain the tenacity of this inequality. Earlier applications of a capabilities approach to work-life balance offer promising inroads, yet the importance of community remains absent. The CAPABLE project will generate fundamentally new knowledge on how work-life balance policies impact an individual’s capability to achieve this balance in Europe by incorporating the understudied dimension of community.
Capabilities reflect what individuals are effectively able to achieve. CAPABLE asks: To what extent do work-life balance policies enhance men and women’s capabilities to achieve work-life balance? To answer this question, we will develop and apply complex models derived from Sen’s capability approach to analyse: 1. the availability, accessibility and design of work-family policies; 2. what these policies mean for men and women’s capabilities to achieve work-life balance based on their embeddedness in individual, community and social contexts; 3. whether work-life policies enhance individual wellbeing; and 4. what policy tools are needed for developing sustainable work-life balance policies that enhance gender equal work-life capabilities. CAPABLE will progress scientific and policy frontiers using innovative, mixed-methods approaches at multiple policy levels. The conceptual clarity and empirical advancements provided will significantly expand our understanding of work-life policies in relation to individual capabilities. Furthermore, it will produce key insights into how sustainable work-life policies addressing gender inequality in work-life can be developed.
Summary
We have witnessed significant work-life policy advancements designed to help men and women more equally combine employment with other spheres of life in recent decades, yet gender inequality persists. Improving gender equality in work-life balance is therefore high on policy agendas throughout Europe. Decades of research in this area have produced key insights but work-family theories fail to sufficiently explain the tenacity of this inequality. Earlier applications of a capabilities approach to work-life balance offer promising inroads, yet the importance of community remains absent. The CAPABLE project will generate fundamentally new knowledge on how work-life balance policies impact an individual’s capability to achieve this balance in Europe by incorporating the understudied dimension of community.
Capabilities reflect what individuals are effectively able to achieve. CAPABLE asks: To what extent do work-life balance policies enhance men and women’s capabilities to achieve work-life balance? To answer this question, we will develop and apply complex models derived from Sen’s capability approach to analyse: 1. the availability, accessibility and design of work-family policies; 2. what these policies mean for men and women’s capabilities to achieve work-life balance based on their embeddedness in individual, community and social contexts; 3. whether work-life policies enhance individual wellbeing; and 4. what policy tools are needed for developing sustainable work-life balance policies that enhance gender equal work-life capabilities. CAPABLE will progress scientific and policy frontiers using innovative, mixed-methods approaches at multiple policy levels. The conceptual clarity and empirical advancements provided will significantly expand our understanding of work-life policies in relation to individual capabilities. Furthermore, it will produce key insights into how sustainable work-life policies addressing gender inequality in work-life can be developed.
Max ERC Funding
1 999 748 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym CAPE
Project Ghosts from the past: Consequences of Adolescent Peer Experiences across social contexts and generations
Researcher (PI) Tina KRETSCHMER
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Call Details Starting Grant (StG), SH3, ERC-2017-STG
Summary Positive peer experiences are crucial for young people’s health and wellbeing. Accordingly, multiple studies (including my own) have described long-term negative psychological and behavioral consequences when adolescents’ peer relationships are dysfunctional. Paradoxically, knowledge on adult social consequences of adolescent peer experiences –relationships with others a decade later - is much less extensive. Informed by social learning and attachment theory, I tackle this gap and investigate whether and how peer experiences are transmitted to other social contexts, and intergenerationally, i.e., passed on to the next generation. My aim is to shed light on how the “ghosts from peer past” affect young adults’ relationships and their children. To this end, I examine longitudinal links between adolescent peer and young adult close relationships and test whether parents’ peer experiences affect offspring’s peer experiences. Psychological functioning, parenting, temperament, genetic, and epigenetic transmission mechanisms are examined separately and in interplay, which 1) goes far beyond the current state-of-the-art in social development research, and 2) significantly broadens my biosocially oriented work on genetic effects in the peer context. My plans utilize data from the TRAILS (Tracking Adolescents’ Individual Lives’ Survey) cohort that has been followed from age 11 to 26. To study intergenerational transmission, the TRAILS NEXT sample of participants with children is substantially extended. This project uniquely studies adult social consequences of peer experiences and, at the same time, follows children’s first steps into the peer world. The intergenerational approach and provision for environmental, genetic, and epigenetic mediation put this project at the forefront of developmental research and equip it with the potential to generate the knowledge needed to chase away the ghosts from the peer past.
