Project acronym ArtMotor
Project Artificial Motor Proteins: toward a designed, autonomous protein motor built from non-motor parts
Researcher (PI) Heiner Linke, Paul CURMI, Birte HOECKER
Host Institution (HI) LUNDS UNIVERSITET
Country Sweden
Call Details Synergy Grants (SyG), SyG, ERC-2020-SyG
Summary Molecular motors and machines are essential for all cellular processes that together enable life. Built from proteins, with a wide range of properties, functionalities and performance characteristics, biological motors perform complex tasks and can transduce chemical energy into mechanical work more efficiently than human-made combustion engines. Sophisticated studies of biological protein motors have led to much structural and biophysical information and the development of models for motor function.
However, from the study of highly evolved, biological motors it remains difficult to discern detailed mechanisms, for example about the relative role of different force generation mechanisms, or how information is communicated across a protein to achieve the necessary coordination. A promising, complementary approach to answering these questions is to build synthetic protein motors from the bottom up. Indeed, much effort has been invested in functional protein design, but so far, the ‘holy grail’ of designing and building a functional synthetic protein motor has not been realized.
The purpose of ArtMotor is to design and build functional, synthetic protein motors capable of moving and transducing energy, based on existing, non-motor protein modules of known molecular function. Harnessing the synergy of expertise in computational protein design, structural and molecular biology, and single-molecule detection, we will use a two-pronged approach to (a) construct relatively simple protein motors that will require external control, while (b) construct, step by step, an autonomous protein motor capable of moving along a track. Such a functional, synthetic protein will constitute a ground-breaking advance in synthetic biology, physics and engineering. In addition to gaining new insights into mechanisms of energy transduction in proteins, we will also inspire other, complex protein designs that may lead to advances in fields from enzyme design to nano-engineering.
Summary
Molecular motors and machines are essential for all cellular processes that together enable life. Built from proteins, with a wide range of properties, functionalities and performance characteristics, biological motors perform complex tasks and can transduce chemical energy into mechanical work more efficiently than human-made combustion engines. Sophisticated studies of biological protein motors have led to much structural and biophysical information and the development of models for motor function.
However, from the study of highly evolved, biological motors it remains difficult to discern detailed mechanisms, for example about the relative role of different force generation mechanisms, or how information is communicated across a protein to achieve the necessary coordination. A promising, complementary approach to answering these questions is to build synthetic protein motors from the bottom up. Indeed, much effort has been invested in functional protein design, but so far, the ‘holy grail’ of designing and building a functional synthetic protein motor has not been realized.
The purpose of ArtMotor is to design and build functional, synthetic protein motors capable of moving and transducing energy, based on existing, non-motor protein modules of known molecular function. Harnessing the synergy of expertise in computational protein design, structural and molecular biology, and single-molecule detection, we will use a two-pronged approach to (a) construct relatively simple protein motors that will require external control, while (b) construct, step by step, an autonomous protein motor capable of moving along a track. Such a functional, synthetic protein will constitute a ground-breaking advance in synthetic biology, physics and engineering. In addition to gaining new insights into mechanisms of energy transduction in proteins, we will also inspire other, complex protein designs that may lead to advances in fields from enzyme design to nano-engineering.
Max ERC Funding
9 999 892 €
Duration
Start date: 2021-09-01, End date: 2027-08-31
Project acronym AWACA
Project Atmospheric WAter Cycle over Antarctica: Past, Present and Future
Researcher (PI) Christophe Genthon, Alexis BERNE, Thomas DUBOS, Valerie MASSON-DELMOTTE
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Synergy Grants (SyG), SyG, ERC-2020-SyG
Summary Climate models predict that precipitation will increase in Antarctica, which will moderate global sea-level rise. Meanwhile, the isotopic composition of snowfall records climate parameters which can be recovered in ice cores. However, there are still major gaps in our understanding of the atmospheric water cycle over Antarctica. For the first time, the AWACA project will provide a consistent and comprehensive combined observation and modeling framework to understand and predict the fate of atmospheric water all along the tropospheric column. Specifically adapted/designed instruments will be combined to form observation platforms deployed at 5 sites along a 1100 km coast-to-plateau transect aligned with the typical moisture-carrying air mass trajectories. The challenges of working in full autonomy in Antarctica, never addressed to such an extent before, will be tackled by collaborating with experts in polar technology and logistics. The resulting data set will make possible the study of the processes driving the water fluxes and composition to an unprecedented level, and the gained insights will be a strong basis to develop new physics parameterizations for regional and climate models. Once validated along the transect but also in other regions of Antarctica thanks to satellite observations and past campaigns, those models will enable us to decipher the past and future variability of the atmospheric water cycle over Antarctica.
