Data-Gouv-ML/pcri-erc-participations-et-projets-laureats huggingface dataset:
Projet ERC : Matryoshka (Horizon 2020, appel 2016, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Computer science and informatics
Entité participante : Vrije Universiteit Amsterdam — Pays : Pays-Bas — Rôle : PI
Acronyme de l'entité : VU
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 994688.0 €

Proof assistants are increasingly used to verify hardware and software and to formalize mathematics. However, despite the success stories, they remain very laborious to use. The situation has improved with the integration of first-order automatic theorem provers -- superposition provers and SMT (satisfiability modulo theories) solvers -- through middleware such as Sledgehammer for Isabelle, codeveloped by the PI; but this research has now reached the point of diminishing returns. Only so much can be done when viewing automatic provers as black boxes. To make interactive verification more cost-effective, we propose to deliver very high levels of automation to users of proof assistants by fusing and extending two lines of research: automatic and interactive theorem proving. This is our grand challenge. Our starting point is that first-order automatic provers are the best tools available for performing most of the logical work. Our approach will be to enrich superposition and SMT with higher-order reasoning in a careful manner, to preserve their desirable properties. We will design proof rules and strategies, guided by representative benchmarks from interactive verification. With higher-order superposition and higher-order SMT in place, we will develop highly automatic provers building on modern superposition provers and SMT solvers, following a novel stratified architecture. To reach end users, these new provers will be integrated in proof assistants, including Coq, Isabelle, and the TLA+ Proof System, and will be available as backends to more specialized verification tools. The users of proof assistants and similar tools stand to experience substantial productivity gains: In the past five years, the success rate of automatic provers on interactive proof obligations from a representative benchmark suite has risen from 47% to 77%; with this project, we aim at 90%--95% proof automation.

Mots-clés : automatic theorem proving,interactive theorem proving,proof assistants,smt solvers,superposition
Projet ERC : VERICOMP (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Computer science and informatics
Entité participante : Weizmann Institute of Science — Pays : Israël — Rôle : PI
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1882460.0 €

Proof systems allow a weak verifier to ascertain the correctness of complex computational statements. Efficiently-verifiable proof systems are fundamental objects in the study of computation, and have led to some of the deepest and most celebrated insights in cryptography and in complexity theory. The vast and rich literature on proof systems focuses primarily on proving the correctness of intractable statements, e.g. ones that are NP-complete. While the verification can be efficient, the proofs themselves cannot be generated in polynomial time. This limits the applicability of such proof systems, both from a theoretical perspective and in their real-world impact. This proposal aims to obtain a comprehensive understanding of proof systems with polynomial-time proof generation, to explore their practical applicability, and to investigate their connections with foundational questions in cryptography and in complexity theory. Our study will focus primarily on interactive proof systems for tractable computations. The proposed research aims to revolutionize our understanding of these foundational objects by providing a complete and tight characterization of the complexity or proving and verifying general statements, by achieving breakthroughs in the study of related proof system notions, such as cryptographic arguments, and by building a fine-grained “algorithmic” theory of proof systems for central polynomial-time computational problems. Our research will leverage these advances towards diverse applications: from real-world security challenges, such as verifying the correctness of computations performed by the cloud and cryptographic “proofs of work”, to a complexity-theoretic understanding of the complexity of approximating problems in P and of solving them on random instances.

Mots-clés : proof systems,interactive proofs,delegating computation
Projet ERC : RCSB (Horizon 2020, appel 2015, Starting grants)
Domaine scientifique : Physical Sciences and Engineering
Panel : Condensed matter physics
Entité participante : Institut Pasteur — Pays : France — Rôle : PI
Type d'entité : Recherche
Financement ERC de l'entité : 1500000.0 €

Proper cell size and shape are important for many biological functions, such as metabolism, signaling, motility, and development. This proposal addresses the fundamental question of how bacteria control their morphology and their cell volume with high precision, using the rod-like bacterium Escherichia coli as a primary model system. Bacterial cell shape is physically determined during growth by the enzymatic expansion and remodeling of the peptidoglycan (PG) cell wall, a partially ordered elastic meshwork that is the pressure-bearing component of the cell envelope. In this proposal we will address two fundamental questions: i) How do cells physically build and remodel their macroscopically ordered cell wall to reproducibly acquire cell shape? We will thus image the dynamics of the PG cell wall and of the enzymatic and structural proteins involved in its expansion, using high-precision video fluorescence microscopy and spectroscopy. From spatio-temporal correlations measured in steady-state experiments and after physical, chemical, or biological perturbations, we will deduce how different physical cues affect and regulate cell-wall expansion. ii) How do bacteria regulate their own cell volume, and what role does intracellular crowding play in this context? The intracellular mass density of bacteria is remarkably well conserved during growth, suggesting that cell size is regulated to maintain a constant level of intracellular crowding. Crowding has been deemed important for the regulation of volume in slowly growing mammalian cells before. Here, we will study the role of intracellular crowding, osmotic pressure, and other physiological quantities on cell-volume regulation in bacteria. Furthermore, we will use phenotypic screening and genetic approaches to identify the pathways involved in cell-volume control. Together, this proposal addresses a fundamental question of self-organization in biology using combined approaches from physics and biology.

