ERC FUNDED PROJECTS

I propose an extensive and ambitious program to greatly increase our understanding of the properties of amorphous solids, focusing mainly on the mechanical and magnetic properties of these fascinating materials, including their modes of failure via plastic flow, shear banding and fracture. Amorphous solids are important in many modern engineering applications, including as important examples structural glasses, metallic glasses and polymeric glasses. Our work combines a careful analysis of computer simulations of model-glasses with analytic theory in which we introduce to material science methods from statistical and nonlinear physics, both of which are subjects of expertise in our group. We challenge some present approaches that try to connect linear elasticity with some objects that carry plasticity; we claim that nonlinear elasticity is crucial, as its signature appears much before plastic failure. Similarly, we break away from current theories that assume that plastic events are spatially localized. We show that in athermal conditions the opposite is true, and we discover very interesting sub-extensive scaling phenomena characterized by a host of scaling exponents that need to be understood. The peculiarities of amorphous solids, in particular their memory of past deformation, call for the identification of new 'order parameters' that are sorely missing in present theories. Understanding the dependence on system size, temperature, external loading rates etc. calls for introducing new approaches and methods from statistical and nonlinear physics. In the body of the proposal we present a number of preliminary results that point towards a radically new way of thinking that we propose to develop to a new theory over the next five years.

1 792 858 €

Start date: 2011-04-01, End date: 2016-03-31

Stem cell (SC) proliferation during development requires tight spatial and temporal regulation to ensure correct cell number and right cell types are formed at the proper positions. Currently very little is known about how SCs are regulated during development. Specifically, it is unclear how SC waves of proliferation are regulated and how the fate of their progeny changes during development. In addition, it has recently become evident that metabolism provides additional complexity in cell fate regulation, highlighting the need for integrating metabolic information across physiological levels. This project will answer the question of how the combination of metabolic state and temporal cues (animal developmental stage) regulate SC fate. I will use Drosophila melanogaster, an animal complex enough to be similar to higher eukaryotes and yet simple enough to dissect the mechanistic details of cell regulation and its impact on the organism. Drosophila neural stem cells, the neuroblasts (NB), are a fantastic model of temporally and metabolically regulated cells. NB lineage fate changes with time, directing the generation of a stereotypical set of neurons, after which they disappear. I have previously found that metabolism is an important regulator of NB cell cycle exit, which occurs in response to an increase in levels of oxidative phosphorylation. Using a multidisciplinary approach combining genetics, cell type/age sorting, multi-omics analysis, fixed and 3D-live NB imaging and metabolite dynamics, I propose an integrative approach to investigate how NBs are regulated in the developing animal. First I will dissect the mechanisms by which metabolism regulates NB fate. Second, I will investigate how metabolism contributes to NB unlimited proliferation and brain tumors. Finally, we will address how temporal transcription factors and hormones dynamically affect cell fate decisions during development.

1 697 493 €

Start date: 2018-02-01, End date: 2023-01-31

The contribution of genetic and epigenetic changes to rewiring of cancer cells into their malignant state has been much studied. But tumors are more than cancer cells and the tumor microenvironment (TME) is a key player in tumor progression. We lack an overarching view of how, despite being genomically stable, the TME is heterogeneously reprogrammed across time and space to promote evolution of aggressive disease. Recently I discovered that Heat-Shock Factor 1 (HSF1), a cytoprotective transcription factor (TF), is vital to this reprogramming, promoting malignancy in patients and mice upon activation in the stroma. Other stress TFs have also been implicated. This leads me to hypothesize that stress responses help tumors adapt and evolve into aggressive malignancies, by enabling heterogeneity and phenotypic diversity in the TME. This plasticity is achieved through cycles of massive transcriptional rewiring orchestrated by a network of stress TFs. To test this hypothesis in a global way we will proceed in three aims. First we will define patterns of stress response activation in the TME by multiplexed immunofluorescence of patient tumors. Then, we will map the associated transcriptional landscape in patients by RNA-sequencing down to single cell resolution and interrogate it in the context of a novel theory of evolutionary tradeoffs so as to discover signatures that promote tumor aggressiveness. Next, we will identify actionable nodes for intervention and test them in cell co-cultures and mouse models. The expected outcome of the proposed research is a detailed network of stress responses that can explain how the TME is rewired in tumors and how variable this rewiring is. This knowledge will provide new ways to target the TME in order to complement treatments focused on cancer cells. More generally, we address key aspects of stress responses, tissue plasticity, hoemostasis and evolution that are expected to be valuable across diverse fields of biology.

1 499 990 €

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

Probabilistically Checkable Proofs (PCPs) encapsulate the striking idea that verification of proofs becomes nearly trivial if one is willing to use randomness. The PCP theorem, proven in the early 90's, is a cornerstone of modern computational complexity theory. It completely revises our notion of a proof, leading to an amazingly robust behavior: A PCP proof is guaranteed to have an abundance of errors if attempting to prove a falsity. This stands in sharp contrast to our classical notion of a proof whose correctness can collapse due to one wrong step. An important drive in the development of PCP theory is the revolutionary effect it had on the field of approximation. Feige et. al. [JACM, 1996] discovered that the PCP theorem is *equivalent* to the inapproximability of several classical optimization problems. Thus, PCP theory has resulted in a leap in our understanding of approximability and opened the gate to a flood of results. To date, virtually all inapproximability results are based on the PCP theorem, and while there is an impressive body of work on hardness-of-approximation, much work still lies ahead. The central goal of this proposal is to obtain stronger PCPs than currently known, leading towards optimal inapproximability results and novel notions of robustness in computation and in proofs. This study will build upon (i) new directions opened up by my novel proof of the PCP theorem [JACM, 2007]; and on (ii) state-of-the-art PCP machinery involving techniques from algebra, functional and harmonic analysis, probability, combinatorics, and coding theory. The broader impact of this study spans a better understanding of limits for approximation algorithms saving time and resources for algorithm designers; and new understanding of robustness in a variety of mathematical contexts, arising from the many connections between PCPs and stability questions in combinatorics, functional analysis, metric embeddings, probability, and more.

1 639 584 €

Start date: 2009-09-01, End date: 2016-06-30

The statistical and computational theory of learning is one of the prime achievements of computer science and engineering. This is evident both in terms of mathematical elegance of capturing intuitive notions rigorously as well as in terms of practical applicability: machine learning has effectively reshaped the way we use information. In this proposal we tackle the very basic notions of learning. Learning theory traditional focuses on statistics and computation. We propose to add information to the characterization of learning: namely the research question we address is: how much information is necessary to learn a certain concept efficiently? The crucial difference from classical learning theory is that traditionally statistical complexity was measured in terms of the number of examples needed to learn a concept. Our question is more finely grained: what if we are allowed to inspect only parts of a given example? Can we reduce the amount of information necessary to successfully learn important concepts? This question is fundamental in understanding learning in general and designing efficient learning algorithms in particular. We show how recent advancements in convex optimization for machine learning yields positive answers to some of the above questions: there exists cases in which much more efficient algorithms exist for learning practically important concepts. Our goal is to characterize learning from the viewpoint of the amount of information necessary to learn, to design new algorithms that access less information than current state-of-the-art and are consequently significantly more efficient. New answers for these fundamental questions will be a breakthrough in our understanding of learning at large with significant potential for impact on the field of machine learning and its applications.

1 453 802 €

Start date: 2013-10-01, End date: 2018-09-30

Type Ia supernovae (SNe Ia) are the incredibly luminous deaths of white dwarfs in binaries. They play a vital role in chemical enrichment, galaxy feedback, stellar evolution, and were instrumental in the discovery of dark energy. However, what are the progenitor systems of SNe Ia, and how they explode remains a mystery. My recent work has concluded the controversial result that there may be more than one way to produce SNe Ia. As SN Ia cosmology samples reach higher precision, understanding subtle differences in their properties becomes increasingly important. A surprising diversity in white-dwarf explosions has also been uncovered, with a much wider-than-expected range in luminosities, light-curve timescales and spectral properties. A key open question is ‘What explosion mechanisms result in normal SNe Ia compared to more exotic transients?’ My team will use novel early-time observations (within hours of explosion) of 100 SNe Ia in a volume-limited search (<75 Mpc). The targets will come from the ATLAS and Pan-STARRS surveys that will provide unprecedented sky coverage and cadence (>20000 square degrees, up to four times a night). These data will be combined with key progenitor diagnostics of each SN (companion interaction, circumstellar material, central density studies). The observed zoo of transients predicted to result from white-dwarf explosions (He-shell explosions, tidal-disruption events, violent mergers) will also be investigated, with the goal of constraining the mechanisms by which white dwarfs can explode. My access to ATLAS/Pan-STARRS and my previous experience puts me in a unique position to obtain ‘day-zero’ light curves, rapid spectroscopic follow-up, and late-time observations. The data will be analysed with detailed spectral modelling to unveil the progenitors and diversity of SNe Ia. This project is timely with the potential for significant breakthroughs to be made before the start of the next-generation ‘transient machine’, LSST in ~2021.