Summary
Climate models predict that precipitation will increase in Antarctica, which will moderate global sea-level rise. Meanwhile, the isotopic composition of snowfall records climate parameters which can be recovered in ice cores. However, there are still major gaps in our understanding of the atmospheric water cycle over Antarctica. For the first time, the AWACA project will provide a consistent and comprehensive combined observation and modeling framework to understand and predict the fate of atmospheric water all along the tropospheric column. Specifically adapted/designed instruments will be combined to form observation platforms deployed at 5 sites along a 1100 km coast-to-plateau transect aligned with the typical moisture-carrying air mass trajectories. The challenges of working in full autonomy in Antarctica, never addressed to such an extent before, will be tackled by collaborating with experts in polar technology and logistics. The resulting data set will make possible the study of the processes driving the water fluxes and composition to an unprecedented level, and the gained insights will be a strong basis to develop new physics parameterizations for regional and climate models. Once validated along the transect but also in other regions of Antarctica thanks to satellite observations and past campaigns, those models will enable us to decipher the past and future variability of the atmospheric water cycle over Antarctica.
Max ERC Funding
13 967 283 €
Duration
Start date: 2021-09-01, End date: 2027-08-31
Project acronym BIOMECANET
Project Integration of the Biochemical and Mechanical Networks of Cell Division
Researcher (PI) Andrea MUSACCHIO, Francois NEDELEC, Thomas SURREY
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Country Germany
Call Details Synergy Grants (SyG), SyG, ERC-2020-SyG
Summary Cellular and sub-cellular organisation at the micrometre length scale ultimately reflects the activity of molecular networks that harness chemical energy to perform precise mechanical work, create functional spatial gradients, and sustain timely temporal changes in molecular activities. In eukaryotic cell division, the biochemical oscillations of the cell cycle drive dramatic morphological changes of the cytoskeleton necessary for bi-orientation of chromosomes and for their subsequent delivery into two daughter cells. This mechanism is at the heart of biology, but it is poorly understood and hard to address because it involves out-of-equilibrium chemistry of many components and Brownian mechanics of the cytoskeleton. BIOMECANET’s extraordinarily ambitious goal is to unravel this interplay by re-engineering it in vitro and by modelling it in silico. To achieve this, BIOMECANET will mobilize an unrivalled catalogue of purified human proteins to reconstitute four fundamental and interlinked biochemical and mechanical protein networks: 1) the cell cycle oscillator with the spindle assembly checkpoint; 2) the metaphase spindle; 3) the chromosome bi-orientation machinery of kinetochores; and 4) the central spindle and its links with the actin cytoskeleton required for cell fission. Then, BIOMECANET will combine these reconstituted networks, integrating temporal control and mechanical forces to analyse the emergence of complex life-like biological function, thus elevating scale and scope of in vitro reconstitutions to an entirely new level. Crucial to the attainment of BIOMECANET’s long-term goals is the synergetic alliance of two biochemists having pioneered different types of biochemical reconstitutions in the complementary areas of cell cycle and chromosome biology (Musacchio) and the cytoskeleton (Surrey), and a theoretician having pioneered physically faithful modelling and simulation of intracellular systems (Nédélec).