Summary
Positive peer experiences are crucial for young people’s health and wellbeing. Accordingly, multiple studies (including my own) have described long-term negative psychological and behavioral consequences when adolescents’ peer relationships are dysfunctional. Paradoxically, knowledge on adult social consequences of adolescent peer experiences –relationships with others a decade later - is much less extensive. Informed by social learning and attachment theory, I tackle this gap and investigate whether and how peer experiences are transmitted to other social contexts, and intergenerationally, i.e., passed on to the next generation. My aim is to shed light on how the “ghosts from peer past” affect young adults’ relationships and their children. To this end, I examine longitudinal links between adolescent peer and young adult close relationships and test whether parents’ peer experiences affect offspring’s peer experiences. Psychological functioning, parenting, temperament, genetic, and epigenetic transmission mechanisms are examined separately and in interplay, which 1) goes far beyond the current state-of-the-art in social development research, and 2) significantly broadens my biosocially oriented work on genetic effects in the peer context. My plans utilize data from the TRAILS (Tracking Adolescents’ Individual Lives’ Survey) cohort that has been followed from age 11 to 26. To study intergenerational transmission, the TRAILS NEXT sample of participants with children is substantially extended. This project uniquely studies adult social consequences of peer experiences and, at the same time, follows children’s first steps into the peer world. The intergenerational approach and provision for environmental, genetic, and epigenetic mediation put this project at the forefront of developmental research and equip it with the potential to generate the knowledge needed to chase away the ghosts from the peer past.
Max ERC Funding
1 464 846 €
Duration
Start date: 2018-02-01, End date: 2023-01-31
Project acronym CATENA
Project Commentary Manuscripts in the History and Transmission of the Greek New Testament
Researcher (PI) HUGH ALEXANDER GERVASE HOUGHTON
Host Institution (HI) THE UNIVERSITY OF BIRMINGHAM
Call Details Consolidator Grant (CoG), SH5, ERC-2017-COG
Summary Manuscripts which contain commentary alongside the biblical text are some of the most significant and complicated witnesses to the Greek New Testament. First compiled around the fifth century, the commentaries consist of chains of extracts from earlier writers (catenae). These manuscripts became the main way in which users encountered both the text and the interpretation of the New Testament; revised editions produced in the eleventh and twelfth centuries continued to hold the field until the invention of printing.
Recent advances have shown that commentary manuscripts play a much more important role than previously thought in the history of the New Testament. The number of known copies has increased by 20% following a preliminary survey last year which identified 100 additional manuscripts. A recent comprehensive textual analysis of the Catholic Epistles indicated that all witnesses from the third generation onwards (some 72% of the total) could stem from the biblical text of three commentary manuscripts occupying a key place in the textual tradition. Investigation of the catena on Mark has shown that the selection of extracts could offer a new approach to understanding the theology of the compilers and the transmission of the commentaries.
The CATENA Project will use digital tools to undertake a fuller examination of Greek New Testament commentary manuscripts than has ever before been possible. This will include an exhaustive survey to establish a complete list of witnesses; a database of extracts to examine their principles of organisation and relationships; and electronic transcriptions to determine their role in the transmission of the biblical text. The results will have a direct impact on editions of the Greek New Testament, providing a new understanding of its text and reception and leading to broader insights into history and culture.
Summary
Manuscripts which contain commentary alongside the biblical text are some of the most significant and complicated witnesses to the Greek New Testament. First compiled around the fifth century, the commentaries consist of chains of extracts from earlier writers (catenae). These manuscripts became the main way in which users encountered both the text and the interpretation of the New Testament; revised editions produced in the eleventh and twelfth centuries continued to hold the field until the invention of printing.
Recent advances have shown that commentary manuscripts play a much more important role than previously thought in the history of the New Testament. The number of known copies has increased by 20% following a preliminary survey last year which identified 100 additional manuscripts. A recent comprehensive textual analysis of the Catholic Epistles indicated that all witnesses from the third generation onwards (some 72% of the total) could stem from the biblical text of three commentary manuscripts occupying a key place in the textual tradition. Investigation of the catena on Mark has shown that the selection of extracts could offer a new approach to understanding the theology of the compilers and the transmission of the commentaries.