1 876 496 €

Start date: 2018-06-01, End date: 2023-05-31

"Learning how to act optimally in high-dimensional stochastic dynamic environments is a fundamental problem in many areas of engineering and computer science. The basic setup is that of an agent who interacts with an environment trying to maximize some long term payoff while having access to observations of the state of the environment. A standard approach to solving this problem is the Reinforcement Learning (RL) paradigm in which an agent is trying to improve its policy by interacting with the environment or, more generally, by using different sources of information such as traces from an expert and interacting with a simulator. In spite of several success stories of the RL paradigm, a unified methodology for scaling-up RL has not emerged to date. The goal of this research proposal is to create a methodology for learning and acting in high-dimensional stochastic dynamic environments that would scale up to real-world applications well and that will be useful across domains and engineering disciplines. We focus on three key aspects of learning and optimization in high dimensional stochastic dynamic environments that are interrelated and essential to scaling up RL. First, we consider the problem of structure learning. This is the problem of how to identify the key features and underlying structures in the environment that are most useful for optimization and learning. Second, we consider the problem of learning, defining, and optimizing skills. Skills are sub-policies whose goal is more focused than solving the whole optimization problem and can hence be more easily learned and optimized. Third, we consider changing the natural reward of the system to obtain desirable properties of the solution such as robustness, adversity to risk and smoothness of the control policy. In order to validate our approach we study two challenging real-world domains: a jet fighter flight simulator and a smart-grid short term control problem."

1 500 000 €

Start date: 2013-01-01, End date: 2017-12-31

The discovery of novel sustainable catalytic reactions is a major current goal. Based on recent discoveries in our group, we plan to develop unprecedented sustainable catalytic reactions with special emphasis on reactions catalyzed by complexes of earth-abundant metals. We have recently discovered an intriguing reaction, namely the oxidation of organic compounds using water, with no added oxidant, evolving H2. This simple, selective reaction, offers now a novel, conceptually new, environmentally benign approach in the field of oxidation of organic compounds, which we will explore. We recently discovered a new mode of activation of multiple bonds by metal-ligand cooperation, including activation of CO2 and nitrile triple bonds, in which reversible C-C bond formation with the ligand is involved. Based on that, activation of nitriles has resulted in unprecedented C-C bond formation involving addition of simple aliphatic nitriles to various α,β-unsaturated carbonyl compounds. This mode of multiple bond activation may open a new approach to catalysis, “template catalysis”, which we plan to explore. In addition, the highly desirable, catalytic activation of the kinetically very stable, potent greenhouse gas N2O for the (so far elusive), efficient oxygen transfer to organic compounds, will be pursued. The use of CO2 in organic synthesis is an important timely topic. Based on its activation by metal ligand cooperation, new catalytic reactions of CO2 will be pursued, including unprecedented carbonylation of non-activated C-H bonds. Most reactions catalysed by metal complexes involve noble metals. Development of sustainable catalysis based on complexes of earth-abundant metals is of great interest. In all topics described above, catalysis by complexes of such metals will be emphasized. Moreover, based on recent results in our group, we plan to develop an unprecedented family of complexes of earth-abundant metals, and pursue novel sustainable catalysis, based on it.

2 497 975 €

Start date: 2016-07-01, End date: 2021-06-30

Immunotherapy recently became an important alternative to conventional treatment regimes, yet cancer remains a universal leading cause of death. Thus, novel cancer theranostic approaches are still much desired. Although altered cell surface glycosylation is one of the hallmarks of cancer, targeting this ‘sweet aim’ for cancer therapy has been elusive, largely due to carbohydrates poor immunogenicity and the low affinity of antibodies against them. A red meat-derived carbohydrate antigen is a novel immunogenic moiety providing a key to unlock the theranostic potential of tumor-associated carbohydrate antigens. This foreign non-human sugar can be acquired only through the diet and subsequently appears on diverse cell surface glycoconjugates as ‘self’, accumulating mostly on carcinomas, and resulting in a polyclonal xeno-autoantibodies response. I have shown that such antibodies have both diagnostic and therapeutic potential, although basic understanding of their specificity and potency is scarce. The primary objective of this proposal is to design a novel personalized cancer therapeutic approach based on xeno-autoantibodies against the dietary sugar antigen. We propose an innovative interdisciplinary approach crossing the boundaries of cancer research, glycosciences, immunology and nanotechnology, with cutting-edge technologies, to design, engineer, screen and fully investigate potent targeting of ‘SweetAim’ moieties. Our discovery line is based on a two-arms platform to generate optimized antibodies for passive/active therapy, together with refined tumor cells through glyco-engineering/reprogramming for unveiling novel theranostics, finally evaluated both in vitro and in vivo. I expect our groundbreaking achievements will lead to promising new clinical tools, particularly for cancer, but also for other chronic inflammation-mediated diseases. Importantly, it will establish fundamental new concepts regarding carbohydrate recognition and response by the immune system.

1 479 995 €

Start date: 2016-12-01, End date: 2021-11-30

Symplectic geometry combines a broad spectrum of interrelated disciplines lying in the mainstream of modern mathematics. The past two decades have given rise to several exciting developments in this field, which introduced new mathematical tools and opened challenging new questions. Nowadays symplectic geometry reaches out to an amazingly wide range of areas, such as differential and algebraic geometry, complex analysis, dynamical systems, as well as quantum mechanics, and string theory. Moreover, symplectic geometry serves as a basis for Hamiltonian dynamics, a discipline providing efficient tools for modeling a variety of physical and technological processes, such as orbital motion of satellites (telecommunication and GPS navigation), and propagation of light in optical fibers (with significant applications to medicine). The proposed research is composed of several innovative studies in the frontier of symplectic geometry and Hamiltonian dynamics, which are of highly significant interest in both fields. These studies have strong interactions on a variety of topics that lie at the heart of contemporary symplectic geometry, such as symplectic embedding questions, the geometry of Hofer’s metric, Lagrangian intersection problems, and the theory of symplectic capacities. My research objectives are twofold. First, to solve the open research questions described below, which I consider to be pivotal in the field. Some of these questions have already been studied intensively, and progress toward solving them would be of considerable significance. Second, some of the studies in this proposal are interdisciplinary by nature, and use symplectic tools in order to address major open questions in other fields, such as the famous Mahler conjecture in convex geometry. My goal is to deepen the connections between symplectic geometry and these fields, thus creating a powerful framework that will allow the consideration of questions currently unattainable.

1 221 921 €

Start date: 2015-03-01, End date: 2021-02-28

Mitochondria at the synapse have a pivotal role in neurotransmitter release, but almost nothing is known about synaptic mitochondria composition or specific functions. Synaptic mitochondria compared to mitochondria in other cells, need to cope with increased calcium load, more oxidative stress, and high demands of energy generation during synaptic activity. My hypothesis is that synaptic mitochondria have acquired specific mechanisms to manage local stress and that disruption of these mechanisms contributes to neurodegeneration. How mitochondria sense their dysfunction is unclear. Even more intriguing is the question how they decide whether their failure should lead to removal of the organelle or dismissal of the complete neuron via cell death. We anticipate that these decisions are not only operational during disease, but might constitute a fundamental mechanism relevant for maintenance of synaptic activity and establishment of new synapses. Recent studies have revealed several genes implicated in neurodegenerative disorders involved in mitochondrial maintenance. However the function of these genes at the synapse, where the initial damage occurs, remains to be clarified. These genes provide excellent starting points to decipher the molecular mechanisms discussed above. Furthermore I propose to use proteomic approaches to identify the protein fingerprint of synaptic mitochondria and to compare them to mitochondria from other tissues. I plan to identify key players of the proposed regulatory pathways involved in intrinsic mitochondria quality control. In a complimentary approach, I will exploit our findings and use in vitro and in vivo experimental approaches to measure mitochondrial function of synaptic versus non-synaptic mitochondria and the relevance of those changes for synaptic function. Our work will unravel the specific properties of synaptic mitochondria and provide much needed insight in their hypothesized predominant role in neurodegenerative disorders.

1 300 000 €

Start date: 2016-09-01, End date: 2021-08-31

While advanced molecular biology approaches provide insight on the role of proteins in cellular processes, their ability to freely modify proteins and control their functions when desired is limited, hindering the achievement of a detailed understanding of the cellular functions of numerous proteins. At the same time, chemical synthesis of proteins allows for unlimited protein design, enabling the preparation of unique protein analogues that are otherwise difficult or impossible to obtain. However, effective methods to introduce these designed proteins into cells are for the most part limited to simple systems. To monitor proteins cellular functions and fates in real time, and in order to answer currently unanswerable fundamental questions about the cellular roles of proteins, the fields of protein synthesis and cellular protein manipulation must be bridged by significant advances in methods for protein delivery and real-time activation. Here, we propose to develop a general approach for enabling considerably more detailed in-cell study of uniquely modified proteins by preparing proteins having the following features: 1) traceless cell delivery unit(s), 2) an activation unit for on-demand activation of protein function in the cell, and 3) a fluorescence probe for monitoring the state and the fate of the protein. We will adopt this approach to shed light on the processes of ubiquitination and deubiquitination, which are critical cellular signals for many biological processes. We will employ our approach to study 1) the effect of inhibition of deubiquitinases in cancer. 2) Examining effect of phosphorylation on proteasomal degradation and on ubiquitin chain elongation. 3) Examining effect of covalent attachment of a known ligase ligand to a target protein on its degradation Moreover, which could trigger the development of new methods to modify the desired protein in cell by selective chemistries and so rationally promote their degradation.

