ERC FUNDED PROJECTS

Mathematical proofs have always been prone to error. Today, proofs can be hundreds of pages long and combine results from many specialisms, making them almost impossible to check. One solution is to deploy modern verification technology. Interactive theorem provers have demonstrated their potential as vehicles for formalising mathematics through achievements such as the verification of the Kepler Conjecture. Proofs done using such tools reach a high standard of correctness. However, existing theorem provers are unsuitable for mathematics. Their formal proofs are unreadable. They struggle to do simple tasks, such as evaluating limits. They lack much basic mathematics, and the material they do have is difficult to locate and apply. ALEXANDRIA will create a proof development environment attractive to working mathematicians, utilising the best technology available across computer science. Its focus will be the management and use of large-scale mathematical knowledge, both theorems and algorithms. The project will employ mathematicians to investigate the formalisation of mathematics in practice. Our already substantial formalised libraries will serve as the starting point. They will be extended and annotated to support sophisticated searches. Techniques will be borrowed from machine learning, information retrieval and natural language processing. Algorithms will be treated similarly: ALEXANDRIA will help users find and invoke the proof methods and algorithms appropriate for the task. ALEXANDRIA will provide (1) comprehensive formal mathematical libraries; (2) search within libraries, and the mining of libraries for proof patterns; (3) automated support for the construction of large formal proofs; (4) sound and practical computer algebra tools. ALEXANDRIA will be based on legible structured proofs. Formal proofs should be not mere code, but a machine-checkable form of communication between mathematicians.

2 430 140 €

Start date: 2017-09-01, End date: 2022-08-31

Our field is cryptology. Our overarching objective is to advance significantly the frontiers in design and analysis of high-security cryptography for the future generation. Particularly, we wish to enhance the efficiency, functionality, and, last-but-not-least, fundamental understanding of cryptographic security against very powerful adversaries. Our approach here is to develop completely novel methods by deepening, strengthening and broadening the algebraic foundations of the field. Concretely, our lens builds on the arithmetic codex. This is a general, abstract cryptographic primitive whose basic theory we recently developed and whose asymptotic part, which relies on algebraic geometry, enjoys crucial applications in surprising foundational results on constant communication-rate two-party cryptography. A codex is a linear (error correcting) code that, when endowing its ambient vector space just with coordinate-wise multiplication, can be viewed as simulating, up to some degree, richer arithmetical structures such as finite fields (or products thereof), or generally, finite-dimensional algebras over finite fields. Besides this degree, coordinate-localities for which simulation holds and for which it does not at all are also captured. Our method is based on novel perspectives on codices which significantly widen their scope and strengthen their utility. Particularly, we bring symmetries, computational- and complexity theoretic aspects, and connections with algebraic number theory, -geometry, and -combinatorics into play in novel ways. Our applications range from public-key cryptography to secure multi-party computation. Our proposal is subdivided into 3 interconnected modules: (1) Algebraic- and Number Theoretical Cryptanalysis (2) Construction of Algebraic Crypto Primitives (3) Advanced Theory of Arithmetic Codices

2 447 439 €

Start date: 2017-10-01, End date: 2022-09-30

The proposed project aims to create a center of excellence that aims at understanding the approximability of NP-hard optimization problems. In particular, for central problems like vertex cover, coloring of graphs, and various constraint satisfaction problems we want to study upper and lower bounds on how well they can be approximated in polynomial time. Many existing strong results are based on what is known as the Unique Games Conjecture (UGC) and a significant part of the project will be devoted to studying this conjecture. We expect that a major step needed to be taken in this process is to further develop the understanding of Boolean functions on the Boolean hypercube. We anticipate that the tools needed for this will come in the form of harmonic analysis which in its turn will rely on the corresponding results in the analysis of functions over the domain of real numbers.