Mots-clés : bacterial growth,cell size homeostasis,peptidoglycan cell wall,super resolution fluorescence microscopy
Projet ERC : ANALYTICS (Horizon 2020, appel 2017, Proof of concept grants)
Entité participante : Helmholtz-Zentrum Dresden-Rossendorf — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : HZDR
Type d'entité : Recherche
Financement ERC de l'entité : 150000.0 €

Prospective biosensing technologies will need to tackle the grand challenges arising from the global demographic changes. Among the most crucial tasks is the monitoring of food and environmental quality as well as the medical diagnosis. Digital fluidics offers vast advantages in performing these tasks relying on tiny containers with reacting biochemical species and allowing massively parallelized assays and high throughput screening using optical detection approaches. I envision that adding not-optical detectors, which electrically probe the analyte responses, will provide a source of new but complementary information, obtained in a label-free and contactless manner. Hence, these all-electric platforms enable monitoring the kinetics of chemical reactions in lab-on-chip format, as well as take over auxiliary tasks, e.g. indexing, counting of droplets, flow monitoring. In frame of the ERC project SMaRT, my team developed a unique detection platform -millifluidic resonance detector- that inductively couples to an analyte and assesses its physico-chemical properties. The unique selling points are (i) non-invasiveness to analyte, (ii) unnecessity of a transparent fluidic channel, (iii) cost efficiency and (iv) portability. Implementing the input from the partner companies, here I aim to reach the commercialization stage pursuing a number of key milestones, i.e. enhance the screening throughput, realize a platform independent of external electronic devices, provide a temperature stabilization of the response, and develop the app. Societal benefits: We demonstrated that the device provides an access to the metabolic activity of living organisms in droplets. This is way beyond the capabilities of the state-of-the-art optical detection. With this feature, the device can address the issue of increasing antibiotic resistance of bacteria and thus help to optimize the antibiotic policy in hospitals and households and to test new drugs in a time- and cost-efficient way.

Mots-clés : droplet fluidics,flow monitoring,digital fluidics,detection platform,metabolic activity of bacteria
Projet ERC : ComplexAssembly (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Life Science
Panel : Integrative Biology: from Genes and Genomes to Systems
Entité participante : Max Planck Society — Pays : Allemagne — Rôle : PI
Acronyme de l'entité : MPG
Type d'entité : Recherche
Financement ERC de l'entité : 717179.09 €

Protein complexes are central to many cellular functions but our knowledge of how cells assemble protein complexes remains very sparse. Biophysical and structural data of assembly intermediates are extremely rare. Particularly in higher eukaryotes, it has become clear that complex assembly by random collision of subunits cannot cope with the spatial and temporal complexity of the intricate architecture of many cellular machines. Here I propose to combine systems biology approaches with in situ structural biology methods to visualize protein complex assembly. I want to investigate experimentally in which order the interfaces of protein complexes are formed and to which extent structures of assembly intermediates resemble those observed in fully assembled complexes. I want develop methods to systematically screen for additional factors involved in assembly pathways. I furthermore want to test the hypothesis that mechanisms must exist in eukaryotes that coordinate local mRNA translation with the ordered formation of protein complex interfaces. I believe that in order to understand assembly pathways, these processes, that so far are often studied autonomously, need to be considered jointly and in a protein complex centric manner. The research proposed here will bridge across these different scientific disciplines. In the long term, a better mechanistic understanding of protein complex assembly and the structural characterization of critical intermediates will be of high relevance for scenarios under which a cell’s protein quality control system has to cope with stress, such as aging and neurodegenerative diseases. It might also facilitate the more efficient industrial production of therapeutically relevant proteins.