2 500 000 €

Start date: 2019-10-01, End date: 2024-09-30

Our understanding of T cell differentiation impacts on vaccine development and on the treatment of (auto) immune disorders. T cells are key players in inflammation, a crucial component of the immune response to pathogens that causes severe damage to the host when uncontrolled. The cytokines Interferon-(IFN-) and Interleukin-17 (IL-17) are critical mediators of the proinflammatory activity of T cells usually designated as “T helper 1” (Th1) and Th17, respectively. Here we propose to investigate the contribution of all T cell lineages - CD4+ and CD8+ cells, and NKT cells – to global Th1 or Th17 immune responses, using various tools including a IFN-/IL-17 double reporter mouse. Importantly, we will study Th1/ Th17 differentiation in vivo, inmodels of infection with Plasmodium berghei or Mycobacterium tuberculosis. We will analyse theindividual and combined contributions of the distinct T cell subsets, their cellular interactions andpotential interdependence in lymphoid organs and in target organs of infection. We further envisage a molecular understanding of how innate (and NKT) and adaptive (CD4+ and CD8+) T cell subsets acquire their respective capacities to produce IFN-or IL-17 in vivo. We will dissect (pre-/ post-) transcriptional mechanisms of regulation of Ifng and Il17 expression in the various T cell subsets, ultimately at the single-cell level. We aim at characterizing networks of transcription factors and microRNAs that regulate Th1/ Th17 differentiation either in all or in specific T cell subsets. We are particularly interested in addressing the constitutive expression of IFN-or IL-17 by innate T lymphocytes, which is set up in the thymus. We will define the molecular components of this “developmental pre-programming” of and NKT cells in comparison with the mechanisms of peripheral induction of CD4+ Th1/ Th17 cell differentiation upon infection. By contrast to the generalized focus on CD4+ T cells, this project will consider Th1/ Th17 differentiation of all T cell lineages and their in vivo contributions to relevant models of infection. I believe this holistic view of organism-based immune parameters and their underlying molecular mechanisms, down to the single-cell level, will significantly advance our understanding of how the Immune System works.

1 500 000 €

Start date: 2010-12-01, End date: 2015-06-30

The aim of this proposal is to determine the economic and technical feasibility of using readily scalable technologies for the development of inexpensive and high performance solutions for heat dissipation for the high-end automobile industry, as well as other markets including household appliances, injection moulding, advanced aircraft and pharmaceutical manufacturing, ranging from the actual fabrication protocols, down to a wide range of finite products. The technology here described is focussed to solving heat dissipation issues by the use of novel 2-dimensional (2D) nanomaterials. While graphene is the most well-known 2D system, hundreds of other inorganic layered materials exist. 2-dimensional materials have immediate and far-reaching potential in several high-impact technological applications amongst which are heat harvesting and dissipation. Our technology will offer very cheap, scalable solution of using advanced 2D nanomaterials for enhanced heat transport. Moreover, our technology offers the advantage of being extremely versatile: 2D nanomaterial dispersions can be sprayed on their own directly onto surfaces or they can be mixed to different matrixes such as Polysil to obtain enhanced resistance to wear, abrasion, oxidation etc. This will allow us to improve the performance of existing systems, as well as improve the performance of new designs. Our developed solutions will not need to be applied through the whole heat recovery system, but mainly at those critical parts that limit the system performance. This technology has the potential of becoming a feasible, easy and efficient solution for a range of manufacturing companies. It will constitute a huge economic return, not to consider the societal overall impact of having much more efficient ways to deal with energy consumption.

129 774 €

Start date: 2016-12-01, End date: 2018-05-31

"One of the most important developments in the communication microelectronics in the last decade was the invention and popularization of “Digital RF”. It transforms the radio frequency (RF) analog functionality of a wireless transceiver into digitally-intensive implementations that operate in time-domain. They are best realized in mainstream nanometer-scale CMOS technologies and easily integrated with digital processors. As a result, RF transceivers based on this new approach now enjoy significant benefits. Consequently, the RF transceivers based on this architecture are now the majority of the 1.5 billion mobile handsets produced annually. The invention and development of “Digital RF” was pioneered in the last decade by this applicant at Texas Instruments in Dallas, Texas, USA. Despite having published over 130 scientific papers, that industrial research focus has been mainly limited to the highest volume segment of the wireless communications market: low-cost GSM/EDGE cellular phones and Bluetooth radios. Unfortunately, that low-cost low-data-rate market segment has already reached the saturation. The fastest growing segments of the wireless communications are now: high-data-rate “smart phones”, ultra-low-power wireless sensor network devices, antenna-array and millimeter-wave transceivers, where the original “Digital RF” approach could not be readily exploited. The goal of this proposal is to revisit and exploit the fundamental theory of the time-domain operation of RF and analog circuits. This way the broad area of the wireless communications, as well as analog and mixed-signal electronics in general, can be transformed for the ready realization in the advanced CMOS technology. This is expected to revolutionize the entire research field to even a larger extent than the “Digital RF” breakthrough in low-cost low-data-rate radios pioneered by this applicant in the last decade."

1 497 000 €

Start date: 2012-09-01, End date: 2017-08-31

The development of vaccines for the treatment of infectious diseases, cancer and autoimmunity depends on our knowledge of T-cell differentiation. This proposal is focused on studying the thymus, the organ responsible for the generation of T cells that are responsive against pathogen-derived antigens, and yet tolerant to self. Within the thymus, thymic epithelial cells (TECs) provide key inductive microenvironments for the development and selection of T cells that arise from hematopoietic progenitors. As a result, defects in TEC differentiation cause syndromes that range from immunodeficiency to autoimmunity, which makes the study of TECs of fundamental, and clinical, importance to understand immunity and tolerance induction. TECs are divided into two functionally distinct cortical (cTECs) and medullary (mTECs) subtypes, which derive from common bipotent TEC progenitors (TEPs). Yet, the genetic and epigenetic details that control cTEC/mTEC lineage specifications from TEPs are unsettled. My objectives are to identify TEC progenitors and their niches within the thymus, define new molecular components involved in their self-renewal and lineage potential, and elucidate the epigenetic codes that regulate the genetic programs during cTEC/mTEC fate decisions. We take a global approach to examine TEC differentiation, which integrates the study of molecular processes taking place at cellular level and the analysis of in vivo mouse models. Using advanced research tools that combine reporter mice, clonogenic assays, organotypic cultures, high-throughput RNAi screen and genome-wide epigenetic and transcriptomic profiling, we will dissect the principles that underlie the self-renewal and lineage differentiation of TEC progenitors in vivo. I believe this project has the potential to contribute to one of the great challenges of modern immunology – modulate thymic function through the induction of TEPs - and therefore, represents a major advance in Health Sciences.

1 491 749 €

Start date: 2015-07-01, End date: 2020-06-30

The creation and accumulation of knowledge are processes at the heart of technological change and economic growth. Attention has been directed at aggregate measures of knowledge production in regional and national contexts, but little consideration has been given to the properties of knowledge produced in specific places. How does the nature of knowledge that is produced vary over space, what conditions the scope of technologies generated in different locations, and how do these knowledge sets impact the performance of local firms and industries? To date, the way in which specific regional knowledge capabilities influence the evolution of local technology trajectories and thus shape geographies of economic prosperity have not yet been considered systematically. The objective of the “Technology Evolution in Regional Economies” (TechEvo) project is to address these significant shortcomings. Focusing on the evolution of scientific and technical knowledge, as indicated by patent, trademark and scientific literature records, the point of departure is the pan-European knowledge space for all 28 European Union member countries, plus Norway and Switzerland, over the time period 1981-2015. The knowledge space, based on the co-occurrence matrix of particular knowledge domains (629), maps the proximity of patent technology classes and enables the development of regional measures of knowledge specialization for all 1,369 (NUTS3) regions. Set in an evolutionary framework the investigation provides ground breaking insights into how innovative entities and individual inventors are embedded in social and cognitive local and non-local networks, and how regional technology trajectories are shaped through entry, exit, and selection processes. TechEvo will provide a wealth of indicators, models and tools that will assist firms and policy makers in place-based investment decisions, and deliver a science and technology policy evaluation tool capable of assessing impact.

1 496 599 €

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

We walk, run and jump using the complex and ingenious musculoskeletal system. It is therefore puzzling that although each of its components has been extensively studied, research of the musculoskeleton as an integrated system and, in particular, of its assembly has been scarce. In recent years, studies conducted in my lab have demonstrated the centrality of cross regulation between musculoskeletal tissues in skeletogenesis. These works have provided me with the inspiration for a revolutionary hypothesis on the way tendons connect to bones, along with sufficient preliminary data on which to base it. The critical component in the assembly of the musculoskeleton is the formation of an attachment unit, where a tendon is inserted into a bone. Instead of two tissues that attach to each other, my novel hypothesis suggests that the entire attachment unit originates from a single pool of progenitor cells, which following differentiation diverges to form a tendon attached to cartilage. With the support of the ERC scheme, I will uncover the previously uncharacterized cellular origin of the attachment unit and the genetic program underlying its development. The attachment unit is a compound tissue, as it is composed of chondrocytes at one end and of tenocytes at the other end. We will investigate the mechanisms that facilitate in situ differentiation of mesenchymal progenitor cells into two distinct cell fates, under one defined niche. In addition, I will identify the contribution of both mechanical stimuli and molecular signals to the development of the attachment unit. The ultimate goal of this program is to provide a complete picture of attachment unit development, in order to promote understanding of musculoskeletal assembly. The acquired knowledge may provide the basis for new therapies for enthesopathies, through tissue engineering or repair.