2 376 000 €

Start date: 2009-01-01, End date: 2014-12-31

Monoclonal antibodies against the EGF receptor (EGFR) provide substantive benefit to colorectal cancer (CRC) patients. However, no genetic lesions that robustly predict ‘addiction’ to the EGFR pathway have been yet identified. Further, even in tumours that regress after EGFR blockade, subsets of drug-tolerant cells often linger and foster ‘minimal residual disease’ (MRD), which portends tumour relapse. Our preliminary evidence suggests that reliance on EGFR activity, as opposed to MRD persistence, could be assisted by genetically-based variations in transcription factor partnerships and activities, gene expression outputs, and biological fates controlled by the WNT/beta-catenin pathway. On such premises, BEAT (Beta-catenin and EGFR Abrogation Therapy) will elucidate the mechanisms of EGFR dependency, and escape from it, with the goal to identify biomarkers for more efficient clinical management of CRC and develop new therapies for MRD eradication. A multidisciplinary approach will be pursued spanning from integrative gene regulation analyses to functional genomics in vitro, pharmacological experiments in vivo, and clinical investigation, to address whether: (i) specific genetic alterations of the WNT pathway affect anti-EGFR sensitivity; (ii) combined neutralisation of EGFR and WNT signals fuels MRD deterioration; (iii) data from analysis of this synergy can lead to the discovery of clinically meaningful biomarkers with predictive and prognostic significance. This proposal capitalises on a unique proprietary platform for high-content studies based on a large biobank of viable CRC samples, which ensures strong analytical power and unprecedented biological flexibility. By providing fresh insight into the mechanisms whereby WNT/beta-catenin signalling differentially sustains EGFR dependency or drug tolerance, the project is expected to put forward an innovative reinterpretation of CRC molecular bases and advance the rational application of more effective therapies.

1 793 421 €

Start date: 2017-10-01, End date: 2022-09-30

This proposal addresses a pressing need from emerging big data applications such as genomics and data center monitoring: besides the scale of processing, big data systems must also enable perpetual, low-latency processing for a broad set of analytical tasks, referred to as big and fast data analysis. Today’s technology falls severely short for such needs due to the lack of support of complex analytics with scale, low latency, and strong guarantees of user performance requirements. To bridge the gap, this proposal tackles a grand challenge: “How do we design an algorithmic foundation that enables the development of all necessary pillars of big and fast data analysis?” This proposal considers three pillars: 1) Parallelism: There is a fundamental tension between data parallelism (for scale) and pipeline parallelism (for low latency). We propose new approaches based on intelligent use of memory and workload properties to integrate both forms of parallelism. 2) Analytics: The literature lacks a large body of algorithms for critical order-related analytics to be run under data and pipeline parallelism. We propose new algorithmic frameworks to enable such analytics. 3) Optimization: To run analytics, today's big data systems are best effort only. We transform such systems into a principled optimization framework that suits the new characteristics of big data infrastructure and adapts to meet user performance requirements. The scale and complexity of the proposed algorithm design makes this project high-risk, at the same time, high-gain: it will lay a solid foundation for big and fast data analysis, enabling a new integrated parallel processing paradigm, algorithms for critical order-related analytics, and a principled optimizer with strong performance guarantees. It will also broadly enable accelerated information discovery in emerging domains such as genomics, as well as economic benefits of early, well-informed decisions and reduced user payments.

2 472 752 €

Start date: 2017-09-01, End date: 2022-08-31

In the last decades, Materials Sciences and Life Sciences, two highly dynamically evolving and interdisciplinary research areas, have been influencing natural and engineering sciences significantly, creating new challenges and opportunities. A prime example for an increasing synergetic overlap of Materials and Life Sciences is provided by biomedical and bioengineering applications, which are of great academic, but also of steadily increasing societal and commercial interest. Bridging the traditional borders of disciplinary thinking in these areas has become one of today’s most challenging tasks for scientists. One group of key materials that are of great importance to biomedical engineering and bioengineering are advanced oxide and non-oxide ceramics with specific functionalities towards biological environments, so-called Bioceramics. The interplay at the interface of ceramics-protein-cells/bacteria is very complex and requires multiscale and interdisciplinary approaches. This expertise, that is under continuous development in my Bioceramics group, encompasses materials processing, shaping, surface functionalisation and cells/bacteria evaluation at the same time. The comprehensive research environment and expertise provides a unique opportunity to engineer materials/surfaces with immediate subsequent biological evaluation in order to achieve an extremely short development time. A centre of focus is the contribution of electrostatic and hydrophilic/hydrophobic interactions to the overall biocompatibility and -activity. The proposed research project includes four closely interrelated subprojects, addressing the following topics: “Interaction of surface functionalised ceramic particles with proteins”, “Cytotoxicity of functionalised oxide particles”, “Fabrication and testing of functionalised porous Al2O3 as filters for water cleaning and bioengineering applications” and “Novel functional scaffold composites for bone tissue engineering”.

