Project acronym 15CBOOKTRADE
Project The 15th-century Book Trade: An Evidence-based Assessment and Visualization of the Distribution, Sale, and Reception of Books in the Renaissance
Researcher (PI) Cristina Dondi
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Country United Kingdom
Call Details Consolidator Grant (CoG), SH6, ERC-2013-CoG
Summary The idea that underpins this project is to use the material evidence from thousands of surviving 15th-c. books, as well as unique documentary evidence — the unpublished ledger of a Venetian bookseller in the 1480s which records the sale of 25,000 printed books with their prices — to address four fundamental questions relating to the introduction of printing in the West which have so far eluded scholarship, partly because of lack of evidence, partly because of the lack of effective tools to deal with existing evidence. The book trade differs from other trades operating in the medieval and early modern periods in that the goods traded survive in considerable numbers. Not only do they survive, but many of them bear stratified evidence of their history in the form of marks of ownership, prices, manuscript annotations, binding and decoration styles. A British Academy pilot project conceived by the PI produced a now internationally-used database which gathers together this kind of evidence for thousands of surviving 15th-c. printed books. For the first time, this makes it possible to track the circulation of books, their trade routes and later collecting, across Europe and the USA, and throughout the centuries. The objectives of this project are to examine (1) the distribution and trade-routes, national and international, of 15th-c. printed books, along with the identity of the buyers and users (private, institutional, religious, lay, female, male, and by profession) and their reading practices; (2) the books' contemporary market value; (3) the transmission and dissemination of the texts they contain, their survival and their loss (rebalancing potentially skewed scholarship); and (4) the circulation and re-use of the illustrations they contain. Finally, the project will experiment with the application of scientific visualization techniques to represent, geographically and chronologically, the movement of 15th-c. printed books and of the texts they contain.
Summary
The idea that underpins this project is to use the material evidence from thousands of surviving 15th-c. books, as well as unique documentary evidence — the unpublished ledger of a Venetian bookseller in the 1480s which records the sale of 25,000 printed books with their prices — to address four fundamental questions relating to the introduction of printing in the West which have so far eluded scholarship, partly because of lack of evidence, partly because of the lack of effective tools to deal with existing evidence. The book trade differs from other trades operating in the medieval and early modern periods in that the goods traded survive in considerable numbers. Not only do they survive, but many of them bear stratified evidence of their history in the form of marks of ownership, prices, manuscript annotations, binding and decoration styles. A British Academy pilot project conceived by the PI produced a now internationally-used database which gathers together this kind of evidence for thousands of surviving 15th-c. printed books. For the first time, this makes it possible to track the circulation of books, their trade routes and later collecting, across Europe and the USA, and throughout the centuries. The objectives of this project are to examine (1) the distribution and trade-routes, national and international, of 15th-c. printed books, along with the identity of the buyers and users (private, institutional, religious, lay, female, male, and by profession) and their reading practices; (2) the books' contemporary market value; (3) the transmission and dissemination of the texts they contain, their survival and their loss (rebalancing potentially skewed scholarship); and (4) the circulation and re-use of the illustrations they contain. Finally, the project will experiment with the application of scientific visualization techniques to represent, geographically and chronologically, the movement of 15th-c. printed books and of the texts they contain.
Max ERC Funding
1 999 172 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym 3D-JOINT
Project 3D Bioprinting of JOINT Replacements
Researcher (PI) Johannes Jos Malda
Host Institution (HI) UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Country Netherlands
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary The world has a significant medical challenge in repairing injured or diseased joints. Joint degeneration and its related pain is a major socio-economic burden that will increase over the next decade and is currently addressed by implanting a metal prosthesis. For the long term, the ideal solution to joint injury is to successfully regenerate rather than replace the damaged cartilage with synthetic implants. Recent advances in key technologies are now bringing this “holy grail” within reach; regenerative approaches, based on cell therapy, are already clinically available albeit only for smaller focal cartilage defects.