1 499 999 €

Start date: 2013-01-01, End date: 2017-12-31

"We propose to develop and implement advanced magnetic resonance detection and micro-imaging techniques that will benefit many biophysical, chemical, physical, and medical applications. Magnetic resonance (MR) is one of the most profound observation methods in science. MR includes Nuclear Magnetic Resonance (NMR) and Electron Spin Resonance (ESR). It has a variety of applications ranging from chemical structure determination to medical imaging and quantum computing. From a scientific standpoint, MR was the main focus of at least seven Nobel prizes in physics, chemistry, and medicine. From an industrial standpoint, MR is a multibillion industry focused on a range of medical (MRI) and chemical applications (MR spectrometers). Despite the fact that magnetic resonance was discovered more than 60 years ago, there is still plenty of room for new methodologies and applications. This research will confront some of the most challenging issues that this field has yet to offer, which also contain the greatest potential benefits. This is what we call “The MR Challenge”. We will focus on three key MR issues: sensitivity, image resolution, and affordability. Our first goal is to substantially improve the sensitivity of MR spectroscopy and the resolution of MR micro-imaging. We will put most of our efforts on ESR spectroscopy and on the detection of NMR information through an ESR signal (ENDOR). At ambient conditions our goal is to achieve a sensitivity of ~10^4 electron spins and a resolution of 1 micron; at low temperatures we will approach single electron spin sensitivity and image resolution as high as 10nm. In terms of affordability, our goal is to introduce a small probe that is capable of acquiring NMR spectra from samples located outside the magnet (an ""ex-situ"" probe). We will also design and construct a new family of hand-held 3D NMR imaging probes. The new capabilities would be applied in the field of single cell imaging and biophysics, materials science, and medicine."

1 250 000 €

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

Energy dissipation is a fundamental process governing the dynamics of physical, chemical and biological systems and is of major importance in condensed matter physics where scattering, loss of quantum information, and even breakdown of topological protection are deeply linked to intricate details of how and where the dissipation occurs. But despite its vital importance, dissipation is currently not a readily measurable microscopic quantity. The aim of this proposal is to launch a new discipline of nanoscale dissipation imaging and spectroscopy and to apply it to study of quantum systems and novel states of matter. The proposed scanning thermal microscopy will be revolutionary in three aspects: the first-ever cryogenic thermal imaging; improvement of thermal sensitivity by five orders of magnitude over the state of the art; and imaging and spectroscopy of dissipation of single atomic defects. We will develop a superconducting quantum interference nano-thermometer on the apex of a sharp tip which will provide non-contact non-invasive low-temperature scanning thermal microscopy with unprecedented target sensitivity of 100 nK/Hz1/2 at 4 K. These advances will enable hitherto impossible direct thermal imaging of the most elemental processes such as phonon emission from a single atomic defect due to inelastic electron scattering, relaxation mechanisms in topological surface and edge states, and variation in dissipation in individual quantum dots due to single electron changes in their occupation. We will utilize this trailblazing tool to uncover nanoscale processes that lead to energy dissipation in novel systems including resonant quasi-bound edge states in graphene, helical surface states in topological insulators, and chiral anomaly in Weyl semimetals, and to provide groundbreaking insight into nonlocal dissipation and transport properties in mesoscopic systems and in 2D topological states of matter including quantum Hall, quantum anomalous Hall, and quantum spin Hall.

3 075 000 €

Start date: 2018-06-01, End date: 2023-05-31

"The Shockley Queisser (SQ) limits the efficiency of single junction photovoltaic (PV) cells and sets the maximum efficiency for Si PV at about 30%. This is because of two constraints: i. The energy PV generates at each conversion event is set by its bandgap, irrespective of the photon’s energy. Thus, energetic photons lose most of their energy to heat. ii. PV cannot harness photons at lower energy than its bandgap. Therefore, splitting energetic photons, and fusing two photons each below the Si bandgap to generate one higher-energy photon that match the PV, push the potential efficiency above the Shockley Queisser limit. Nonlinear optics (NLO) offers efficient frequency conversion, yet it is inefficient at the intensity and the coherence level of solar and thermal radiation. Here I propose new thermodynamic concepts for frequency conversion of partially incoherent light aiming to overcome the SQ limit for single junction PVs. Specifically, I propose entropy driven up-conversion of low energy photons such as in thermal radiation to emission that matches Si PV cell. This concept is based on coupling ""hot phonons"" to Near-IR emitters, while the bulk remains at low temperature. As preliminary results we experimentally demonstrate entropy-driven ten-fold up-conversion of 10.6m excitation to 1m at internal efficiency of 27% and total efficiency of 10%. This is more efficient by orders of magnitude from any prior art, and opens the way for efficient up-conversion of thermal radiation. We continue by applying similar thermodynamic ideas for harvesting the otherwise lost thermalization in single junction PVs and present the concept of ""optical refrigeration for ultra-efficient PV"" with theoretical efficiencies as high as 69%. We support the theory by experimental validation, showing enhancement in photon energy of 107% and orders of magnitude enhancement in the number of accessible photons for high-bandgap PV. This opens the way for disruptive innovation in photovoltaics"

1 500 000 €

Start date: 2015-07-01, End date: 2020-06-30

Central tolerance is shaped in the thymus, a primary lymphoid organ, where immature T lymphocytes are “educated” into mature cells, capable of recognizing foreign antigens, while tolerating the body’s own components. This process is driven mainly by two separate lineages of thymic epithelial cells (TECs), the cortical (cTEC) and the medullary (mTEC). While cTECs are critical at the early stages of T cell development, mTECs play a pivotal role in negative selection of self-reactive thymocytes and the generation of Foxp3+ regulatory T (Treg) cells. Crucial to the key role of mTECs in the screening of self-reactive T cell clones, is their unique capacity to promiscuously express and present almost all self-antigens, including thousands of tissue-specific antigen (TSA) genes. Strikingly, the expression of most of this TSA repertoire in mTECs is regulated by a single transcriptional regulator called Aire. Indeed, Aire deficiency in mice and human patients results to multi-organ autoimmunity. Although there has been dramatic progress in our understanding of how thymic epithelial cells shape and govern the establishment of adaptive immunity and of immunological self-tolerance, there are still several outstanding questions with no comprehensive answers. Therefore, in the research proposed herein, we wish to provide more comprehensive answers to these still elusive, but very fundamental questions. Specifically we will aim at: 1.) Delineation of molecular mechanisms controlling TEC development and thymus organogenesis; 2.) Delineation of molecular mechanisms underlying promiscuous gene expression in the thymus; 3.) Identification and characterization of molecular determinants responsible for the breakdown of thymus-dependent self-tolerance. To this end, we will build upon our recently published data, as well as unpublished preliminary data and utilize several state-of-the-art and interdisciplinary approaches, which have become an integral part of our lab’s toolbox.

2 220 000 €

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

Treating tumors with immune-related therapies is one of the most exciting and promising advancements made in the past decade. Cancer immunotherapy drugs have captured nearly 50% of the overall oncology drugs market. TIGIT is an important checkpoint inhibitory receptor discovered by our group in 2009. It is constitutively expressed by various immune cells and its expression is further increased on tumor infiltrating lymphocytes (TILs). TIGIT recognizes two main ligands, PVR and Nectin2 that are highly expressed on various tumors. Blockage of TIGIT on TILs either alone or in combination with another checkpoint inhibitory receptor, PD-1, leads to increased T and Natural Killer (NK) cell activity in vitro and inhibited tumor growth in vivo. We developed 9 different anti-TIGIT mAbs during my BacNK ERC advanced grant and previously. In the POC grant TIGITtherapy, which already attracted interest from several bio pharma companies, I propose testing which of the 9 anti-TIGIT mAbs and TIGIT-Ig are able to antagonize TIGIT activity.