Summary
Cellular and sub-cellular organisation at the micrometre length scale ultimately reflects the activity of molecular networks that harness chemical energy to perform precise mechanical work, create functional spatial gradients, and sustain timely temporal changes in molecular activities. In eukaryotic cell division, the biochemical oscillations of the cell cycle drive dramatic morphological changes of the cytoskeleton necessary for bi-orientation of chromosomes and for their subsequent delivery into two daughter cells. This mechanism is at the heart of biology, but it is poorly understood and hard to address because it involves out-of-equilibrium chemistry of many components and Brownian mechanics of the cytoskeleton. BIOMECANET’s extraordinarily ambitious goal is to unravel this interplay by re-engineering it in vitro and by modelling it in silico. To achieve this, BIOMECANET will mobilize an unrivalled catalogue of purified human proteins to reconstitute four fundamental and interlinked biochemical and mechanical protein networks: 1) the cell cycle oscillator with the spindle assembly checkpoint; 2) the metaphase spindle; 3) the chromosome bi-orientation machinery of kinetochores; and 4) the central spindle and its links with the actin cytoskeleton required for cell fission. Then, BIOMECANET will combine these reconstituted networks, integrating temporal control and mechanical forces to analyse the emergence of complex life-like biological function, thus elevating scale and scope of in vitro reconstitutions to an entirely new level. Crucial to the attainment of BIOMECANET’s long-term goals is the synergetic alliance of two biochemists having pioneered different types of biochemical reconstitutions in the complementary areas of cell cycle and chromosome biology (Musacchio) and the cytoskeleton (Surrey), and a theoretician having pioneered physically faithful modelling and simulation of intracellular systems (Nédélec).
Max ERC Funding
10 613 236 €
Duration
Start date: 2021-07-01, End date: 2027-06-30
Project acronym BOLD
Project A background-free experiment to discover the nature of neutrinos based on single Barium Atom Light Detection
Researcher (PI) Juan GOMEZ, Fernando COSSIO, Roxanne GUENE
Host Institution (HI) FUNDACION DONOSTIA INTERNATIONAL PHYSICS CENTER
Country Spain
Call Details Synergy Grants (SyG), SyG, ERC-2020-SyG
Summary Searching for neutrinoless double beta decays (NLDBD) is the only practical way to establish if the neutrinos are their own antiparticles, a discovery of enormous importance for particle physics and cosmology. Due to the smallness of neutrino masses, the lifetime of NLDBD is expected to be much longer than the ones from the noise associated with the natural radioactive chains. A positive identification of NLDBD decays requires finding a signal that cannot be mimicked by radioactive backgrounds. In particular, the NLDBD decay of Xe-136 could be established by detecting the doubly ionized daughter atom, Ba2+ created in the decay. Such a detection could be achieved via a sensor made of a monolayer of molecular indicators. The Ba2+ would be captured by one of the molecules in the sensor, and the presence of the single Ba2+-complexed indicator would be subsequently revealed by a fluorescent response after interrogation with a laser system. Our proposed sensor is based on a new type of molecular bicolor fluorescent indicators, able to shift their emission spectra when complexed with Ba2+. The interrogation and detection system will be based in fast, two photon absorption microscopy.
The primary goals of this proposal are: 1, a full demonstration of the feasibility of a sensor capable of detecting single Ba2+ ions in a High Pressure Xenon Chamber (HPXe), and 2) the construction of a large HPXe demonstrator, the BOLD detector, which will implement a full Barium Tagging Detector System and will demonstrate the feasibility of building a background-free experiment at the ton-scale, with large discovery potential.
Summary
Searching for neutrinoless double beta decays (NLDBD) is the only practical way to establish if the neutrinos are their own antiparticles, a discovery of enormous importance for particle physics and cosmology. Due to the smallness of neutrino masses, the lifetime of NLDBD is expected to be much longer than the ones from the noise associated with the natural radioactive chains. A positive identification of NLDBD decays requires finding a signal that cannot be mimicked by radioactive backgrounds. In particular, the NLDBD decay of Xe-136 could be established by detecting the doubly ionized daughter atom, Ba2+ created in the decay. Such a detection could be achieved via a sensor made of a monolayer of molecular indicators. The Ba2+ would be captured by one of the molecules in the sensor, and the presence of the single Ba2+-complexed indicator would be subsequently revealed by a fluorescent response after interrogation with a laser system. Our proposed sensor is based on a new type of molecular bicolor fluorescent indicators, able to shift their emission spectra when complexed with Ba2+. The interrogation and detection system will be based in fast, two photon absorption microscopy.
The primary goals of this proposal are: 1, a full demonstration of the feasibility of a sensor capable of detecting single Ba2+ ions in a High Pressure Xenon Chamber (HPXe), and 2) the construction of a large HPXe demonstrator, the BOLD detector, which will implement a full Barium Tagging Detector System and will demonstrate the feasibility of building a background-free experiment at the ton-scale, with large discovery potential.