One of these key technologies is three-dimensional (3D) bio-printing, which provides a greatly controlled placement and organization of living constructs through the layer-by-layer deposition of materials and cells. These tissue constructs can be applied as tissue models for research and screening. However, the lack of biomechanical properties of these tissue constructs has hampered their application to the regeneration of damaged, degenerated or diseased tissue.
Having established a cartilage-focussed research laboratory in the University Medical Center Utrecht, I have addressed this biomechanical limitation of hydrogels through the use of hydrogel composites. Specifically, I have pioneered a 3D bio-printing technology that combines accurately printed small diameter thermoplast filaments with cell invasive hydrogels to form strong fibre-reinforced constructs. This, in combination with bioreactor technology, is the key to the generation of larger, complex tissue constructs with cartilage-like biomechanical resilience. With 3D-JOINT I will use my in-depth bio-printing and bioreactor knowledge and experience to develop a multi-phasic 3D-printed biological replacement of the joint.
Summary
The world has a significant medical challenge in repairing injured or diseased joints. Joint degeneration and its related pain is a major socio-economic burden that will increase over the next decade and is currently addressed by implanting a metal prosthesis. For the long term, the ideal solution to joint injury is to successfully regenerate rather than replace the damaged cartilage with synthetic implants. Recent advances in key technologies are now bringing this “holy grail” within reach; regenerative approaches, based on cell therapy, are already clinically available albeit only for smaller focal cartilage defects.
One of these key technologies is three-dimensional (3D) bio-printing, which provides a greatly controlled placement and organization of living constructs through the layer-by-layer deposition of materials and cells. These tissue constructs can be applied as tissue models for research and screening. However, the lack of biomechanical properties of these tissue constructs has hampered their application to the regeneration of damaged, degenerated or diseased tissue.
Having established a cartilage-focussed research laboratory in the University Medical Center Utrecht, I have addressed this biomechanical limitation of hydrogels through the use of hydrogel composites. Specifically, I have pioneered a 3D bio-printing technology that combines accurately printed small diameter thermoplast filaments with cell invasive hydrogels to form strong fibre-reinforced constructs. This, in combination with bioreactor technology, is the key to the generation of larger, complex tissue constructs with cartilage-like biomechanical resilience. With 3D-JOINT I will use my in-depth bio-printing and bioreactor knowledge and experience to develop a multi-phasic 3D-printed biological replacement of the joint.
Max ERC Funding
1 998 871 €
Duration
Start date: 2015-07-01, End date: 2020-06-30
Project acronym 3DPROTEINPUZZLES
Project Shape-directed protein assembly design
Researcher (PI) Lars Ingemar ANDRe
Host Institution (HI) MAX IV Laboratory, Lund University
Country Sweden
Call Details Consolidator Grant (CoG), LS9, ERC-2017-COG
Summary Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.
Summary
Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.
Max ERC Funding
2 325 292 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym 9 SALT
Project Reassessing Ninth Century Philosophy. A Synchronic Approach to the Logical Traditions
Researcher (PI) Christophe Florian Erismann
Host Institution (HI) UNIVERSITAT WIEN
Country Austria
Call Details Consolidator Grant (CoG), SH5, ERC-2014-CoG
Summary This project aims at a better understanding of the philosophical richness of ninth century thought using the unprecedented and highly innovative method of the synchronic approach. The hypothesis directing this synchronic approach is that studying together in parallel the four main philosophical traditions of the century – i.e. Latin, Greek, Syriac and Arabic – will bring results that the traditional enquiry limited to one tradition alone can never reach. This implies pioneering a new methodology to overcome the compartmentalization of research which prevails nowadays. Using this method is only possible because the four conditions of applicability – comparable intellectual environment, common text corpus, similar methodological perspective, commensurable problems – are fulfilled. The ninth century, a time of cultural renewal in the Carolingian, Byzantine and Abbasid empires, possesses the remarkable characteristic – which ensures commensurability – that the same texts, namely the writings of Aristotelian logic (mainly Porphyry’s Isagoge and Aristotle’s Categories) were read and commented upon in Latin, Greek, Syriac and Arabic alike.