1 536 120 €

Start date: 2009-01-01, End date: 2013-12-31

Recent evidence demonstrates that cancer is overtaking cardiovascular disease as the number one cause of mortality in Europe. This is largely due to the lack of preventative measures for common (e.g. breast) or highly fatal (e.g. ovarian) human cancers. Most cancers are multifactorial in origin. The core hypothesis of this research programme is that the extremely high risk of BRCA1/2 germline mutation carriers to develop breast and ovarian cancer is a net consequence of cell-autonomous (direct effect of BRCA mutation in cells at risk) and cell non-autonomous (produced in distant organs and affecting organs at risk) factors which both trigger epigenetic, cancer-initiating effects. The project’s aims are centered around the principles of systems medicine and built on a large cohort of BRCA mutation carriers and controls who will be offered newly established cancer screening programmes. We will uncover how ‘cell non-autonomous’ factors work, provide detail on the epigenetic changes in at-risk tissues and investigate whether these changes are mechanistically linked to cancer, study whether we can neutralise this process and measure success in the organs at risk, and ideally in easy to access samples such as blood, buccal and cervical cells. In my Department for Women’s Cancer we have assembled a powerful interdisciplinary team including computational biologists, functionalists, immunologists and clinician scientists linked to leading patient advocacy groups which is extremely well placed to lead this pioneering project to develop the fundamental understanding of cancer development in women with BRCA mutations. To reset the epigenome, re-establishing normal cell identity and consequently reducing cancer risk without the need for surgery and being able to monitor the efficacy using multicellular epigenetic outcome predictors will be a major scientific and medical breakthrough and possibly applicable to other chronic diseases.

2 497 841 €

Start date: 2017-09-01, End date: 2022-08-31

"This proposal aims to create a new generation of security assurance. It investigates whether one can certify an inter-connected dynamically changing system in such a way that one can prove its security properties without disclosing sensitive information about the system's blueprint. This has several compelling advantages. First, the security of large-scale dynamically changing systems will be significantly improved. Second, we can prove properties of topologies, hosts and users who participate in transactions in one go, while keeping sensitive information confidential. Third, we can prove the integrity of graph data structures to others, while maintaining their their confidentiality. This will benefit EU governments and citizens through the increased security of critical systems. The proposal pursues the main research hypothesis that usable confidentiality-preserving security assurance will trigger a paradigm shift in security and dependability. It will pursue this objective by the creation of new cryptographic techniques to certify and prove properties of graph data structures. A preliminary investigation in 2015 showed that graph signature schemes are indeed feasible. The essence of this solution can be traced back to my earlier research on highly efficient attribute encodings for anonymous credential schemes in 2008. However, the invention of graph signature schemes only clears one obstacle in a long journey to create a new generation of security assurance systems. There are still many complex obstacles, first and foremost, assuring ""soundness"" in the sense that integrity proofs a verifier accepts translate to the state of the system at that time. The work program involves six WPs: 1) to develop graph signatures and new cryptographic primitives; 2) to establish cross-system soundness; 3) to handle scale and change; 4) to establish human trust and usability; 5) to create new architectures; and 6) to test prototypes in practice."

1 485 643 €

Start date: 2017-11-01, End date: 2022-10-31

An important goal of stem cell therapy is to create “customized” cells that are genetically identical to the patient, which upon transplantation can restore damaged tissues. Such cells can be obtained by in vitro direct reprogramming of somatic cells into embryonic stem (ES)-like cells, termed induced pluripotent stem cells (iPSC). This approach also opens possibilities for modelling human diseases in vitro. However, major hurdles remain that restrain fulfilling conventional human iPSC/ESC potential, as they reside in an advanced primed pluripotent state. Such hurdles include limited differentiation capacity and functional variability. Further, in vitro iPSC based research platforms are simplistic and iPSC based “humanized” chimeric mouse models may be of great benefit. The recent isolation of distinct and new “mouse-like” naive pluripotent states in humans that correspond to earlier embryonic developmental state(s), constitutes a paradigm shift and may alleviate limitations of conventional primed iPSCs/ESCs. Thus, our proposal aims at dissecting the human naïve pluripotent state(s) and to unveil pathways that facilitate their unique identity and flexible programming. Specific goals: 1) Transcriptional and Epigenetic Design Principles of Human Naïve Pluripotency 2) Signalling Principles Governing Human Naïve Pluripotency Maintenance and Differentiation 3) Defining Functional Competence and Safety of Human Naïve Pluripotent Stem Cells in vitro 4) Novel human naïve iPSC based cross-species chimeric mice for studying human differentiation and disease modelling in vivo. These aims will be conducted by utilizing engineered human iPSC/ESC models, CRISPR/Cas9 genome-wide screening, advanced microscopy and ex-vivo whole embryo culture methods. Our goals will synergistically lead to the design of strategies that will accelerate the safe medical application of human naive pluripotent stem cells and their use in disease specific modelling and applied stem cell research.