150 000 €

Start date: 2017-07-01, End date: 2018-12-31

Hepatitis C Virus (HCV) infection affects over 3% of the world population and is the leading cause of chronic liver disease worldwide. Current treatments are effective in only 50% of the cases and associated with significant side effects. Therefore, there is a pressing need for the development of alternative treatments. Recently, our group and others demonstrated that the HCV lifecycle is critically dependent on host lipid metabolism. In this context, we demonstrated that the grapefruit flavonoid naringenin blocks HCV production through PPAR± and LXR±, transcriptional regulators of hepatic lipid metabolism. While these results are promising, our ability to rationally control metabolic pathways in infected cells is limited due to an incomplete understanding of the regulation of hepatic metabolism by its underlying transcriptional network. This project aims to develop a comprehensive model of hepatic metabolism by integrating metabolic fluxes with transcriptional regulation enabling the rational design of transcriptional-interventions which will minimize HCV replication and release. Our approach is to develop two microfabricated platforms that will enable high-throughput data acquisition and a human-relevant screening. One component is the Transcriptional Activity Array (TAA), a microdevice for the high-throughput temporal acquisition of transcriptional activity data. The second is the Portal Circulation Platform (PCP) which integrates intestinal absorption module with a liver metabolism compartment enabling the high-throughput human-relevant screening of treatments as a substitute to animal experiments. This work will lead to the development of novel drug combinations for the treatment of HCV infection and impact the treatment of diabetes, obesity, and dyslipidemia.

1 994 395 €

Start date: 2010-04-01, End date: 2015-03-31

Now that a Higgs-like particle has been discovered naturalness becomes the most pressing and fundamental question within the reach of the Large Hadron Collider (LHC). The main contribution that destabilises the electroweak scale comes from a top-quark loop. The key for addressing the naturalness problem is thus identifying the top partners that are stabilizing the weak scale. We consider the following two general possibilities in which the partners have escaped detection: (I) the top partners are light but elusive, this calls for a theoretical explanation as well as for new innovative experimental techniques for signal exhumation; (II) the partners are relatively heavy and the signal would consist of energetic (boosted) top from the decay of its partner. I plan to carry out a comprehensive research program designed to attack these challenges, and I believe that I am uniquely prepared to do this. Regarding (I), as proven below, current searches have not considered the impact of non-trivial flavor physics, e.g. splitting between the first two generation partner masses, as well as the mixing between the top-partners and other flavors. The consequences are: (i) significantly weaker mass bounds on some of the partners (e.g. the scharm, charm-supersymmetric-partner); (ii) improved naturalness as even the stops (or fermion partners) can be lighter; and (iii) modified Higgs rates in composite models. Regarding (II), with collaborators I have been the first one to understand the difficulties of dealing with highly boosted top jets, and since then I was intensively involved in developing theoretical as well as novel techniques to study them, including coauthoring two important papers with the CDF and ATLAS collaborations. To uncover these new possibilities, expertise in collider phenomenology and flavor physics is required. I have a proven record in these frontiers and thus, given the required support, am well positioned to pursue this quest to save naturalness.

1 434 154 €

Start date: 2014-07-01, End date: 2019-06-30

Triggered by condensed matter, a new frontier recently emerged: Photonic Topological Insulators (PTIs). These are photonic structures where the transport of light is topologically protected: light propagates in a unidirectional manner without reflection, even in the presence of corners, defects, or disorder. The first step toward PTIs was the electromagnetic analogue of the quantum Hall effect, employing magnetic fields in gyrooptic media. Bringing the concepts of topological insulators into photonics required fundamentally different effects, eluding researchers until in 2013 we demonstrated the first PTI. That, along with experiments in silicon photonics and pioneering theory work, launched the field of Topological Photonics. This proposal aims to explore the possibility of the “next big thing”, a fundamentally new concept, never suggested before in any context, with high potential impact on fundamentals and on lasers technology: we will explore the idea of the Topological Insulator Laser. Topological Insulator Lasers are lasers where the lasing mode is topologically protected: light propagates around the cavity unaffected by disorder and defects. Based on our preliminary studies, we envision that by lasing in a topological mode, the interplay between the topology and gain will lead to a highly efficient laser, robust to defects and disorder, that lases in a single mode even at high gain values. The road to achieve this goes against current knowledge: topological insulators are linear Hermitian closed systems, whereas the topological insulator laser is a non-Hermitian, highly nonlinear, open system. Our study will be theoretical and experimental, starting at the fundamentals of topological transport in systems with gain, and we will take it all the way to experimentally demonstrate the concepts in several different platforms. The idea of the Topological Insulator Laser is unique: success will mark a new milestone in optics and topological physics.

1 864 000 €

Start date: 2018-06-01, End date: 2023-05-31

Much of the current intense study of molecular conduction junctions is motivated by their possible technological applications, however this research focuses on fundamental questions associated with the properties and operation of such systems. Junctions based on redox molecules often show non-linear conduction behavior as function of imposed bias. Optical interactions in molecular junctions pertain to junction characterization and control. Issues of heating and thermal stability require a proper definition of thermal states (effective temperature) and the understanding of heat production and thermal conduction in non-equilibrium junctions. This proposal focuses on theoretical problems pertaining to these phenomena with the following goals: (a) Develop theoretical methodologies for treating non-equilibrium molecular systems under the combined driving of electrical bias, thermal gradients and optical fields; (b) provide theoretical tools needed for the understanding and interpretation of new and ongoing experimental efforts involving thermal, optical and redox (charging) phenomena in molecular junctions, and (c) use the acquired insight to suggest new methods for characterization, functionality, control and stability of molecular junctions.

842 420 €

Start date: 2008-12-01, End date: 2014-05-31

The complex functions of a living cell are carried out through the coordinated activity of many genes. Since transcription is a key step in establishing such coordinated activity, much effort was devoted to its study, and tremendous progress was made in identifying many of the transcription factors and regulatory DNA elements involved in the regulation of specific systems. However, very few attempts were made at going beyond these phenomenological and qualitative descriptions. Consequently, we are far from a quantitative and predictive understanding of transcriptional regulation. Through this program, I aim to develop a mechanistic understanding of transcriptional regulation, and for the first time model the entire process. We wish to go much beyond identifying and qualitatively describing the involved components, and arrive at a quantitative understanding of how transcriptional programs are encoded in the DNA sequences. To this end, my team and I will first work to mechanistically understand various building blocks of the transcriptional system, including: mechanisms of activation and repression; binding cooperativity; binding competition; transcription factors and chromatin interplay; architectural features of promoters that are important for its function; and the transcription functions “computed” by promoters. Since existing data are clearly insufficient for addressing such questions, I have opened an experimental lab and began to assemble a multidisciplinary team of scientists whose expertise span the experimental biology, computer science, physics, statistics, and mathematics disciplines, that will work synergistically to generate the appropriate data, analyze it, and use it to construct and experimentally validate models for the above transcriptional building blocks. We will then integrate all the insights gained into unified and quantitative models that should significantly enhance our understanding of the mechanistic workings of transcriptional regulation.

1 005 600 €

Start date: 2008-07-01, End date: 2013-06-30

Inheritance of acquired traits is a topic of long-standing interest and controversy. While some of the classic Lamarckian ideas have been dismissed, more recent observations suggest that certain characteristics acquired by an animal during its lifetime might be transmitted to the next generations. Recently I described, for the first time in animals, a biological context in which acquired traits are inherited via small RNA molecules, which ignore the boundary between the soma and the germ line (“The Weizmann Barrier”). Specifically, I showed that the nematode C.elegans inherit an acquired trait, antiviral resistance, through transgenerational transmission of antiviral small RNAs (viRNAs), which mediate RNA interference (RNAi) (Cell, 2011). viRNAs, which protect the worm from viral propagation, pass down to many ensuing generations in a non-Mendelian manner, in the absence of their DNA template, and thus defend RNAi-deficient progeny from viral propagation. Here I suggest defining the rules that govern RNA-mediated transgenerational inheritance of acquired traits and exploring its contribution for the genetics of complex traits. My first efforts will be directed towards elucidating the mechanism behind transgenerational transmission of small RNAs; I established a well-defined system for monitoring transgenerational silencing that should allow unveiling of its genetic and biochemical basis. Second, I will examine whether responses to relevant environmental stresses carry on to the next generations so that the progeny is better prepared to cope with similar conditions. Lastly, I will explore whether sensing of environmental cues by the nervous system drives small RNA biogenesis, which transfer transgenerationally and mediate inheritance of neuronally-encoded traits. While the idea that RNA encodes for “Inherited Memory” sounds heretic at first, my preliminary efforts suggest that inherited small RNAs may indeed transmit information about ancestral acquired experiences.

1 500 000 €

Start date: 2014-02-01, End date: 2019-01-31

"The TRANSRIGHTS project investigates transgender lives and the institutional apparatus that frames them. Rather than focusing exclusively on self displayed identities, four lines of inquiry will be developed. Firstly, gender politics and sexual rights are analyzed as the opposition between politics of equality and of difference is unable to provide answers for the inclusion of trans-people. Secondly, by comparing the lives of trans-people in five European countries – Portugal, France, United Kingdom, the Netherlands and Sweden – we wish to attain an overview of how institutional frameworks impact on these lives. Thirdly, our approach will take into account the immigration of trans-individuals to Europe, whether in search for recognition or as a way of survival often leading to sex work. Fourthly, by comparing different countries, different groups of transgender people, different forms of attaining inclusion or dealing with exclusion, different conceptions of gender citizenship and sexual rights, we wish not only to gain a deeper understanding of societal change and its impact on the lives of transgender individuals, but also to identify the gaps between policies and rights and the categories actually mobilized for self-identification. Such a task implies examining the voices of trans-people, the effect of policies on the materiality of lives as well as conceptualizations of selfhood that do not necessarily confine to the European context. Project outputs will contribute to the fields of gender, sexuality and citizenship by providing a grounded theoretical debate, discussing the gender categories of citizenship. Trans-people are a heterogeneous group that represents one of the most challenging boundaries for framing this debate within and beyond Europe. The voices of trans-people are essential to avoid an excessive reduction of lives to institutional categories, whether from the institutional apparatus, the LGBT movements or the social sciences."