Logic is fundamental to philosophical enquiry. The contested question is the human capacity to rationalise, analyse and describe the sensible reality, to understand the ontological structure of the world, and to define the types of entities which exist. The use of this unprecedented synchronic approach will allow us a deeper understanding of the positions, a clear identification of the a priori postulates of the philosophical debates, and a critical evaluation of the arguments used. It provides a unique opportunity to compare the different traditions and highlight the heritage which is common, to stress the specificities of each tradition when tackling philosophical issues and to discover the doctrinal results triggered by their mutual interactions, be they constructive (scholarly exchanges) or polemic (religious controversies).
Summary
This project aims at a better understanding of the philosophical richness of ninth century thought using the unprecedented and highly innovative method of the synchronic approach. The hypothesis directing this synchronic approach is that studying together in parallel the four main philosophical traditions of the century – i.e. Latin, Greek, Syriac and Arabic – will bring results that the traditional enquiry limited to one tradition alone can never reach. This implies pioneering a new methodology to overcome the compartmentalization of research which prevails nowadays. Using this method is only possible because the four conditions of applicability – comparable intellectual environment, common text corpus, similar methodological perspective, commensurable problems – are fulfilled. The ninth century, a time of cultural renewal in the Carolingian, Byzantine and Abbasid empires, possesses the remarkable characteristic – which ensures commensurability – that the same texts, namely the writings of Aristotelian logic (mainly Porphyry’s Isagoge and Aristotle’s Categories) were read and commented upon in Latin, Greek, Syriac and Arabic alike.
Logic is fundamental to philosophical enquiry. The contested question is the human capacity to rationalise, analyse and describe the sensible reality, to understand the ontological structure of the world, and to define the types of entities which exist. The use of this unprecedented synchronic approach will allow us a deeper understanding of the positions, a clear identification of the a priori postulates of the philosophical debates, and a critical evaluation of the arguments used. It provides a unique opportunity to compare the different traditions and highlight the heritage which is common, to stress the specificities of each tradition when tackling philosophical issues and to discover the doctrinal results triggered by their mutual interactions, be they constructive (scholarly exchanges) or polemic (religious controversies).
Max ERC Funding
1 998 566 €
Duration
Start date: 2015-09-01, End date: 2021-02-28
Project acronym A-DIET
Project Metabolomics based biomarkers of dietary intake- new tools for nutrition research
Researcher (PI) Lorraine Brennan
Host Institution (HI) UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN
Country Ireland
Call Details Consolidator Grant (CoG), LS7, ERC-2014-CoG
Summary In todays advanced technological world, we can track the exact movement of individuals, analyse their genetic makeup and predict predisposition to certain diseases. However, we are unable to accurately assess an individual’s dietary intake. This is without a doubt one of the main stumbling blocks in assessing the link between diet and disease/health. The present proposal (A-DIET) will address this issue with the overarching objective to develop novel strategies for assessment of dietary intake.
Using approaches to (1) identify biomarkers of specific foods (2) classify people into dietary patterns (nutritypes) and (3) develop a tool for integration of dietary and biomarker data, A-DIET has the potential to dramatically enhance our ability to accurately assess dietary intake. The ultimate output from A-DIET will be a dietary assessment tool which can be used to obtain an accurate assessment of dietary intake by combining dietary and biomarker data which in turn will allow investigations into relationships between diet, health and disease. New biomarkers of specific foods will be identified and validated using intervention studies and metabolomic analyses. Methods will be developed to classify individuals into dietary patterns based on biomarker/metabolomic profiles thus demonstrating the novel concept of nutritypes. Strategies for integration of dietary and biomarker data will be developed and translated into a tool that will be made available to the wider scientific community.