2 000 000 €

Start date: 2017-11-01, End date: 2022-10-31

Despite decades of research, developing ways to overcome drug resistance in cancer is the most challenging bottleneck for curative therapies. This is because, in some forms of cancer, the cancer stem cells from which the diseases arise are constantly evolving, particularly under the selective pressures of drug therapies, in order to survive. The events leading to drug resistance can occur within one or more individual cancer stem cell(s) – and the features of each of these cells need to be studied in detail in order to develop drugs or drug combinations that can eradicate all of them. The BCR-ABL+ and BCR-ABL- myeloproliferative neoplasms (MPN) are a group of proliferative blood diseases that can be considered both exemplars of precision medicine and of the drug resistance bottleneck. While significant advances in the management of MPN have been made using life-long and expensive tyrosine kinase inhibitors (TKI), patients are rarely cured of their disease. This is because TKI fail to eradicate the leukaemia stem cells (LSC) from which MPN arise and which persist in patients on treatment, often leading to pervasive drug resistance, loss of response to therapy and progression to fatal forms of acute leukaemia. My goal is to change the way we study the LSC that persist in MPN patients as a means of delivering more effective precision medicine in MPN that is a “game-changer” leading to therapy-free remission (TFR) and cure. Here, I will apply an innovative strategy, ChAMPioN, to study the response of the MPN LSC to TKI in innovative pre-clinical laboratory models and directly in patients with MPN - up to the resolution of individual LSC. This work will reveal, for the first time, the molecular and clonal evolution of LSC during TKI therapies, thus enabling the development of more accurate predictions of TKI efficacy and resistance and rational approaches for curative drug therapies.

3 005 818 €

Start date: 2018-01-01, End date: 2022-12-31

In CIO, common interactive objects are developed and explored to extend human control over the technological environment by human beings, both individually and together. CIO leads to a coherent framework of user interfaces to be applied in interaction design. Common interactive objects will provide a useful frame for furthering human computer interaction (HCI) theory, development of interaction design methods and the underlying technical platforms. Common interactive objects will empower users to better understand and develop the technologies they use. When carried through, the project offers new ways for people to construct and configure human physical and virtual environments, together, over time and within communities. The main objectives of CIO are to 1. develop the conception of common interactive objects in order to offer a new understanding of human-computer interaction, focusing on human control. 2. develop support for building user interfaces in a coherent and unified framework. 3. make common interactive objects that will empower users to better understand and develop the technologies they use. 4. carry out ground-breaking research regarding the technological basis of common interactive objects with focus on malleability, control and shareability over time. CIO is methodologically rooted in HCI. CIO’s research methods combine empirical, analytical, theoretical, and design approaches, all with focus on the relationship between common interactive objects and their human users. CIO presents the idea that common interactive objects may radically innovate our understanding of use and building user interfaces. The gains of CIO will be a coherent new, high-impact way of understanding and building HCI across physical and virtual structures, bringing control back to the users. The risks are in delivering this alternative in a manner that is able to confront the current strong commercial interests in the Internet-of-Things and the 'new' Artificial Intelligence

2 398 993 €

Start date: 2017-12-01, End date: 2022-11-30

As more and more economic activity is moving to the Internet, familiar economic mechanisms are being deployed at unprecedented scales of size, speed, and complexity. In many cases this new complexity becomes the defining feature of the deployed economic mechanism and the quantitative difference becomes a key qualitative one. A well-studied example of such situations is how the humble single-item auction suddenly becomes a billion-times repeated online ad auction, or even becomes a combinatorial auction with exponentially many possible outcomes. Similar complexity explosions occur with various markets, with information dissemination, with pricing structures, and with many other economic mechanisms. The aim of this proposal is to study the role and implications of such complexity and to start developing a coherent economic theory that can handle it. We aim to identify various measures of complexity that are crucial bottlenecks and study them. Examples of such complexities include the amount of access to data, the length of the description of a mechanism, its communication requirements, the cognitive complexity required from users, and, of course, the associated computational complexity. On one hand we will attempt finding ways of effectively dealing with complexity when it is needed, and on the other hand, attempt avoiding complexity, when possible, replacing it with ``simple'' alternatives without incurring too large of a loss.