Mots-clés : protein complex assembly,local translation,cryo electron tomography,quantitative mass spectrometry,nuclear pore complex
Projet ERC : ChaperoneRegulome (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : Max Planck Society — Pays : Allemagne — Rôle : Partner
Acronyme de l'entité : MPG
Type d'entité : Recherche
Financement ERC de l'entité : 0.0 €

Protein misfolding causes devastating health conditions such as neurodegeneration. Although the disease-causing protein is widely expressed, its misfolding occurs only in certain cell-types such as neurons. What governs the susceptibility of some tissues to misfolding is a fundamental question with biomedical relevance. Molecular chaperones help cellular proteins fold into their native conformation. Despite the generality of their function, chaperones are differentially expressed across various tissues. Moreover exposure to misfolding stress changes chaperone expression in a cell-type-dependent manner. Thus cell-type-specific regulation of chaperones is a major determinant of susceptibility to misfolding. The molecular mechanisms governing chaperone levels in different cell-types are not understood, forming the basis of this proposal. We will take a multidisciplinary approach to address two key questions: (1) How are chaperone levels co-ordinated with tissue-specific demands on protein folding? (2) How do different cell-types regulate chaperone genes when exposed to the same misfolding stress? Cellular chaperone levels and their response to misfolding stress are both driven by transcriptional changes and influenced by chromatin. The proposed work will bring the conceptual, technological and computational advances of chromatin/ transcription field to understand chaperone biology and misfolding diseases. Using in vivo mouse model and in vitro differentiation model, we will investigate molecular mechanisms that control chaperone levels in relevant tissues. Our work will provide insights into functional specialization of chaperones driven by tissue-specific folding demands. We will develop a novel and ambitious approach to assess protein-folding capacity in single cells moving the chaperone field beyond state-of-the-art. Thus by implementing genetic, computational and biochemical approaches, we aim to understand cell-type-specificity of chaperone regulation.

Mots-clés : molecular chaperones,heat shock proteins,stress,protein misfolding,gene regulation
Projet ERC : ChaperoneRegulome (Horizon 2020, appel 2018, Consolidator grants)
Domaine scientifique : Life Science
Panel : Cellular, Developmental and Regenerative Biology
Entité participante : University of Cambridge — Pays : Royaume-Uni — Rôle : PI
Acronyme de l'entité : U. Cambridge
Type d'entité : Enseignement supérieur ou secondaire
Financement ERC de l'entité : 1992500.0 €

Protein misfolding causes devastating health conditions such as neurodegeneration. Although the disease-causing protein is widely expressed, its misfolding occurs only in certain cell-types such as neurons. What governs the susceptibility of some tissues to misfolding is a fundamental question with biomedical relevance. Molecular chaperones help cellular proteins fold into their native conformation. Despite the generality of their function, chaperones are differentially expressed across various tissues. Moreover exposure to misfolding stress changes chaperone expression in a cell-type-dependent manner. Thus cell-type-specific regulation of chaperones is a major determinant of susceptibility to misfolding. The molecular mechanisms governing chaperone levels in different cell-types are not understood, forming the basis of this proposal. We will take a multidisciplinary approach to address two key questions: (1) How are chaperone levels co-ordinated with tissue-specific demands on protein folding? (2) How do different cell-types regulate chaperone genes when exposed to the same misfolding stress? Cellular chaperone levels and their response to misfolding stress are both driven by transcriptional changes and influenced by chromatin. The proposed work will bring the conceptual, technological and computational advances of chromatin/ transcription field to understand chaperone biology and misfolding diseases. Using in vivo mouse model and in vitro differentiation model, we will investigate molecular mechanisms that control chaperone levels in relevant tissues. Our work will provide insights into functional specialization of chaperones driven by tissue-specific folding demands. We will develop a novel and ambitious approach to assess protein-folding capacity in single cells moving the chaperone field beyond state-of-the-art. Thus by implementing genetic, computational and biochemical approaches, we aim to understand cell-type-specificity of chaperone regulation.

Mots-clés : molecular chaperones,heat shock proteins,stress,protein misfolding,gene regulation
Projet ERC : Ti-EM (Horizon 2020, appel 2016, Consolidator grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : Vlaams Instituut voor Biotechnologie — Pays : Belgique — Rôle : PI
Acronyme de l'entité : VIB
Type d'entité : Recherche
Financement ERC de l'entité : 1777157.0 €