1 262 943 €

Start date: 2014-09-01, End date: 2019-08-31

The Internet of Things is shaping the evolution of information society, requiring an increasing number of objects with embedded electronics, sensors and connectivity. This spurs the need for systems where summing to performance and low cost, multifunctionality has to be assured. In this context, TREND aims to take transparent electronics into as-of-yet unexplored levels of integration, by combining on flexible substrates transparent and high-speed nanocircuits with energy harvesting capabilities, all based on multicomponent metal oxide nanowires (NWs). For this end, sustainable and recyclable materials as ZnO, SnO2, TiO2 and Cu2O will be synthesized in different forms of heterostructured NWs, using low-temperature and low-cost solution processes. For precise positioning, NWs will be directly grow on flexible substrates using seed layers patterned by nanoimprint lithography. This will be crucial for integration in different nanotransistor structures, which will be combined into digital/analog nanocircuits following planar and 3D approaches. Energy will be provided by piezoelectric nanogenerators with innovative structures and materials. Final platform of nanocircuits+nanogenerators will make use of NW interconnects, bringing a new dimension to the systems-on-foil concept. The research will be carried out at FCT-UNL, in a group pioneering transparent electronics. My PhD on oxide materials/devices and proven expertise on circuit integration, oxide nanostructure synthesis and nanofabrication/characterization tools will be a decisive contribute to the implementation of the proposal. TREND is an ambitious multidisciplinary project motivating advances in materials science, engineering, physics and chemistry, with impact extending from consumer electronics to health monitoring wearable devices. By promoting new ideas for practical ends, it will contribute to place Europe in the leading position of such strategic areas, where sustainability and innovation are key factors.

1 500 000 €

Start date: 2017-01-01, End date: 2021-12-31

Translation maps the transcriptome onto the proteome. It is regulated at the initiation levels and also by mRNA secondary structure, and – our current focus – by the interplay between the mRNA and tRNA pools. Although a lot is known about the mechanics of translation, its effects on physiology, particularly on proliferation and differentiation in mammals presents major open questions. tRNAProlif offers an approach that consists of genome-wide measurements and analyses of the tRNA and mRNAs pools, and the interplay between them, in proliferative and differentiated cells. The project will explain how changes in translation affect, and are affected by, these two states. We rely on our preliminary results that show a striking dichotomy in codon usage: genes involved in cellular proliferation have distinct codon usage compared to genes involved in differentiation and other multi-cellular process. Further, the tRNA pool consists of two distinct sub-populations: tRNAs whose codons are enriched among the proliferation genes are induced in proliferation and cancer, and tRNAs whose codons are enriched in differentiation genes are repressed in proliferation and are induced in differentiation. Towards understanding this “tRNA Switch” we aim at: Causality: We will determine whether the tRNA pool affects the proliferation/differentiation status of cell. Conversely, we will determine the effects of the proliferation/differentiation status on the tRNA pool. Regulation: We will establish the regulatory scheme that governs the “tRNA Switch”: we will determine the effects of transcriptional and post-transcriptional regulation on the tRNAs, depending on cell state. We will determine how the balance between the two tRNA sub-populations affects the proteome. Evolution: We will conduct comparative genomics of regulation of tRNA availability and codon usage and its effect on physiology in multiple species.

1 540 000 €

Start date: 2014-04-01, End date: 2019-03-31

The human body is host to a huge number of bacteria. While bacteria were first detected in human tumors over 150 years ago, our knowledge about their number, identity or effects in different human tumor types is still mostly rudimentary. Over the last few years we focused on studying the tumor microbiome. We developed multiple methods to characterize and visualize intra-tumor bacteria, taking special measures to tell apart true tumor-bacteria from contamination. Profiling over 1,800 human tumors and normal adjacent tissues demostrated that bacteria are prevalent in many tumor types and that each tumor type has a unique microbial signature. This application aims to capitalize on our cutting-edge research tools, vast experience and comprehensive preliminary data to shed light on the uncharted field of the tumor microbiome. We plan to: (1) Characterize the different microbial communities (bacteria, fungi, others) and their dynamics in human tumors. We strive to provide a near complete narrative of how bacteria are distributed in the tumor, their association with immune cells and their dynamic changes with tumor development, metastasis and drug treatments. (2) Study the effects that microbial communities may have on tumor biology, focusing primarily on tumor microbiome-mediated drug resistance and on tumor microbiome effects on tumor-associated macrophages. (3) Exploit intra-tumor microbial communities for translational opportunities and novel therapeutics, in particular as an adjunct to current mainstay therapy or delivering innovative therapeutics via live bacteria. Thus, this project will transform our understanding of the structure and function of intra-tumor microbial communities and will pave the way for us, as well as many others, to translate our findings into novel therapeutic options for cancer patients.

2 000 000 €

Start date: 2019-05-01, End date: 2024-04-30

"The aim of the proposed research is gaining a better understanding of locally compact groups and their lattices. Our tools are mainly ergodic theoretical. We propose a variety of novel ideas that open new horizons for research. The first meta idea is the adoption of tools from the semi-simple theory in order to apply them for general locally compact groups. In particular, we suggest a construction of a ""Weyl group"" and an abstract definition of rank for every locally compact group. We are able to construct a ""Coxeter complex"" and we foresee a construction of a ""building like"" object. A second set of ideas concerns the category of measure equivalences, which is a natural generalization of the notion of a lattice in a group. This category is long known to be a measurable counterpart of the better studied category of quasi-isometries, yet it misses a good definition of self measure equivalences of an object, analog to the group of quasi-isometries. We suggest such a definition, and propose to study it, among a variety of related constructions. A full implementation of our ideas requires a better understanding of locally compact groups. Thus, an important aspect of the proposed research is that it leaves plenty of room for the study of specific examples and test cases."

1 150 000 €

Start date: 2012-09-01, End date: 2018-08-31

Microfluidic systems, in general, have proven important platforms for biomedical assays. These systems benefit from reduced requirements for expensive reagents, short analysis times, and portability. Although microfluidic systems are convenient platforms, their use in the life sciences is still limited mainly due to the high-level fabrication expertise required for construction. Integrated microfluidics is one of the most sophisticated three-dimensional (multi layer) solution. It requires soft lithography (PDMS based chips), for production of high complexity microfluidic systems (multiple serial or parallel processes). Integrated microfluidics in particular is almost non-existent in the industry due to the low yield and uncontrolled production process. My ERC project (MUDLOC-2012) is to develop a microfluidic platform for multidimensional protein array analysis. It uses complex multilayer microfluidic devices that consist of 2 PDMS layers and a glass microarray. The integrated microfluidics system contains thousands of micromechanical valves in micrometer dimensions, controlling thousands of parallel reactions. Our research demands production of hundreds of such devices. We, as all others who produce integrated microfluidics, suffered from frustrating low yield (15%). In order to improve fabrication yield and to fabricate devices with increased density, we designed and manufactured, a first of its kind, full production process sequence, semi automatic Microfluidic Device Assembly System (µDAS). This resulted in a direct increase of device complexity and yield (85%) over the last half year. The 2nd generation automated µDAS prototype will become a generic assembly tool for soft lithography. µDAS will enable a critical production standard and process control, which will pave the road for significant penetration of complex integrated microfluidics technology into both academia and industry.

150 000 €

Start date: 2015-04-01, End date: 2016-09-30

Multidimensional nuclear magnetic resonance (nD NMR) plays a unique role in Science as a primary tool for the characterization of biomolecules, as part of drug-discovery processes, and in clinical imaging (MRI). Further progress in NMR is hampered by this spectroscopy s low sensitivity, arising from the weak interactions that it involves. The prospects of solving this problem by continuing with incremental bigger machines approaches are poor, given the high maturity reached by existing technologies. The present Project deals with this issue by departing from traditional concepts, and relying on two incipient but highly promising developments in the field. One of these pertains ex situ dynamic nuclear hyperpolarization, an approach capable of eliciting liquid state NMR signals that surpass those afforded by the highest-field spectrometers by factors e10,000. While capable of providing super-signals hyperpolarization has the drawback of involving irreversible changes in the physical state of the sample. This makes it incompatible with nD NMR technologies, requiring the collection of multiple scans identical to one another except for systematic delay variations. As second component in this high-risk/high-gain Project we propose merging hyperpolarization with &quot;ultrafast&quot; methods that we have recently developed for completing arbitrary nD NMR/MRI acquisitions within a single scan. The resulting synergy could increase sensitivity by orders of magnitude, while demanding negligibly small amounts of spectrometer/scanner time to complete nD acquisitions. This should provide an ideal starting point for the analysis of a variety of organic and structural biology problems, and provide new tools to explore in vivo metabolism focusing on cancer biomarkers.