Max ERC Funding
9 373 587 €
Duration
Start date: 2021-03-01, End date: 2027-02-28
Project acronym CARBOCENTRE
Project Activity-Based Profiling of Glycoprocessing Enzymes for Human Health and a Sustainable Society
Researcher (PI) Herman Overkleeft, Gideon DAVIES, Carme ROVIRA
Host Institution (HI) UNIVERSITEIT LEIDEN
Country Netherlands
Call Details Synergy Grants (SyG), SyG, ERC-2020-SyG
Summary Enzymes that produce and degrade oligosaccharides and glycoconjugates are present in all kingdoms of life. The ability to visualize, modulate and understand these carbohydrate-active enzymes (CAZymes) therefore offers great potential for human health and sustainable industries. To provide a “disruptive” shift in our understanding, we adopt in this proposal a multidisciplinary approach combining structural biology, enzymology, computational chemistry, organic synthesis, and chemical biology, with major leaders in these fields part of our CARBOCENTRE Synergy Team. Three fundamental strands will specifically target and ‘capture’ glycoprocessing enzyme active sites. Biochemical and 3-D structural analyses will inform computational dissection of the reaction coordinate of key enzymes for human health and biotechnology processes. Building on our founding work on retaining glycosidases we will also target inverting glycosidases and glycosyltransferases. Following fundamental analyses, our probes will feed research in two major application domains of human health and biotechnology: 1. To provide visualization, diagnosis, and inhibitor assays and clinical lead compounds for enzymes in cancers and genetic diseases (lysosomal storage disorders). 2. To explore the natural diversity of CAZymes and to discover, quantify and optimize new enzymes for food and household applications and for biomass conversion to biofuels. In an iterative cycle, structural biology and enzymology (Davies, York), will inform, through structures of enzymes and enzyme-inhibitor complexes, theoretical and computational chemistry (Rovira, Barcelona), which in turn will guide the design and synthesis (Overkleeft, Leiden), of inhibitors and activity-based probes for ensuing chemical biology studies in the domains of biomedicine and biotechnology.
Summary
Enzymes that produce and degrade oligosaccharides and glycoconjugates are present in all kingdoms of life. The ability to visualize, modulate and understand these carbohydrate-active enzymes (CAZymes) therefore offers great potential for human health and sustainable industries. To provide a “disruptive” shift in our understanding, we adopt in this proposal a multidisciplinary approach combining structural biology, enzymology, computational chemistry, organic synthesis, and chemical biology, with major leaders in these fields part of our CARBOCENTRE Synergy Team. Three fundamental strands will specifically target and ‘capture’ glycoprocessing enzyme active sites. Biochemical and 3-D structural analyses will inform computational dissection of the reaction coordinate of key enzymes for human health and biotechnology processes. Building on our founding work on retaining glycosidases we will also target inverting glycosidases and glycosyltransferases. Following fundamental analyses, our probes will feed research in two major application domains of human health and biotechnology: 1. To provide visualization, diagnosis, and inhibitor assays and clinical lead compounds for enzymes in cancers and genetic diseases (lysosomal storage disorders). 2. To explore the natural diversity of CAZymes and to discover, quantify and optimize new enzymes for food and household applications and for biomass conversion to biofuels. In an iterative cycle, structural biology and enzymology (Davies, York), will inform, through structures of enzymes and enzyme-inhibitor complexes, theoretical and computational chemistry (Rovira, Barcelona), which in turn will guide the design and synthesis (Overkleeft, Leiden), of inhibitors and activity-based probes for ensuing chemical biology studies in the domains of biomedicine and biotechnology.