Advances made in A-DIET will enable nutrition epidemiologist’s to properly examine the relationship between diet and disease and develop clear public health messages with regard to diet and health. Additionally results from A-DIET will allow researchers to accurately assess people’s diet and implement health promotion strategies and enable dieticians in a clinical environment to assess compliance to therapeutic diets such as adherence to a high fibre diet or a gluten free diet.
Summary
In todays advanced technological world, we can track the exact movement of individuals, analyse their genetic makeup and predict predisposition to certain diseases. However, we are unable to accurately assess an individual’s dietary intake. This is without a doubt one of the main stumbling blocks in assessing the link between diet and disease/health. The present proposal (A-DIET) will address this issue with the overarching objective to develop novel strategies for assessment of dietary intake.
Using approaches to (1) identify biomarkers of specific foods (2) classify people into dietary patterns (nutritypes) and (3) develop a tool for integration of dietary and biomarker data, A-DIET has the potential to dramatically enhance our ability to accurately assess dietary intake. The ultimate output from A-DIET will be a dietary assessment tool which can be used to obtain an accurate assessment of dietary intake by combining dietary and biomarker data which in turn will allow investigations into relationships between diet, health and disease. New biomarkers of specific foods will be identified and validated using intervention studies and metabolomic analyses. Methods will be developed to classify individuals into dietary patterns based on biomarker/metabolomic profiles thus demonstrating the novel concept of nutritypes. Strategies for integration of dietary and biomarker data will be developed and translated into a tool that will be made available to the wider scientific community.
Advances made in A-DIET will enable nutrition epidemiologist’s to properly examine the relationship between diet and disease and develop clear public health messages with regard to diet and health. Additionally results from A-DIET will allow researchers to accurately assess people’s diet and implement health promotion strategies and enable dieticians in a clinical environment to assess compliance to therapeutic diets such as adherence to a high fibre diet or a gluten free diet.
Max ERC Funding
1 995 548 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
Project acronym A-FRO
Project Actively Frozen - contextual modulation of freezing and its neuronal basis
Researcher (PI) Marta de Aragao Pacheco Moita
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Country Portugal
Call Details Consolidator Grant (CoG), LS5, ERC-2018-COG
Summary When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.
Summary
When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.
Max ERC Funding
1 969 750 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym A-HERO
Project Anthelmintic Research and Optimization
Researcher (PI) Jennifer Irene Keiser
Host Institution (HI) SCHWEIZERISCHES TROPEN- UND PUBLIC HEALTH-INSTITUT
Country Switzerland
Call Details Consolidator Grant (CoG), LS7, ERC-2013-CoG
Summary "I propose an ambitious, yet feasible 5-year research project that will fill an important gap in global health. Specifically, I will develop and validate novel approaches for anthelmintic drug discovery and development. My proposal pursues the following five research questions: (i) Is a chip calorimeter suitable for high-throughput screening in anthelmintic drug discovery? (ii) Is combination chemotherapy safe and more efficacious than monotherapy against strongyloidiasis and trichuriasis? (iii) What are the key pharmacokinetic parameters of praziquantel in preschool-aged children and school-aged children infected with Schistosoma mansoni and S. haematobium using a novel and validated technology based on dried blood spotting? (iv) What are the metabolic consequences and clearance of praziquantel treatment in S. mansoni-infected mice and S. mansoni- and S. haematobium-infected children? (v) Which is the ideal compartment to study pharmacokinetic parameters for intestinal nematode infections and does age, nutrition, co-infection and infection intensity influence the efficacy of anthelmintic drugs?
My proposed research is of considerable public health relevance since it will ultimately result in improved treatments for soil-transmitted helminthiasis and pediatric schistosomiasis. Additionally, at the end of this project, I have generated comprehensive information on drug disposition of anthelmintics. A comprehensive database of metabolite profiles following praziquantel treatment will be available. Finally, the proof-of-concept of chip calorimetry in anthelmintic drug discovery has been established and broadly validated."