2 499 780 €

Start date: 2010-03-01, End date: 2015-02-28

Much of the research on the foundations of graph algorithms is carried out under the assumption that the algorithm has full knowledge of the input data. In spite of the theoretical appeal and simplicity of this setting, the assumption that the algorithm has full knowledge does not always hold. Indeed uncertainty and partial knowledge arise in many settings. One example is where the data is very large, in which case even reading the entire data once is infeasible, and sampling is required. Another example is where data changes occur over time (e.g., social networks where information is fluid). A third example is where processing of the data is distributed over computation nodes, and each node has only local information. Randomization is a powerful tool in the classic setting of graph algorithms with full knowledge and is often used to simplify the algorithm and to speed-up its running time. However, physical computers are deterministic machines, and obtaining true randomness can be a hard task to achieve. Therefore, a central line of research is focused on the derandomization of algorithms that relies on randomness. The challenge of derandomization also arise in settings where the algorithm has some degree of uncertainty. In fact, in many cases of uncertainty the challenge and motivation of derandomization is even stronger. Randomization by itself adds another layer of uncertainty, because different results may be attained in different runs of the algorithm. In addition, in many cases of uncertainty randomization often comes with additional assumptions on the model itself, and therefore weaken the guarantees of the algorithm. In this proposal I will investigate the power of randomization in uncertain environments. I will focus on two fundamental areas of graph algorithms with uncertainty. The first area relates to dynamic algorithms and the second area concerns distributed graph algorithms.

1 500 000 €

Start date: 2019-10-01, End date: 2024-09-30

Information in the nervous system is typically represented in activity patterns distributed across large populations of neurons in three dimensions, and there is a lot of current interest in the development of systems that can volumetrically image these patterns (or other distributed processes) in real-time. During our work towards imaging responses to artificial retinal stimulation we have developed a solution for remotely manipulating the illumination plane during temporal-focusing multiphoton imaging (a powerful bio-microscopy and photo-manipulation modality). This technique and its variations could provide unprecedented access into rapid 3D imaging at an exciting time for the neuroimaging field, where major initiatives for high-resolution brain activity mapping have been launched, and could potentially also be applied towards innovative approaches to micro-endoscopy and other applications.

150 000 €

Start date: 2015-02-01, End date: 2016-07-31

Almost 100 years ago, Warburg described a metabolic change in energy flux that occurs during carcinogenesis. Since then, multiple studies have demonstrated how anabolic synthesis of macromolecules can be altered to support cancer cell progression. Yet, the potential effect of altered catabolic degradation of macromolecules on tumour carcinogenesis has been much less studied. The urea cycle (UC) is the main catabolic pathway by which mammals excrete waste nitrogen. Although the complete UC pathway is liver-specific, most tissues express different combinations of UC enzymes according to the cellular needs. Surprisingly, we find that changes in expression of UC components causing UC dysregulation, (UCD) is a global phenomenon in cancer, metabolically augmenting net nitrogen usage for the synthesis of macromolecules by reducing nitrogen waste. This metabolic alteration is associated with poor patient prognosis. Thus, we hypothesise that UCD provides a major metabolic advantage to multiple aspects of carcinogenesis and as such, leads to specific, identifiable genomic and biochemical signatures, with implications for cancer diagnosis and therapy. To pursue our hypothesis, we will incorporate state-of-the-art comparative genomic, peptidomic, metabolomic, and molecular approaches to explore this scientific “blind spot” of nitrogen metabolism in carcinogenesis. We will investigate how UCD causally affects carcinogenesis, by characterising tumour-specific functions of UC enzymes (Aim I), correlating tumour phenotypes with systemic biomarkers (Aim II), and testing the treatment efficacy of drug combinations targeting UCD in cancers (Aim III). Our proposal, strengthened by my training as a physician scientist, harbours considerable potential for translational diagnostic and therapeutic utility of our findings, enabling us to i) identify new diagnostic biomarkers for monitoring cancer initiation and progression and ii) predict and enhance the therapeutic response.

2 000 000 €

Start date: 2019-05-01, End date: 2024-04-30

The impact of a building design or renovation on the behavior of its intended occupants can be assessed only after the building has been built and occupied (or the renovation has been completed). This is a risky proposition, because design mistakes can cause severe consequences in terms of under-performing buildings, reduced productivity, absenteeism, and general user dissatisfaction. During our ERC-funded project, titled NextGenBim, we were able to develop and demonstrate a method to computationally simulate human behavior in built environments, which allows representing the intended occupants and their activities in a given building. In this PoC we aim to develop a software simulator that allows: (1) to visualize, analyze and evaluate trade-offs between several design options for a new building; and (2) to evaluate the systemic implication of proposed renovations on the operations of a building. The software will potentially impact millions of professionals (architects, civil engineers, internal designers, facility mangers, etc.), especially in the healthcare sector, where large budgets are spent to build and renovate facilities, and in the educational sector, which invests heavily in computer-aided design software to train the next generation of professionals.

150 000 €

Start date: 2017-06-01, End date: 2018-11-30

Cells process information using biochemical networks of interacting proteins and genes. We wish to understand the principles that guide the design of such networks. In particular, we are interested in the interplay between variability, inherent to biological systems, and the precision of cellular computing. To better understand this interplay, we will: (1) Characterize the extent of gene expression variability and define its genetic determinants, (2) Reveal how variability is buffered and (3) Describe instances where variability (or 'noise') is an integral part of cellular computation. The study will be conducted in the multidisciplinary atmosphere of our lab, by students trained in physics, computer science, chemistry and biology. Specific issues include: 1. Gene expression variability: we will focus on the influence of chromatin structure on gene expression variability, as suggested by our bioinformatics analysis. 2. Robustness and scaling in embryonic patterning: We will study the means by which fluctuations are buffered during the development of multicellular organisms. We will focus on the robustness of morphogen gradients to protein levels, and on the ability to maintain proportionate pattern in tissues of different size. 3. Noise-driven transitions in a fluctuating environment: Our preliminary results suggest that noise plays an integral part in phosphate homeostasis in S. cerevisiae. We will characterize the role of noise in this system and study its evolutionary implications. Together, our study will shed light on one we believe to be the fundamental challenge of biological information processing: ensuring a reliable and reproducible function in the highly variable biological environment. Our study will furthermore define novel multidisciplinary, system-level paradigms and approaches that will guide further studies of bio-molecular systems

2 200 000 €

Start date: 2009-01-01, End date: 2013-10-31

Recent evidence suggests that VEGF and the vasculature play multiple roles in organ homeostasis, functions extending far beyond their traditional roles in tissue perfusion. The proposed study represents a vascular-centred approach to the neurovascular unit thriving to gain further insights on the many ways by which blood vessels may affect proper brain functioning. Major focus is on the vascular stem cell niche, i.e. the contention that blood vessels are a key component of adult stem cell niches, including a niche securing proper function of neuronal stem cells (NSCs). Further insights on the niche are also critical for contemplated implementation of stem-cell based therapy. In this multidisciplinary study combining the fields of vascular biology, neurobiology, stem cell biology, and aging research, we harness unique transgenic methodologies to conditionally manipulate (via VEGF) the vasculature within the stem cell niches. We provide a first compelling proof that blood vessels at the niche indeed control stem cells properties and behaviour, evidenced by showing that mere expansion of the niche vasculature and independently of VEGF) increases dramatically adult hippocampal neurogenesis, a process known to be associated with improved cognitive performance. We will determine what aspects of stem cell biology are controlled by juxtaposed, directly contacting blood vessels and will identify signalling systems mediating the vascular/stem cell cross-talk. Adult neurogenesis is known to rapidly decline with age and ways to sustain the process are highly desired. We hypothesize and, in fact, provide initial evidence that expanding and 'rejuvenating' the niche vasculature can override the natural age-dependent decline of adult neurogenesis. Proposed experiments will extend this exciting finding and thrive to uncover the underlying mechanisms.

2 499 980 €

Start date: 2013-03-01, End date: 2018-02-28

Angiogenesis is the mechanism of blood vessel formation from pre-existing ones and is vital for nutrient and oxygen delivery to all cells in the organism. However, dysregulation of angiogenesis is detrimental for the organism. Excessive or abnormal angiogenesis is a hallmark of cancer and various retinopathies and favours tumour growth and metastasis, and vision loss, respectively. Excessive or abnormal angiogenesis is fuelled by hypoxia-driven expression of high levels of vascular endothelial growth factor (VEGF), the main pro-angiogenic molecule that stimulates the formation of new blood vessels. Although VEGF-centric anti-angiogenic therapies do exist, their efficacy is limited by their specificity and numerous side effects, hampering greatly their potential clinical benefits. Therefore, there is an urgent need for improved anti-VEGF therapeutic strategies. The aim of this PoC project is to identify a novel class of anti-VEGF drugs. We designed an innovative and unique screening method to identify an unexplored mechanism to inhibit VEGF function in vivo, which has the prospect of reduced toxicity and, thus, enhanced clinical efficacy. This project will enable the creation of a start-up company to commercialize the newly identified class of drugs for subsequent clinical development to curb cancer and retinopathies. We aim at improving patient survival and well-being, and reducing the economic burden associated with these diseases.