Max ERC Funding
9 057 250 €
Duration
Start date: 2021-06-01, End date: 2027-05-31
Project acronym COREX
Project From correlations to explanations: towards a new European prehistory
Researcher (PI) Kristian Kristiansen, Kurt Henrik KJAER, Mark THOMAS
Host Institution (HI) GOETEBORGS UNIVERSITET
Country Sweden
Call Details Synergy Grants (SyG), SyG, ERC-2020-SyG
Summary The study of the past is undergoing a dramatic transformation: researchers in the fields of archaeology, genetics, linguistics, history and archaeometry are blurring the lines delimiting their respective fields, and working in increasingly collaborative efforts to understand how history and prehistory unfolded. Recent debates stress the need for new explanatory models which integrate both micro- and macro-level historical processes, and diverse types of datasets. We approach this challenge by applying novel modelling approaches allowing us to move from correlations to explanations of how changes have been shaped by the dynamic interaction of cultural innovation, migration, admixture, population growth and collapse, landscape transformation, dietary change, biological adaptation, social structure, and the emergence of new diseases. To achieve this overall goal the project is built upon four specific aims, which translates into four work packages: WP1: Database for C14, cultural and subsistence (including isotope) data, ancient genomes, eDNA sites, fossil pollen datasets and strontium samples WP2: Environmental DNA and high- resolution local environments,WP3 Exploratory analyses and discriminative models, WP4 Generative models and explanations. Our findings will serve to determine what the impact of the movement of people was on the European landscape, simultaneously on multiple scales: continental, regional and local, providing a research program defying the boundaries of archaeology, genetics and mathematical modelling.Thus, by identifying prehistoric regularities in the interactions of human biology, social and economic organisation, and demography we will be able to compare them to anthropological and historical models of such processes in recent times, to form a more comprehensive understanding of the nature of migration, integration and cultural change, then and now.
Summary
The study of the past is undergoing a dramatic transformation: researchers in the fields of archaeology, genetics, linguistics, history and archaeometry are blurring the lines delimiting their respective fields, and working in increasingly collaborative efforts to understand how history and prehistory unfolded. Recent debates stress the need for new explanatory models which integrate both micro- and macro-level historical processes, and diverse types of datasets. We approach this challenge by applying novel modelling approaches allowing us to move from correlations to explanations of how changes have been shaped by the dynamic interaction of cultural innovation, migration, admixture, population growth and collapse, landscape transformation, dietary change, biological adaptation, social structure, and the emergence of new diseases. To achieve this overall goal the project is built upon four specific aims, which translates into four work packages: WP1: Database for C14, cultural and subsistence (including isotope) data, ancient genomes, eDNA sites, fossil pollen datasets and strontium samples WP2: Environmental DNA and high- resolution local environments,WP3 Exploratory analyses and discriminative models, WP4 Generative models and explanations. Our findings will serve to determine what the impact of the movement of people was on the European landscape, simultaneously on multiple scales: continental, regional and local, providing a research program defying the boundaries of archaeology, genetics and mathematical modelling.Thus, by identifying prehistoric regularities in the interactions of human biology, social and economic organisation, and demography we will be able to compare them to anthropological and historical models of such processes in recent times, to form a more comprehensive understanding of the nature of migration, integration and cultural change, then and now.
Max ERC Funding
9 759 609 €
Duration
Start date: 2021-05-01, End date: 2027-04-30
Project acronym ENSEMBLE
Project Structure and functions of the brain extracellular space
Researcher (PI) Laurent Groc, Erwan BEZARD, Laurent COGNET, Valentin NAGERL
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Synergy Grants (SyG), SyG, ERC-2020-SyG
Summary Brain research has made tremendous progress over the last few decades in nearly all areas of investigation with the exception of one: the extracellular space (ECS). It is however a key compartment defined as the web-like space between brain cells, filled with a myriad of molecules that enable brain functions and homeostasis. How molecules navigate in the ECS is a very important, yet unsolved, challenge that precludes conceptual advance in brain science and innovation in therapeutics (e.g. immunotherapy). The lack of knowledge is mainly due to the absence of dedicated investigation strategies for such a complex and finely structured biological entity. Our ground-breaking project (ENSEMBLE) will shed light on the conceptual and methodological roadblocks that have prevented us from understanding the fine architecture of the ECS and how molecules navigate within it throughout the brain. We posit that molecular diffusion in the ECS is locally regulated by the properties of the ECS, which is essential for brain functions. Four world-class scientists, L. Groc (molecular neuroscience, CNRS), E. Bezard (systems neuroscience, INSERM), L. Cognet (optics & nanoscience, CNRS), and U.V. Nägerl (neurophotonics, Univ. Bordeaux), team up to develop and apply unconventional investigation approaches, based on original nano-imaging strategies (super-resolution microscopy and carbon nanotube/nanoparticle tracking), to the in vivo brain. Yet, to consider and achieve such an experimental and multidisciplinary tour de force a side-by-side and daily interactive effort is necessary. Thanks to our complementary expertise and geographical proximity, ENSEMBLE will provide a unique opportunity to unveil in vivo the structure and functions of this crucial brain compartment and will offer a new theoretical and experimental framework to manipulate molecule navigation. The ENSEMBLE project will also cross-fertilize the fields of nanoscience, optical imaging, organ pathophysiology and immunotherapy.