The CATENA Project will use digital tools to undertake a fuller examination of Greek New Testament commentary manuscripts than has ever before been possible. This will include an exhaustive survey to establish a complete list of witnesses; a database of extracts to examine their principles of organisation and relationships; and electronic transcriptions to determine their role in the transmission of the biblical text. The results will have a direct impact on editions of the Greek New Testament, providing a new understanding of its text and reception and leading to broader insights into history and culture.
Max ERC Funding
1 756 928 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym CHROMDOM
Project Chromosomal domain formation, compartmentalization and architecture
Researcher (PI) Johannes STIGLER
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), LS1, ERC-2017-STG
Summary The three-dimensional organization of chromosomes is necessary for hereditary fidelity and gene regulation. Recent studies have found that eukaryotic interphase chromosomes are spatially organized in compartments, chiefly topologically associated domains (TADs), in a hierarchical order of nested chromatin loops, coining the term “chromosome folding”. TADs are clusters of genes and regulatory elements that are confined to their genomic compartment by spatially constricting their accessible range of action. The folded structure of chromosomes through long-range loops enables mutual interactions of distant genomic loci that otherwise would not be in contact.
While crosslinking-based chromosome conformation capture (3C) techniques have revealed the underlying structure of interphase chromosomes, the molecular mechanism of how chromosome-organizing proteins, such as the insulator CTCF or the structural maintenance of chromosomes (SMC) complex cohesin build the chromosomal scaffold and contribute to genomic organization, is not understood.
Due to the complexity of the processes involved, biochemical information on how chromosomal proteins contribute to the establishment of TADs is scarce. I have previously demonstrated that single molecule techniques can be used to study the interactions of single cohesin complexes with DNA, chromatin and DNA-bound proteins and to resolve processes that are inaccessible in bulk biochemical experiments. In this project, I will use and expand the high-throughput single molecule technique of DNA curtains to study the molecular details of how chromosomal scaffolding proteins and genetic insulators form the basis for the three-dimensional folding of chromosomes. My experiments will build a novel experimental platform to study the dynamics of chromosomal configuration and maintenance in a reconstituted single molecule assay and will reveal the molecular details that drive the organization of chromosomes into hierarchically organized structures.
Summary
The three-dimensional organization of chromosomes is necessary for hereditary fidelity and gene regulation. Recent studies have found that eukaryotic interphase chromosomes are spatially organized in compartments, chiefly topologically associated domains (TADs), in a hierarchical order of nested chromatin loops, coining the term “chromosome folding”. TADs are clusters of genes and regulatory elements that are confined to their genomic compartment by spatially constricting their accessible range of action. The folded structure of chromosomes through long-range loops enables mutual interactions of distant genomic loci that otherwise would not be in contact.
While crosslinking-based chromosome conformation capture (3C) techniques have revealed the underlying structure of interphase chromosomes, the molecular mechanism of how chromosome-organizing proteins, such as the insulator CTCF or the structural maintenance of chromosomes (SMC) complex cohesin build the chromosomal scaffold and contribute to genomic organization, is not understood.
Due to the complexity of the processes involved, biochemical information on how chromosomal proteins contribute to the establishment of TADs is scarce. I have previously demonstrated that single molecule techniques can be used to study the interactions of single cohesin complexes with DNA, chromatin and DNA-bound proteins and to resolve processes that are inaccessible in bulk biochemical experiments. In this project, I will use and expand the high-throughput single molecule technique of DNA curtains to study the molecular details of how chromosomal scaffolding proteins and genetic insulators form the basis for the three-dimensional folding of chromosomes. My experiments will build a novel experimental platform to study the dynamics of chromosomal configuration and maintenance in a reconstituted single molecule assay and will reveal the molecular details that drive the organization of chromosomes into hierarchically organized structures.
Max ERC Funding
1 499 350 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym CIRCOMMUNICATION
Project Deciphering molecular pathways of circadian clock communication
Researcher (PI) gad ASHER
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Call Details Consolidator Grant (CoG), LS1, ERC-2017-COG
Summary The overarching objective of this interdisciplinary project is to elucidate mechanisms through which billions of individual clocks in the body communicate with each other and tick in harmony. The mammalian circadian timing system consists of a master clock in the brain and subsidiary oscillators in almost every cell of the body. Since these clocks anticipate environmental changes and function together to orchestrate daily physiology and behavior their temporal synchronization is critical.