150 000 €

Start date: 2019-03-01, End date: 2020-08-31

Facial reconstruction usually involves the use of autologous grafts or composite tissue allografts, which are highly complex tissues that pose significant challenges to tissue engineering experts. Tissue engineering of independent facial elements, e.g., bone, adipose, skin and muscle tissues, has been demonstrated. However, to date, no composite soft tissues composed of multiple facial layers have been created. Composite facial tissue engineering will require proper innervation and vascularization, essential to support generation of large thick implants. However, techniques for effective innervation of engineered tissues are currently insufficient and generation of well-vascularized large and thick engineered tissues is still one of the major obstacles limiting their translation to the clinic. Our goal is to engineer thick, composite, human-scale, facial tissues (muscle-adipose-dermis composite, and bone) of a personally adaptable shape, that will be vascularized in-vitro, and innervated upon transplantation. Our concept is to create in-vitro a functional vascular network (VesselNet), composed of both large and small vessels, within engineered constructs, which will allow for the generation of thick engineered tissues under continuous flow conditions. 3D bio-printing techniques will be applied to create the engineered tissues. These tissues will serve as a model to study mechanisms involved in vessel anastomosis, and tissue organization and stabilization. The applicability of the engineered composite soft and bone tissues will be evaluated in facial, breast and abdominal wall defect reconstruction models, and in an open fracture model. Such engineered large-scale composite tissues are expected to have a major impact on reconstructive surgery and will shed light on yet unknown tissue organization mechanisms.

2 375 000 €

Start date: 2019-09-01, End date: 2024-08-31

Phytoplankton blooms are ephemeral events of exceptionally high primary productivity that regulate the flux of carbon across marine food webs. The cosmopolitan coccolithophore Emiliania huxleyi (Haptophyta) is a unicellular eukaryotic alga responsible for the largest oceanic algal blooms covering thousands of square kilometers. These annual blooms are frequently terminated by a specific large dsDNA E. huxleyi virus (EhV). Despite the huge ecological importance of host-virus interactions, the ability to assess their ecological impact is limited to current approaches, which focus mainly on quantification of viral abundance and diversity. On the molecular basis, a major challenge in the current understanding of host-virus interactions in the marine environment is the ability to decode the wealth of “omics” data and translate it into cellular mechanisms that mediate host susceptibility and resistance to viral infection. In the current proposal we intend to provide novel functional insights into molecular mechanisms that regulate host-virus interactions at the single-cell level by unravelling phenotypic heterogeneity within infected populations. By using physiological markers and single-cell transcriptomics, we propose to discern between host subpopulations and define their different “metabolic states”, in order to map them into different modes of susceptibility and resistance. By using advanced metabolomic approaches, we also aim to define the infochemical microenvironment generated during viral infection and examine how it can shape host phenotypic plasticity. Mapping the transcriptomic and metabolic footprints of viral infection will provide a meaningful tool to assess the dynamics of active viral infection during natural E. huxleyi blooms. Our novel approaches will pave the way for unprecedented quantification of the “viral shunt” that drives nutrient fluxes in marine food webs, from a single-cell level to a population and eventually ecosystem levels.

2 749 901 €

Start date: 2016-11-01, End date: 2021-10-31

The right to make one’s own decisions and to have these decisions respected by law is a basic human freedom which most adults take for granted. However, for many people with disabilities (especially people with intellectual, psycho-social and other cognitive disabilities) this fundamental right has been denied – informally, in the private sphere, and formally, in the public sphere through States’ laws and policies. Since the entry into force of the UN Convention on the Rights of Persons with Disabilities, there is an emerging consensus in human rights discourse that all people, regardless of their decision-making skills, should enjoy ‘legal capacity’ on an equal basis—that is, the right to be recognised as a person before the law and the subsequent right to have one’s decisions legally recognised. To date most of the literature on how this right should be realised has been developed by non-disabled scholars without the direct input of people with disabilities themselves. The VOICES project will take a radical approach to develop new law reform ideas based on this concept of ‘universal legal capacity.’ Its primary objective is to develop reform proposals based on the lived experience of disability. The project will support individuals who self-identify as disabled to develop personal narratives about their experiences in exercising, or being denied, legal capacity. Through a collaborative process, legal and social science scholars will then work with people with disabilities to develop their personal narratives to frame and ground concrete proposals for law reform in previously unexplored areas – including consent to sex, contractual capacity, criminal responsibility and consent to medical treatment. In this way, the legitimacy of people with disabilities’ perspectives on the options for law reform will be validated, and this will create a powerful argument for legal change.

891 386 €

Start date: 2015-06-01, End date: 2018-11-30

Watecco is a unique, photoacoustics based profiler, designed to determine the depth distribution of natural phytoplankton assemblages and of algal cells in mass cultures and of their photosynthetic efficiency. It can report the stratification of the light absorbing photosynthetic pigments and is unique in its sensitivity to document changes in the quantum yield of phototrophic plankters. The profiler is of great importance in following the health and photosynthetic light utilization efficiency of natural and manmade water bodies, freshwater and marine. Since increase in photosynthetic efficiency and the related proliferation of algal biomass of phytoplankton in lakes, rivers and in the sea occurs mainly as a result of nutrient enrichment, or anthropogenic eutrophication, as well as due to Global Climate Change related water acidification, Watecco can provide an early warning alert call to environmental pollution by urban or farm sewage, compromising the safety of water supplies and coastal fisheries. Furthermore, the capability of Watecco to provide fast, real time data on the efficiency of photobioreactors and algal mass cultures makes it a unique tool in the optimization of these devices for attaining high yields of their target products. Commercialization activities of Watecco include market analysis, financial and business planning, legal workup, IPR protection and contracting with manufacturers and investors. The project also covers the finalization of the development of a submersible prototype, a user friendly interface, and its field testing and data validation. This innovative technology will yield reliable and robust data for coastal authorities responsible for evaluation of the proliferation and collapse of algal populations, marine labs and nature reserves, water supply authorities, industries involved in the mass culture of algae for the production of biodiesel and fine chemicals, and installations based on high-rate-algal sewage treatment systems.

149 775 €

Start date: 2014-11-01, End date: 2016-04-30

Our idea is to revisit the recording of time-series of sea surface elevations in extreme conditions. A better understanding of extreme waves is vital in harbour and coastal monitoring, coastal engineering, offshore design and operations, maritime traffic control, meteorological and climatological studies, wave and wind energy studies. Within the framework of the ERC Advanced Grant MULTIWAVE, which started in April 2012, we brought new physical and mathematical insights into the dynamic shaping mechanisms and statistics of rogue waves, both in optics and in hydrodynamics. While in optics the measurement of such extreme events is accurate, the measurement of extreme waves in the ocean is quite delicate. Moreover experiments can be repeated in optics while in the ocean one has to wait for extreme waves. There are several techniques to measure waves in the ocean: the traditional in-situ techniques as well as remote sensing or optical techniques. They all have advantages and drawbacks and none of them has ever been calibrated against extreme ocean waves. We believe that the in-situ technique once improved remains the best technique for now. Together with the industrial subcontractor, we will optimize wave buoy sensor technology for extreme waves. Based on the fundamental know-how from MULTIWAVE, we are in a position to allow settings to be optimized in the initial design phase prior to ocean deployment and then to test the performance of the optimized device. We will select areas off the west coast of Ireland and times of the year when the probability of recording extreme waves and rogue waves in particular is the highest. If the recorded time-series are robust and accurate, the new wave buoy will be the first wave buoy that can be trusted for recording extreme waves. A market search of existing wave measuring devices currently available will be performed. We believe that the potential market is huge.

139 140 €

Start date: 2014-09-01, End date: 2016-02-29

Wolbachia are arguably the most prevalent intracellular bacteria in animals, infecting filarial nematodes and up to 66% of arthropod species. Wolbachia are maternally transmitted and can induce a large range of strong phenotypes on their hosts. However, very little is known on how they induce these phenotypes and how they interact with the host at the molecular level. One main difficulty with this system is that Wolbachia have been genetically intractable. We will study how Wolbachia confers protection to viruses, a phenomenon that is currently being applied to fight dengue and Zika viruses. We also aim at understanding how these endosymbiont titres are regulated, a crucial aspect of their biology. We will identify host and Wolbachia genes that regulate these processes by performing classical genetic screens in Drosophila and develop a new method to perform a forward genetic screen in Wolbachia. Our previous analysis of natural variants of Wolbachia will also be extended in order to identify alleles associated with differential growth and antiviral protection. We will characterize candidate Wolbachia genes, from the previous analysis and current results in the lab, by performing a new method to obtain loss-of-function mutants in target Wolbachia genes. We will also focus on putative effector proteins of Wolbachia with the purpose of identifying cellular location, induced phenotypes, and host interacting proteins. Drosophila genes will be characterized by classical genetic methods in this model organism. The identification and characterization of Wolbachia and host genes involved in antiviral protection and Wolbachia proliferation will provide key insights to these basic biological problems. Moreover, the knowledge generated and new Wolbachia variants may have an application in the fight against arboviruses transmitted by mosquitoes and human diseases caused by filarial nematodes.

1 999 500 €

Start date: 2018-07-01, End date: 2023-06-30