2 026 706 €

Start date: 2017-05-01, End date: 2022-04-30

Acute myeloid leukemia (AML) is a group of hematologic malignancies which, due to their molecular and clinical heterogeneity, have been traditionally difficult to classify and treat. Recently, next-generation, whole-genome sequencing has uncovered several recurrent somatic mutations that better define the landscape of AML genomics. Despite these advances in deciphering AML molecular subsets, there have been no concurrent improvements in AML therapy which still relies on the ‘antracycline+cytarabine’ scheme. Hereto, only about 40-50% of adult young patients are cured whilst most of the elderly succumb to their disease. Therefore, new therapeutic approaches which would take advantage of the new discoveries are clearly needed. In the past years, we discovered and characterized nucleophosmin (NPM1) mutations as the most frequent genetic alteration (about 30%) in AML, and today NPM1-mutated AML is a new entity in the WHO classification of myeloid neoplasms. However, mechanisms of leukemogenesis and a specific therapy for this leukemia are missing. Here, I aim to unravel the complex network of molecular interactions that take place in this distinct genetic subtype, and find their vulnerabilities to identify new targets for therapy. To address this issue, I will avail of relevant pre-clinical models developed in our laboratories and propose two complementary strategies: 1) a screening-based approach, focused either on the target, by analyzing synthetic lethal interactions through CRISPR-based genome-wide interference, or on the drug, by high-throughput chemical libraries screenings; 2) a hypothesis-driven approach, based on our recent gained novel insights on the role of specific intracellular pathways/genes in NPM1-mutated AML and on pharmacological studies with ‘old’ drugs, which we have revisited in the specific AML genetic context. I expect our discoveries will lead to find novel therapeutic approaches and make clinical trials available to patients as soon as possible.

1 883 750 €

Start date: 2017-04-01, End date: 2022-03-31

In this proposal we plan to extend mathematical foundations of algorithms for various variants of the minimum cut problem within theoretical computer science. Recent advances in understanding the structure of small cuts and tractability of cut problems resulted in a mature algorithmic toolbox for undirected graphs under the paradigm of parameterized complexity. In this position, we now aim at a full understanding of the tractability of cut problems in the more challenging case of directed graphs, and see opportunities to apply the aforementioned successful structural approach to advance on major open problems in other paradigms in theoretical computer science. The specific goals of the project are grouped in the following three themes. Directed graphs. Chart the parameterized complexity of graph separation problems in directed graphs and provide a fixed-parameter tractability toolbox, equally deep as the one in undirected graphs. Provide tractability foundations for routing problems in directed graphs, such as the disjoint paths problem with symmetric demands. Planar graphs. Resolve main open problems with respect to network design and graph separation problems in planar graphs under the following three paradigms: parameterized complexity, approximation schemes, and cut/flow/distance sparsifiers. Recently discovered connections uncover significant potential in synergy between these three algorithmic approaches. Tree decompositions. Show improved tractability of graph isomorphism testing in sparse graph classes. Combine the algorithmic toolbox of parameterized complexity with the theory of minimal triangulations to advance our knowledge in structural graph theory, both pure (focused on the Erdos-Hajnal conjecture) and algorithmic (focused on the tractability of Maximum Independent Set and 3-Coloring).