Summary
Brain research has made tremendous progress over the last few decades in nearly all areas of investigation with the exception of one: the extracellular space (ECS). It is however a key compartment defined as the web-like space between brain cells, filled with a myriad of molecules that enable brain functions and homeostasis. How molecules navigate in the ECS is a very important, yet unsolved, challenge that precludes conceptual advance in brain science and innovation in therapeutics (e.g. immunotherapy). The lack of knowledge is mainly due to the absence of dedicated investigation strategies for such a complex and finely structured biological entity. Our ground-breaking project (ENSEMBLE) will shed light on the conceptual and methodological roadblocks that have prevented us from understanding the fine architecture of the ECS and how molecules navigate within it throughout the brain. We posit that molecular diffusion in the ECS is locally regulated by the properties of the ECS, which is essential for brain functions. Four world-class scientists, L. Groc (molecular neuroscience, CNRS), E. Bezard (systems neuroscience, INSERM), L. Cognet (optics & nanoscience, CNRS), and U.V. Nägerl (neurophotonics, Univ. Bordeaux), team up to develop and apply unconventional investigation approaches, based on original nano-imaging strategies (super-resolution microscopy and carbon nanotube/nanoparticle tracking), to the in vivo brain. Yet, to consider and achieve such an experimental and multidisciplinary tour de force a side-by-side and daily interactive effort is necessary. Thanks to our complementary expertise and geographical proximity, ENSEMBLE will provide a unique opportunity to unveil in vivo the structure and functions of this crucial brain compartment and will offer a new theoretical and experimental framework to manipulate molecule navigation. The ENSEMBLE project will also cross-fertilize the fields of nanoscience, optical imaging, organ pathophysiology and immunotherapy.
Max ERC Funding
9 992 473 €
Duration
Start date: 2021-05-01, End date: 2027-04-30
Project acronym FungalTolerance
Project Unraveling the complexity of fungal drug tolerance at multiple scales of biology
Researcher (PI) Judith Berman, Markus RALSER, Markus RALSER, Markus RALSER, Markus RALSER, Markus RALSER, Markus RALSER, Markus RALSER, Markus RALSER, Markus RALSER, Markus RALSER, Markus RALSER
Host Institution (HI) TEL AVIV UNIVERSITY
Country Israel
Call Details Synergy Grants (SyG), SyG, ERC-2020-SyG
Summary Mortality from invasive fungal infections approaches 50%, despite the use of available antifungal drugs. While bacterial studies have focused on drug resistance, the rare appearance of antifungal drug resistance does not explain these treatment failures. Antifungal tolerance is a poorly understood property that is expressed to different degrees in different non-resistant isolates, yet has not been measured routinely in the clinic or in most research studies. We do not know how tolerance differs between isolates, what biological mechanisms drive it, how it affects only some cells in a single isolate, or whether it can be inhibited to improve treatment outcomes. Recently, the Berman lab found that tolerance is an intrinsic property, in which some cells of a non-resistant isolate continue growing in the presence of the drug that has the potential to explain antifungal treatment failures. In parallel, the Ralser lab found that inhibitors of metabolic pathways affect the stress survival of some cells and the Berman lab found that these inhibitors can clear tolerance and convert an antifungal drug from fungistatic to fungicidal, thereby killing the cells and halting their adaptation. Together, we combine expertise in pathogenic fungi (Berman) and metabolic systems (Ralser) to reach fundamental understandings of tolerance across the range of its biological scales by: 1) capturing the diversity of tolerance in a genomic and proteomic data resource of >1000 isolates; 2) identifying metabolic pathways and molecular mechanisms that drive tolerance within isolates; and 3) probing processes and compounds that affect phenotypic heterogeneity between cells and suppress tolerance. By elucidating the mechanisms that drive tolerance and fungal single-cell diversity, we propose to render tolerance targetable, providing a paradigm shift in anti-fungal treatment strategies.