Summary
"I propose an ambitious, yet feasible 5-year research project that will fill an important gap in global health. Specifically, I will develop and validate novel approaches for anthelmintic drug discovery and development. My proposal pursues the following five research questions: (i) Is a chip calorimeter suitable for high-throughput screening in anthelmintic drug discovery? (ii) Is combination chemotherapy safe and more efficacious than monotherapy against strongyloidiasis and trichuriasis? (iii) What are the key pharmacokinetic parameters of praziquantel in preschool-aged children and school-aged children infected with Schistosoma mansoni and S. haematobium using a novel and validated technology based on dried blood spotting? (iv) What are the metabolic consequences and clearance of praziquantel treatment in S. mansoni-infected mice and S. mansoni- and S. haematobium-infected children? (v) Which is the ideal compartment to study pharmacokinetic parameters for intestinal nematode infections and does age, nutrition, co-infection and infection intensity influence the efficacy of anthelmintic drugs?
My proposed research is of considerable public health relevance since it will ultimately result in improved treatments for soil-transmitted helminthiasis and pediatric schistosomiasis. Additionally, at the end of this project, I have generated comprehensive information on drug disposition of anthelmintics. A comprehensive database of metabolite profiles following praziquantel treatment will be available. Finally, the proof-of-concept of chip calorimetry in anthelmintic drug discovery has been established and broadly validated."
Max ERC Funding
1 927 350 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym AbioEvo
Project Conditions for the emergence of evolution during abiogenesis
Researcher (PI) Philippe Nghe
Host Institution (HI) ECOLE SUPERIEURE DE PHYSIQUE ET DECHIMIE INDUSTRIELLES DE LA VILLE DEPARIS
Country France
Call Details Consolidator Grant (CoG), LS1, ERC-2020-COG
Summary Abiogenesis, the transition from non-living to living matter, is at the core of the origin of life question. However, the dynamical processes underlying abiogenesis remain unknown.
The AbioEvo project aims to test the hypothesis that RNA-catalysed RNA recombination, if coupled with template-based mechanisms, provides a gradual route for the emergence of evolution by natural selection, starting from collective autocatalysis, toward template-based replication. Indeed, recombination allows both self-reproduction and shuffling of other sequences, thus, once combined with templating, provides the basic ingredients of reproduction, heredity and variation required for Darwinian evolution.
The project decomposes the problem into five steps: (WP1) the study of molecular-level mechanisms to generate and stabilize novel sequences by recombination and templating; (WP2) collective dynamics integrating these mechanisms into the properties of reproduction with heredity, variation, and selection, in order to establish proof-of-concepts of evolutionary modes; (WP3) viability thresholds of recombination-based replicators from increasingly random substrates; (WP4) conditions for open-ended evolution toward template-based replication; (WP5) experimentally informed theoretical estimates of the probability of the proposed evolutionary transitions.
The project would provide first demonstrations of evolution by natural selection in a purely chemical system, gradual and experimentally accessible paths from oligomers to template-based replication, and a method to evaluate prebiotic plausibility from sequence-to-function relationships, kinetics and evolutionary dynamics.
Summary
Abiogenesis, the transition from non-living to living matter, is at the core of the origin of life question. However, the dynamical processes underlying abiogenesis remain unknown.
The AbioEvo project aims to test the hypothesis that RNA-catalysed RNA recombination, if coupled with template-based mechanisms, provides a gradual route for the emergence of evolution by natural selection, starting from collective autocatalysis, toward template-based replication. Indeed, recombination allows both self-reproduction and shuffling of other sequences, thus, once combined with templating, provides the basic ingredients of reproduction, heredity and variation required for Darwinian evolution.
The project decomposes the problem into five steps: (WP1) the study of molecular-level mechanisms to generate and stabilize novel sequences by recombination and templating; (WP2) collective dynamics integrating these mechanisms into the properties of reproduction with heredity, variation, and selection, in order to establish proof-of-concepts of evolutionary modes; (WP3) viability thresholds of recombination-based replicators from increasingly random substrates; (WP4) conditions for open-ended evolution toward template-based replication; (WP5) experimentally informed theoretical estimates of the probability of the proposed evolutionary transitions.