1 228 250 €

Start date: 2017-03-01, End date: 2022-02-28

Insects bristle with sensors, but how do they exploit this rich sensory information to achieve their extraordinary stability and manoeuvrability? Bird and insect wings deform in flight, and have passively deployable structures such as feathers and flaps, but how do they exploit these features when aircraft designers shy away from aeroelasticity? Birds fly without a vertical tailfin, but how do they maintain yaw stability when most aircraft require one to fly safely? Questions such as these drive my research on bird and insect flight dynamics. My research is unique in using the engineering tools of flight dynamics and control theory to analyse physiological and biomechanical data from real animals. One research track will use measurements of the forces and torques generated by insects flying tethered in a virtual-reality flight simulator to parameterise their equations of motion, in order to model the input-output relationships of their sensorimotor control systems. A second research track will measure the detailed wing kinematics and deformations of free-flying insects in order to analyse the effects of aeroelasticity on flight manoeuvres. A third research track will measure the wing and tail kinematics of free-flying birds using onboard wireless video cameras, and use system identification techniques to model how these affect the body dynamics measured using onboard instrumentation. Applying these novel experimental techniques will allow me to make and test quantitative predictions about flight stability and control. This highly interdisciplinary research bridges the fields of physiology and biomechanics, with significant feeds to and from engineering. My research will break new ground, developing novel experimental techniques and theoretical models in order to test and generate new hypotheses of adaptive function. Its broader impacts include the public interest in all things flying, and potential military and civilian applications in flapping micro-air vehicles.

1 954 565 €

Start date: 2008-06-01, End date: 2014-05-31

This project aims to (i) resolve challenging graph problems in distributed and dynamic settings, with a focus on connectivity problems (such as computing edge connectivity and distances), and (ii) on the way develop a systematic approach to attack problems in these settings, by thoroughly exploring relevant algorithmic and complexity-theoretic landscapes. Tasks include - building a hierarchy of intermediate computational models so that designing algorithms and proving lower bounds can be done in several intermediate steps, - explaining the limits of algorithms by proving conditional lower bounds based on old and new reasonable conjectures, and - connecting techniques in the two settings to generate new insights that are unlikely to emerge from the isolated viewpoint of a single field. The project will take advantage from and contribute to the developments in many young fields in theoretical computer science, such as fine-grained complexity and sublinear algorithms. Resolving one of the connectivity problems will already be a groundbreaking result. However, given the approach, it is likely that one breakthrough will lead to many others.

1 500 000 €

Start date: 2017-02-01, End date: 2022-01-31

Error correcting codes are combinatorial objects which have traditionally been used to enhance the transmission of data on unreliable media. They have experienced a phenomenal growth since their birth some fifty years ago. Today, everyday tasks such as listening to a CD, accessing the hard disk of an electronic device, talking on a wireless phone, or downloading files from the Internet are impossible without the use of error-correcting codes. Though traditional communication still occupies centerstage in the realm of applied coding theory, emerging applications are changing the rules of the game, and calling for a new type of coding theory capable of addressing future needs. These are not limited to physical applications, however. In fact, coding theory is an integral part of solutions offered by researchers outside traditional physical communication to solve fundamental problems of interest, such as the complexity of computation, reliable transfer of bulk data, cryptographic protocols, self correcting software, signal processing, or even computational biology.While research in the past fifty years has put traditional coding theory on firm theoretical grounds, emerging applications are in need of new tools and methods to design, analyze, and implement coding technologies capable of dealing with future needs. This is the main concern of the present proposal. To strike the right balance between length and impact we have identified five areas of research that span the full spectrum of coding theory ranging from fundamental theoretical aspects to practical applications. We set out to develop new theoretical and practical models for the design and analysis of codes, and explore new application areas hitherto untouched. A unique feature of this proposal is our choice of the tools, ranging from classical areas of algebra, combinatorics, and probability theory, to ideas and methods from theoretical computer science.

1 959 998 €

Start date: 2009-04-01, End date: 2013-03-31

We are building a parallel and independent (orthogonal) translational machinery for the encoded biosynthesis of unnatural polymers in living cells. The orthogonal translation system has many potential applications beyond those possible with the natural translation system: I propose to use it: 1) To expand the chemical scope of monomers that can be polymerized by the ribosome in living cells, allowing the incorporation of monomers with unnatural backbones into proteins; 2) To increase the efficiency of in vivo unnatural amino acid mutagenesis via amber suppression, so that no truncated protein is produced and multi-site incorporation of unnatural amino acids is possible; 3) To create probes of protein function for use in vivo; 4) To free numerous codons for simultaneous encoding of multiple distinct unnatural monomers, and to experimentally explore alternate genetic codes; 5) To explore the evolution of encoded unnatural polymers toward new cellular functions.