Protein synthesis and degradation, energy metabolism, signalling, processing of information-encoding polymers (RNA and DNA) are facilitated and regulated by molecular machines, protein complexes that undergo significant conformational changes in time as they facilitate their function. To be able to control the biological processes rationally and with high precision it is essential to understand their mechanism at atomic level. A powerful way to gain detailed insight onto function of these proteins is to see these molecules at atomic resolution while they function. The high-resolution structures of biological macromolecules obtained by X-ray crystallography, NMR and more recently single particle electron cryogenic microscopy (cryo-EM) have provided insights onto the way many molecular machines are constructed. These methods generally provide snapshots of discrete long-lived states, visualizing the conformational changes along the reaction trajectory at high-resolution often remains an elusive objective. The aim of my proposal is to develop methods for visualizing transient conformations of protein complexes by time-resolved single particle cryo-EM. Time-resolved cryo-EM combines structural study with kinetics by freeze-trapping kinetic intermediates in a biological reaction and has potential to provide atomic-resolution ‘movies’ of functioning biological complexes. Technical limitations however so far restricted widespread use and utilization of the complete potential of this technique. Main part of this project is dedicated to development of microfluidic instruments for cryo-EM sample preparation. If successful, our approaches will allow trapping kinetic intermediates of molecular machines with millisecond time-resolution using picogram amounts of protein sample. The developed method will be applied to resolve key functional conformations of respiratory complex I and observe regulatory trajectories of ligand-gated ion channels.

Mots-clés : kinetics,molecular machines,time resolved,image processing
Projet ERC : MaCChines (Horizon 2020, appel 2017, Advanced grants)
Domaine scientifique : Life Science
Panel : Biotechnology and Biosystems Engineering
Entité participante : En-fist center odlicnosti — Pays : Slovénie — Rôle : Partner
Type d'entité : Recherche
Financement ERC de l'entité : 134286.25 €

Proteins are the most versatile and complex smart nanomaterials, forming molecular machines and performing numerous functions from structure building, recognition, catalysis to locomotion. Nature however explored only a tiny fraction of possible protein sequences and structures. Design of proteins with new, in nature unseen shapes and features, offers high rewards for medicine, technology and science. In 2013 my group pioneered the design of a new type of modular coiled-coil protein origami (CCPO) folds. This type of de novo designed proteins are defined by the sequence of coiled-coil (CC) dimer-forming modules that are concatenated by flexible linkers into a single polypeptide chain that self-assembles into a polyhedral cage based on pairwise CC interactions. This is in contrast to naturally evolved proteins where their fold is defined by a compact hydrophobic core. We recently demonstrated the robustness of this strategy by the largest de novo designed single chain protein, construction of tetrahedral, pyramid, trigonal prism and bipyramid cages that self-assemble in vivo. This proposal builds on unique advantages of CCPOs and represents a new frontier of this branch of protein design science. I propose to introduce functional domains into selected positions of CCPO cages, implement new types of building modules that will enable regulated CCPO assembly and disassembly, test new strategies of caging and release of cargo molecules for targeted delivery, design knotted and crosslinked protein cages and introduce toehold displacement for the regulated structural rearrangement of CCPOs required for designed molecular machines, which will be demonstrated on protein nanotweezers. Technology for the positional combinatorial library-based single pot assembly of CCPO genes will provide high throughput of CCPO variants. Project will result in new methodology, understanding of potentials of CCPOs for designed molecular machines and in demonstration of different applications.

Mots-clés : synthetic biology,bionanostructures,geneticaly encoded molecular machines,recombinant protein,protein cages,golden gate gene assembly
Projet ERC : Protein Lego (Horizon 2020, appel 2014, Consolidator grants)
Domaine scientifique : Life Science
Panel : Molecules of Life: Biological Mechanisms, Structures and Functions
Entité participante : Max Planck Society — Pays : Allemagne — Rôle : Partner
Acronyme de l'entité : MPG
Type d'entité : Recherche
Financement ERC de l'entité : 21250.0 €

Proteins are ubiquitous, very diverse, and participate in virtually every cellular process. Nature has generated this impressive set of proteins using mechanisms such as recombination of smaller, sub-domain sized protein fragments that serve as building blocks in a Lego-like manner. Based on these observations we propose a rational design strategy in which new functional proteins are build from fragments of existing proteins. With this approach we aim to tackle a long-standing goal in biochemistry, namely the design of complex, custom-made proteins. Initial experiments that recombine fragments from the same as well as from different folds have been successful in creating new proteins. Moreover, the utilized fragments contribute their unique functional properties to the protein chimeras, which is a tremendous advantage of using existing subunits for the design. Here, we aim to generalize this approach. We will identify common structural fragments and classify them based on their associated functions. We will build stable hybrid proteins from different folds, transfer functional sites associated with particular fragments, and thereby learn about general design rules. The proposed approach offers a rigorous test for the identification of minimal determinants of protein structure and function. It simultaneously allows us to test our understanding of protein evolution and will have profound implications on the current view of structural classification and interactions. And lastly, the development of a reliable methodology for the design of complex proteins will be very valuable for synthetic biology and bioengineering approaches.

Mots-clés : protein design,protein engineering,molecular evolution,origin of protein domains,structural classification