Our recent finding that oxygen serves as a resetting cue for circadian clocks points towards the unprecedented involvement of blood gases as time signals. We will apply cutting edge continuous physiological measurements in freely moving animals, alongside biochemical/molecular biology approaches and advanced cell culture setup to determine the molecular role of oxygen, carbon dioxide and pH in circadian clock communication and function.
The intricate nature of the mammalian circadian system demands the presence of communication mechanisms between clocks throughout the body at multiple levels. While previous studies primarily addressed the role of the master clock in resetting peripheral clocks, our knowledge regarding the communication among clocks between and within peripheral organs is rudimentary. We will reconstruct the mammalian circadian system from the bottom up, sequentially restoring clocks in peripheral tissues of a non-rhythmic animal to (i) obtain a system-view of the peripheral circadian communication network; and (ii) study novel tissue-derived circadian communication mechanisms.
This integrative proposal addresses fundamental aspects of circadian biology. It is expected to unravel the circadian communication network and shed light on how billions of clocks in the body function in unison. Its impact extends beyond circadian rhythms and bears great potential for research on communication between cells/tissues in various fields of biology.
Summary
The overarching objective of this interdisciplinary project is to elucidate mechanisms through which billions of individual clocks in the body communicate with each other and tick in harmony. The mammalian circadian timing system consists of a master clock in the brain and subsidiary oscillators in almost every cell of the body. Since these clocks anticipate environmental changes and function together to orchestrate daily physiology and behavior their temporal synchronization is critical.
Our recent finding that oxygen serves as a resetting cue for circadian clocks points towards the unprecedented involvement of blood gases as time signals. We will apply cutting edge continuous physiological measurements in freely moving animals, alongside biochemical/molecular biology approaches and advanced cell culture setup to determine the molecular role of oxygen, carbon dioxide and pH in circadian clock communication and function.
The intricate nature of the mammalian circadian system demands the presence of communication mechanisms between clocks throughout the body at multiple levels. While previous studies primarily addressed the role of the master clock in resetting peripheral clocks, our knowledge regarding the communication among clocks between and within peripheral organs is rudimentary. We will reconstruct the mammalian circadian system from the bottom up, sequentially restoring clocks in peripheral tissues of a non-rhythmic animal to (i) obtain a system-view of the peripheral circadian communication network; and (ii) study novel tissue-derived circadian communication mechanisms.
This integrative proposal addresses fundamental aspects of circadian biology. It is expected to unravel the circadian communication network and shed light on how billions of clocks in the body function in unison. Its impact extends beyond circadian rhythms and bears great potential for research on communication between cells/tissues in various fields of biology.
Max ERC Funding
1 999 945 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym COLSOC
Project The Legacy of Colonialism: Origins and Outcomes of Social Protection
Researcher (PI) Carina SCHMITT
Host Institution (HI) UNIVERSITAET BREMEN
Call Details Starting Grant (StG), SH3, ERC-2017-STG
Summary Social protection has been one of the most popular instruments for promoting human development across the globe. However, the great majority of the global population is not or only partly covered by social protection. Especially in developing countries it is often the very poorest who do not receive essential social benefits. This is highly problematic since inclusive social protection is assumed to be a key factor for national productivity, global economic growth and domestic stability. Social protection in many developing countries can be traced back to colonial times. Surprisingly, the influence of colonialism has been a blind spot for existing theories and empirical studies of comparative social policy. In this project it is argued that the colonial legacy in terms of the imperial strategy of the colonial power, the characteristics of the colonized society and the interplay between the two is crucial in explaining early and contemporary social protection. Hence, the main objective of this project is to systematically understand how colonialism has shaped the remarkable differences in social protection and its postcolonial outcomes. Given the paucity of our information and understanding of social protection in former colonies, an interactive dataset on the characteristics, origins and outcomes of social protection will be developed including comprehensive data on former British and French colonies from the beginning of the 20th century until today. The dataset will be backed by insights derived from four case studies elucidating the causal mechanisms between the colonial legacy and early and contemporary social protection. The proposed project breaks new ground by improving our understanding of why social protection in some developing countries has led to more inclusive societies while reinforcing existing inequalities in others. Such an understanding is a prerequisite in informing the contemporary struggle against poverty and social inequality.