Summary
Mortality from invasive fungal infections approaches 50%, despite the use of available antifungal drugs. While bacterial studies have focused on drug resistance, the rare appearance of antifungal drug resistance does not explain these treatment failures. Antifungal tolerance is a poorly understood property that is expressed to different degrees in different non-resistant isolates, yet has not been measured routinely in the clinic or in most research studies. We do not know how tolerance differs between isolates, what biological mechanisms drive it, how it affects only some cells in a single isolate, or whether it can be inhibited to improve treatment outcomes. Recently, the Berman lab found that tolerance is an intrinsic property, in which some cells of a non-resistant isolate continue growing in the presence of the drug that has the potential to explain antifungal treatment failures. In parallel, the Ralser lab found that inhibitors of metabolic pathways affect the stress survival of some cells and the Berman lab found that these inhibitors can clear tolerance and convert an antifungal drug from fungistatic to fungicidal, thereby killing the cells and halting their adaptation. Together, we combine expertise in pathogenic fungi (Berman) and metabolic systems (Ralser) to reach fundamental understandings of tolerance across the range of its biological scales by: 1) capturing the diversity of tolerance in a genomic and proteomic data resource of >1000 isolates; 2) identifying metabolic pathways and molecular mechanisms that drive tolerance within isolates; and 3) probing processes and compounds that affect phenotypic heterogeneity between cells and suppress tolerance. By elucidating the mechanisms that drive tolerance and fungal single-cell diversity, we propose to render tolerance targetable, providing a paradigm shift in anti-fungal treatment strategies.
Max ERC Funding
9 690 918 €
Duration
Start date: 2021-03-01, End date: 2027-02-28
Project acronym GENIE
Project GENIE: GeoEngineering and NegatIve Emissions pathways in Europe
Researcher (PI) Benjamin Sovacool, Jan Christoph MINX, Keywan RIAHI
Host Institution (HI) AARHUS UNIVERSITET
Country Denmark
Call Details Synergy Grants (SyG), SyG, ERC-2020-SyG
Summary Geoengineering technologies, such as solar radiation management (SRM), and negative emissions technologies, such as greenhouse gas removal (GGR), are emerging options to address climate change. This project will investigate the environmental, technical, social, legal, and policy dimensions of GGR and SRM. We provide an urgently needed interdisciplinary and holistic perspective of these technologies in order to understand conditions under which they might be deployed at scale. Our meta-analytical framework integrates insights from social science, engineering and physical science disciplines to provide a comprehensive view of GGR and SRM in the transition to climate neutrality in Europe and the world. The project will conduct excellent research and generate a robust, scientific assessment for evidence-based policymaking. Our research framework consists of three pillars—techno-economic systems, socio-technical systems, and systems of political action—within which we place six work packages (WPs). These are: (1) Understanding the current state and future potential of GGR and SRM technologies in terms of their technical and economic features; (2) Analysing bottlenecks in transitions to climate neutrality and their implications for deployment; (3) Identifying social acceptance and legitimacy constraints, (4) Learning, diffusion, and adoption; (5) Implications for Sustainable Development Goals of archetypical mitigation pathways; and 6) Policy options and governance. A crosscutting WP7 synthesizes research along three salient, but under-researched themes: A) Socio-technical change; B) Managing transition risks; and C) Political economy and feasibility of deployment. WP8 focuses on stakeholder engagement, entailing scenario co-design, science-policy dialogue formats, and specific outreach formats for target groups.