The project would provide first demonstrations of evolution by natural selection in a purely chemical system, gradual and experimentally accessible paths from oligomers to template-based replication, and a method to evaluate prebiotic plausibility from sequence-to-function relationships, kinetics and evolutionary dynamics.
Max ERC Funding
2 000 000 €
Duration
Start date: 2021-06-01, End date: 2026-05-31
Project acronym ACCENT
Project How antibodies and complement orchestrate protective immune responses against bacteria
Researcher (PI) suzan ROOIJAKKERS
Host Institution (HI) UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Country Netherlands
Call Details Consolidator Grant (CoG), LS6, ERC-2020-COG
Summary Due to antibiotic resistance, there is now great interest in the development of antibody-based therapies against bacterial infections, for instance via antibodies that boost the host immune system. In order to kill bacteria, antibodies should trigger activation of the complement cascade, which forms bactericidal Membrane Attack Complex (MAC) pores and strongly enhances phagocytosis. Although the power of complement could be exploited for antibody therapies, such developments are hampered by our limited insights into the mechanisms underlying antibody-dependent complement activation on bacteria. My team has developed unique assays to study complement activation on bacteria. In this proposal, we will combine our function-driven approaches with novel B cell sequencing methods to identify anti-bacterial antibodies with strong complement-activating potential. We will develop novel approaches to identify the variable (VH:VL) sequences of human antibodies that recognize whole bacterial cells. After FACS sorting of memory B cells or yeast Fab display, we will use multi-well functional assays to select monoclonal antibodies driving potent complement activation and subsequent killing of E. coli (via neutrophils or MAC). Thanks to our unique tools and unprecedented insights, we are in an unique position to decipher basic mechanisms by which antibodies induce bacterial killing via neutrophils or MAC. We will combine live-cell imaging and structural approaches to determine how bactericidal antibodies assemble lethal MAC pores in the bacterial cell envelope. Finally, we will explore the design of potent antibody combinations and study the mechanisms by which antibodies steer different effector functions, both in the context of clinical and non-pathogenic E. coli strains. Altogether, this grant will lead to fundamental knowledge about the functioning of the immune system and provide a biological basis for the development of antibody-based therapies against bacteria.
Summary
Due to antibiotic resistance, there is now great interest in the development of antibody-based therapies against bacterial infections, for instance via antibodies that boost the host immune system. In order to kill bacteria, antibodies should trigger activation of the complement cascade, which forms bactericidal Membrane Attack Complex (MAC) pores and strongly enhances phagocytosis. Although the power of complement could be exploited for antibody therapies, such developments are hampered by our limited insights into the mechanisms underlying antibody-dependent complement activation on bacteria. My team has developed unique assays to study complement activation on bacteria. In this proposal, we will combine our function-driven approaches with novel B cell sequencing methods to identify anti-bacterial antibodies with strong complement-activating potential. We will develop novel approaches to identify the variable (VH:VL) sequences of human antibodies that recognize whole bacterial cells. After FACS sorting of memory B cells or yeast Fab display, we will use multi-well functional assays to select monoclonal antibodies driving potent complement activation and subsequent killing of E. coli (via neutrophils or MAC). Thanks to our unique tools and unprecedented insights, we are in an unique position to decipher basic mechanisms by which antibodies induce bacterial killing via neutrophils or MAC. We will combine live-cell imaging and structural approaches to determine how bactericidal antibodies assemble lethal MAC pores in the bacterial cell envelope. Finally, we will explore the design of potent antibody combinations and study the mechanisms by which antibodies steer different effector functions, both in the context of clinical and non-pathogenic E. coli strains. Altogether, this grant will lead to fundamental knowledge about the functioning of the immune system and provide a biological basis for the development of antibody-based therapies against bacteria.