1 782 918 €

Start date: 2009-01-01, End date: 2014-12-31

EPIC will automatically construct Evolutionary Program Improvement Collaborators (called Epi-Collaborators) that suggest code changes that improve software according to multiple functional and non-functional objectives. The Epi-Collaborator suggestions will include transplantation of code from a donor system to a host, grafting of entirely new features `grown' (evolved) by the Epi-Collaborator, and identification and optimisation of tuneable `deep' parameters (that were previously unexposed and therefore unexploited). A key feature of the EPIC approach is that all of these suggestions will be underpinned by automatically-constructed quantitative evidence that justifies, explains and documents improvements. EPIC aims to introduce a new way of developing software, as a collaboration between human and machine, exploiting the complementary strengths of each; the human has domain and contextual insights, while the machine has the ability to intelligently search large search spaces. The EPIC approach directly tackles the emergent challenges of multiplicity: optimising for multiple competing and conflicting objectives and platforms with multiple software versions. Keywords: Search Based Software Engineering (SBSE), Evolutionary Computing, Software Testing, Genetic Algorithms, Genetic Programming.

2 159 035 €

Start date: 2017-10-01, End date: 2022-09-30

More than 3.5 million people are newly diagnosed with heart failure every year in Europe with a long-term prognosis of 50% mortality within 4 years. There is a major need for more innovative, regenerative therapies that have the potential to change the course of disease. My hypothesis is that we can recondition heart failure by stimulating cardiac repair with extracellular vesicles that are derived from progenitor cells. In my laboratory, extracellular released vesicles containing a cocktail of stimulating factors, are amongst the most potent vectors for cardiac repair. To achieve a sustainable and long-term therapeutic effect of these vesicles and enhance cardiac function by stimulating myocardial repair, we will 1) improve local cardiac delivery of progenitor cell-derived extracellular vesicles, 2) understand the mechanism of action of extracellular vesicles, and 3) stimulate extracellular vesicles release and/or production by progenitor cells. These questions form the rationale for the current proposal in which we will co-inject extracellular vesicles and slow-release biomaterials into the damaged myocardium. By subsequent genetic tracing, we will determine fate mapping of injected vesicles in vivo, and perform further mechanistic understanding in in vitro culture models of targeted and identified myocardial cell types. Moreover, we will upscale the vesicles production by progenitor cells further via bioreactor culturing and medium-throughput screening on factors that stimulate vesicles release. The use of stem cell-derived extracellular vesicles to stimulate cardiac repair will potentially allow for an off-the shelf approach, including mechanistic understanding and future clinical use. Additionally, since these vesicles act as a natural carrier system outperforming current artificial drug delivery, we might understand and mimic their characteristics to enhance local (RNA-based) drug delivery systems for cardiovascular application.

1 997 298 €

Start date: 2017-09-01, End date: 2022-08-31

One of the grand challenges of computer graphics has been to generate images indistinguishable from photographs for a naïve observer. As this challenge is mostly completed and computer generated imagery starts to replace photographs (product catalogues, special effects in cinema), the next grand challenge is to produce imagery that is indistinguishable from the real-world. Tremendous progress in capture, manipulation and display technologies opens the potential to achieve this new challenge (at the research stage) in the next 5-10 years. Electronic displays offer sufficient resolution, frame rate, dynamic range, colour gamut and, in some configurations, can produce binocular and focal depth cues. However, most of the work done in this area ignores or does not sufficiently address one of the key aspects of this problem - the performance and limitations of the human visual system. The objective of this project is to characterise and model the performance and limitations of the human visual system when observing complex dynamic 3D scenes. The scene will span a high dynamic range (HDR) of luminance and provide binocular and focal depth cues. In technical terms, the project aims to create a visual model and difference metric for high dynamic range light fields (HDR-LFs). The visual metric will replace tedious subjective testing and provide the first automated method that can optimize encoding and processing of HDR-LF data. Perceptually realistic video will impose enormous storage and processing requirements compared to traditional video. The bandwidth of such rich visual content will be the main bottleneck for new imaging and display technologies. Therefore, the final objective of this project is to use the new visual metric to derive an efficient and approximately perceptually uniform encoding of HDR-LFs. Such encoding will radically reduce storage and bandwidth requirements and will pave the way for future highly realistic image and video content.