Summary
Geoengineering technologies, such as solar radiation management (SRM), and negative emissions technologies, such as greenhouse gas removal (GGR), are emerging options to address climate change. This project will investigate the environmental, technical, social, legal, and policy dimensions of GGR and SRM. We provide an urgently needed interdisciplinary and holistic perspective of these technologies in order to understand conditions under which they might be deployed at scale. Our meta-analytical framework integrates insights from social science, engineering and physical science disciplines to provide a comprehensive view of GGR and SRM in the transition to climate neutrality in Europe and the world. The project will conduct excellent research and generate a robust, scientific assessment for evidence-based policymaking. Our research framework consists of three pillars—techno-economic systems, socio-technical systems, and systems of political action—within which we place six work packages (WPs). These are: (1) Understanding the current state and future potential of GGR and SRM technologies in terms of their technical and economic features; (2) Analysing bottlenecks in transitions to climate neutrality and their implications for deployment; (3) Identifying social acceptance and legitimacy constraints, (4) Learning, diffusion, and adoption; (5) Implications for Sustainable Development Goals of archetypical mitigation pathways; and 6) Policy options and governance. A crosscutting WP7 synthesizes research along three salient, but under-researched themes: A) Socio-technical change; B) Managing transition risks; and C) Political economy and feasibility of deployment. WP8 focuses on stakeholder engagement, entailing scenario co-design, science-policy dialogue formats, and specific outreach formats for target groups.
Max ERC Funding
9 187 902 €
Duration
Start date: 2021-05-01, End date: 2027-04-30
Project acronym KiloNeurons
Project Population Codes for Space in the Mammalian Cortex
Researcher (PI) Edvard Ingjald Moser, Yoram BURAK
Host Institution (HI) NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Country Norway
Call Details Synergy Grants (SyG), SyG, ERC-2020-SyG
Summary A major goal in neuroscience is to understand neural computation in the mammalian cortex. Since the 1950s, we have learnt how cells respond to changes in the environment but the cells have largely been observed one at a time. However, single-cell recording cannot access the complexity of distributed processing and coding in the large, intermixed cell populations of the cortex. To understand this complexity, we need population-wide activity measurements, at single-cell resolution, as well as theoretical models to interpret the data. In this project, we shall combine experiments and theory to enable a paradigmatic shift from single-cell to population analysis for a prototypical high-level cortical system, the navigation system of the mammalian medial entorhinal-hippocampal region. In this system, spatial firing correlates of individual cells are so evident that they have been given simple, descriptive names – such as place cells, grid cells, and head direction cells. The wealth of information on the phenomenology of these cells, and the existence of theoretical frameworks that offer strong predictions on their population-wide activity patterns, renders the system perfect for population-level analyses of cortical computation. We shall introduce experimental tools to obtain the amount and specificity of multi-neuron data required to decipher neural population codes in freely navigating rodents. Guided initially by theory on attractor network dynamics, we shall identify regularities in firing and connectivity patterns of thousands of simultaneously monitored neurons and use the data to test, refine and develop theoretical models. This exercise will be extended to less-understood high-end systems such as lateral entorhinal cortex, where computational operations have remained elusive due to the lack of similar single-cell correlates. The project is transformative in that it will uncover fundamental and general mechanisms of high-end cortical population coding in mammals.
Summary
A major goal in neuroscience is to understand neural computation in the mammalian cortex. Since the 1950s, we have learnt how cells respond to changes in the environment but the cells have largely been observed one at a time. However, single-cell recording cannot access the complexity of distributed processing and coding in the large, intermixed cell populations of the cortex. To understand this complexity, we need population-wide activity measurements, at single-cell resolution, as well as theoretical models to interpret the data. In this project, we shall combine experiments and theory to enable a paradigmatic shift from single-cell to population analysis for a prototypical high-level cortical system, the navigation system of the mammalian medial entorhinal-hippocampal region. In this system, spatial firing correlates of individual cells are so evident that they have been given simple, descriptive names – such as place cells, grid cells, and head direction cells. The wealth of information on the phenomenology of these cells, and the existence of theoretical frameworks that offer strong predictions on their population-wide activity patterns, renders the system perfect for population-level analyses of cortical computation. We shall introduce experimental tools to obtain the amount and specificity of multi-neuron data required to decipher neural population codes in freely navigating rodents. Guided initially by theory on attractor network dynamics, we shall identify regularities in firing and connectivity patterns of thousands of simultaneously monitored neurons and use the data to test, refine and develop theoretical models. This exercise will be extended to less-understood high-end systems such as lateral entorhinal cortex, where computational operations have remained elusive due to the lack of similar single-cell correlates. The project is transformative in that it will uncover fundamental and general mechanisms of high-end cortical population coding in mammals.
Max ERC Funding
9 976 875 €
Duration
Start date: 2021-02-01, End date: 2027-01-31