Max ERC Funding
2 000 000 €
Duration
Start date: 2021-06-01, End date: 2026-05-31
Project acronym Acclimatize
Project Hypothalamic mechanisms of thermal homeostasis and adaptation
Researcher (PI) Jan SIEMENS
Host Institution (HI) UNIVERSITATSKLINIKUM HEIDELBERG
Country Germany
Call Details Consolidator Grant (CoG), LS5, ERC-2017-COG
Summary Mammalian organisms possess the remarkable ability to maintain internal body temperature (Tcore) within a narrow range close to 37°C despite wide environmental temperature variations. The brain’s neural “thermostat” is made up by central circuits in the hypothalamic preoptic area (POA), which orchestrate peripheral thermoregulatory responses to maintain Tcore. Thermogenesis requires metabolic fuel, suggesting intricate connections between the thermoregulatory centre and hypothalamic circuits controlling energy balance. How the POA detects and integrates temperature and metabolic information to achieve thermal balance is largely unknown. A major question is whether this circuitry could be harnessed therapeutically to treat obesity.
We have recently identified the first known molecular temperature sensor in thermoregulatory neurons of the POA, transient receptor potential melastatin 2 (TRPM2), a thermo-sensitive ion channel. I aim to use TRPM2 as a molecular marker to gain access to and probe the function of thermoregulatory neurons in vivo. I propose a multidisciplinary approach, combining local, in vivo POA temperature stimulation with optogenetic circuit-mapping to uncover the molecular and cellular logic of the hypothalamic thermoregulatory centre and to assess its medical potential to counteract metabolic syndrome.
Acclimation is a beneficial adaptive process that fortifies thermal responses upon environmental temperature challenges. Thermoregulatory neuron plasticity is thought to mediate acclimation. Conversely, maladaptive thermoregulatory changes affect obesity. The cell-type-specific neuronal plasticity mechanisms underlying these changes within the POA, however, are unknown.
Using ex-vivo slice electrophysiology and in vivo imaging, I propose to characterize acclimation- and obesity-induced plasticity of thermoregulatory neurons. Ultimately, I aim to manipulate thermoregulatory neuron plasticity to test its potential counter-balancing effect on obesity.
Summary
Mammalian organisms possess the remarkable ability to maintain internal body temperature (Tcore) within a narrow range close to 37°C despite wide environmental temperature variations. The brain’s neural “thermostat” is made up by central circuits in the hypothalamic preoptic area (POA), which orchestrate peripheral thermoregulatory responses to maintain Tcore. Thermogenesis requires metabolic fuel, suggesting intricate connections between the thermoregulatory centre and hypothalamic circuits controlling energy balance. How the POA detects and integrates temperature and metabolic information to achieve thermal balance is largely unknown. A major question is whether this circuitry could be harnessed therapeutically to treat obesity.
We have recently identified the first known molecular temperature sensor in thermoregulatory neurons of the POA, transient receptor potential melastatin 2 (TRPM2), a thermo-sensitive ion channel. I aim to use TRPM2 as a molecular marker to gain access to and probe the function of thermoregulatory neurons in vivo. I propose a multidisciplinary approach, combining local, in vivo POA temperature stimulation with optogenetic circuit-mapping to uncover the molecular and cellular logic of the hypothalamic thermoregulatory centre and to assess its medical potential to counteract metabolic syndrome.
Acclimation is a beneficial adaptive process that fortifies thermal responses upon environmental temperature challenges. Thermoregulatory neuron plasticity is thought to mediate acclimation. Conversely, maladaptive thermoregulatory changes affect obesity. The cell-type-specific neuronal plasticity mechanisms underlying these changes within the POA, however, are unknown.
Using ex-vivo slice electrophysiology and in vivo imaging, I propose to characterize acclimation- and obesity-induced plasticity of thermoregulatory neurons. Ultimately, I aim to manipulate thermoregulatory neuron plasticity to test its potential counter-balancing effect on obesity.
Max ERC Funding
1 902 500 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