1 868 855 €

Start date: 2017-07-01, End date: 2022-06-30

"The recent developments of the Tomographic Particle Image Velocimetry technique and of the non-intrusive pressure field characterization method, by the applicant at TU Delft Aerospace Engineering, now opens unforeseen perspectives in the area of unsteady flow diagnostics and experimental aero-acoustics. As a result of this work it is now possible not only to quantify complex flows in their three-dimensional structure, but also to extract quantities such as pressure. The current research proposal aims at the development of an innovative approach to experimental aero-acoustics and flow control making use of the recently developed Tomographic-PIV technique. The objective is to fully describe and quantify the flow pattern and the related acoustic source term at its origin, which is of paramount importance to understand and control the processes like acoustic noise production and flow separation dominating aerodynamic drag. This is relevant for the improvement of aircrafts design as far as drag reduction and noise emission is related and should enable the development of ""greener"" aircrafts for a sustainable growth of aviation in populated areas, in harmony with the technology innovation policy in Europe (7th Framework Programme) and TU Delft sustainable development focus (CleanEra, Cost-Effective Low emission And Noise Efficient regional Aircraft) at Aerospace Engineering. To achieve this step it is required that such new-generation diagnostic approach by the Tomo-PIV technique is further developed into a quadri-dimensional measurement tool (4D-PIV), enabling to extract the relevant acoustic information from the experimental observation invoking the aeroacoustic analogies. A wide industrial and academic network (DLR, AIRBUS, DNW, NLR, LaVision, EWA, JMBC Burgerscentrum) developed in recent years is available to exploit the results of the proposed activity."

1 498 000 €

Start date: 2008-08-01, End date: 2013-07-31

Fiber-top sensors (D. Iannuzzi et al., patent application number PCT/NL2005/000816) are a new generation of miniaturized devices obtained by carving tiny movable structures directly on the cleaved edge of an optical fiber. The light coupled into the fiber allows measurements of the position of the micromechanical parts with sub-nanometer accuracy. The monolithic structure of the device, the absence of electronic contacts on the sensing head, and the simplicity of the working principle offer unprecedented opportunities for the development of scientific instruments for applications in and outside research laboratories. For example, a fiber-top scanning probe microscope (also in the form of a PenFM, where a fiber-top atomic force microscope would be incorporated in a pen-like stylus) could be routinely used in harsh environments and could be easily handled by untrained personnel or through remote control systems – a fascinating perspective for utilization, among others, in surgery rooms and space missions. Similarly, the development of fiber-top biochemical sensors could be exploited for the implementation of portable equipment for in vivo and Point of Care medical testing. Fiber-top sensors could be used for the measurement of parameters of medical relevance in interstitial fluid or in blood – an interesting opportunity for intensive care monitoring and early detection of life-threatening diseases. This scenario calls for a coordinated research program dedicated to this novel generation of devices. It is my intention to forge a laboratory gravitating around fiber-top technology. My group will have the opportunity to pioneer this research area and to become the reference point in the field, on the forefront of an emerging subject that might represent a major breakthrough in the future development of micromachined sensors.

1 799 915 €

Start date: 2008-06-01, End date: 2013-05-31

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease world-wide. HCV-induced end-stage liver disease such as liver cirrhosis and hepatocellular carcinoma represent a major concern in global health. Treatment options for chronic hepatitis C are limited and no vaccine against HCV infection is available. Vaccine development is hampered by several obstacles. High viral variability and escape from host immune responses render antigen selection a major challenge. Antigen selection requires thorough studies to identify conserved T cell and neutralization epitopes and to decipher neutralization mechanisms, aiming to discover the optimal viral target for immune responses counteracting HCV escape strategies. At the same time it is important to develop antigen presentation systems that are efficient in patients with impaired antiviral immune responses, as often observed during chronic hepatitis C. While most vaccine development programs are based on improving HCV cellular immunity, it is essential to associate, in a same vaccine formulation, immunogens able to induce broad spectrums neutralizing and cellular responses. Owing to recent progresses in the field, here we propose a project aiming to overcome the current limitations in vaccine development by addressing the improvement of B cell responses targeting HCV infection. This will be achieved by a detailed investigation of: 1) mechanisms of antibody-mediated neutralization and escape, 2) impact of lipoproteins associating with the viral particle during assembly/release and counteracting neutralization and 3) cell entry steps that can potentially be targeted by antibodies, including those that are not induced naturally. Thus, through the combined expertise of the team in molecular virology, immunology, clinical hepatology and vectorology, we aim to rationalize the development of B cell immunogens and neutralizing antibodies for novel antiviral immunopreventive strategies targeting HCV infection.

2 447 357 €

Start date: 2009-04-01, End date: 2014-12-31