Summary
Social protection has been one of the most popular instruments for promoting human development across the globe. However, the great majority of the global population is not or only partly covered by social protection. Especially in developing countries it is often the very poorest who do not receive essential social benefits. This is highly problematic since inclusive social protection is assumed to be a key factor for national productivity, global economic growth and domestic stability. Social protection in many developing countries can be traced back to colonial times. Surprisingly, the influence of colonialism has been a blind spot for existing theories and empirical studies of comparative social policy. In this project it is argued that the colonial legacy in terms of the imperial strategy of the colonial power, the characteristics of the colonized society and the interplay between the two is crucial in explaining early and contemporary social protection. Hence, the main objective of this project is to systematically understand how colonialism has shaped the remarkable differences in social protection and its postcolonial outcomes. Given the paucity of our information and understanding of social protection in former colonies, an interactive dataset on the characteristics, origins and outcomes of social protection will be developed including comprehensive data on former British and French colonies from the beginning of the 20th century until today. The dataset will be backed by insights derived from four case studies elucidating the causal mechanisms between the colonial legacy and early and contemporary social protection. The proposed project breaks new ground by improving our understanding of why social protection in some developing countries has led to more inclusive societies while reinforcing existing inequalities in others. Such an understanding is a prerequisite in informing the contemporary struggle against poverty and social inequality.
Max ERC Funding
1 486 250 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
Project acronym CONT-END
Project Attempts to Control the End of Life in People with Dementia: Two-level Approach to Examine Controversies
Researcher (PI) Jenny VAN DER STEEN
Host Institution (HI) ACADEMISCH ZIEKENHUIS LEIDEN
Call Details Consolidator Grant (CoG), SH3, ERC-2017-COG
Summary In dementia at the end of life, cognitive and physical decline imply that control is typically lost. CONT-END will examine control in the context of three emerging interventions which contain a controversial element of striving for control in the process of dying with dementia: advance care planning of the end of life, use of new technology to monitor symptoms when unable to self-report, and euthanasia. To perform outstanding research, the proposed research examines control at the level of clinical practice, but also at the level of end-of-life research practice. The latter provides ample opportunities for researchers to control the research process. That is, research designs are often flexible and we will study if and how this impacts research in an emotionally charged area. I will take an empirical mixed-methods approach to study the two practices in parallel. The work is organised in three related Work Packages around three research questions. (1) In a 6-country study, I will examine if and when people with dementia, family caregivers and physicians (900 respondents) find the interventions, shown on video, acceptable. (2) A cluster-randomised 3-armed controlled trial in 279 patients and their family caregivers assesses effects of two types of advance care planning differing in level of control (detailed advance treatment orders versus goal setting and coping based) on outcomes ranging from favourable to less favourable, and whether effects differ in subgroups. Cases in which the technology is preferred or applied are observed. (3) Ethnographic fieldwork in two different end-of-life research practices and a Delphi study to synthesize CONT-END’s findings assess how researchers shape findings. This greatly improves the quality of CONT-END and provides the input to develop new methodology for improving research quality and integrity.
Summary
In dementia at the end of life, cognitive and physical decline imply that control is typically lost. CONT-END will examine control in the context of three emerging interventions which contain a controversial element of striving for control in the process of dying with dementia: advance care planning of the end of life, use of new technology to monitor symptoms when unable to self-report, and euthanasia. To perform outstanding research, the proposed research examines control at the level of clinical practice, but also at the level of end-of-life research practice. The latter provides ample opportunities for researchers to control the research process. That is, research designs are often flexible and we will study if and how this impacts research in an emotionally charged area. I will take an empirical mixed-methods approach to study the two practices in parallel. The work is organised in three related Work Packages around three research questions. (1) In a 6-country study, I will examine if and when people with dementia, family caregivers and physicians (900 respondents) find the interventions, shown on video, acceptable. (2) A cluster-randomised 3-armed controlled trial in 279 patients and their family caregivers assesses effects of two types of advance care planning differing in level of control (detailed advance treatment orders versus goal setting and coping based) on outcomes ranging from favourable to less favourable, and whether effects differ in subgroups. Cases in which the technology is preferred or applied are observed. (3) Ethnographic fieldwork in two different end-of-life research practices and a Delphi study to synthesize CONT-END’s findings assess how researchers shape findings. This greatly improves the quality of CONT-END and provides the input to develop new methodology for improving research quality and integrity.
Max ERC Funding
1 988 972 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
