ERC FUNDED PROJECTS

CoralWarm will generate for the first time projections of temperate and subtropical coral survival by integrating sublethal temperature increase effects on metabolic and skeletal processes in Mediterranean and Red Sea key species. CoralWarm unique approach is from the nano- to the macro-scale, correlating molecular events to environmental processes. This will show new pathways to future investigations on cellular mechanisms linking environmental factors to final phenotype, potentially improving prediction powers and paleoclimatological interpretation. Biological and chemical expertise will merge, producing new interdisciplinary approaches for ecophysiology and biomineralization. Field transplantations will be combined with controlled experiments under IPCC scenarios. Corals will be grown in aquaria, exposing the Mediterranean species native to cooler waters to higher temperatures, and the Red Sea ones to gradually increasing above ambient warming seawater. Virtually all state-of-the-art methods will be used, by uniquely combining the investigators expertise. Expected results include responses of algal symbionts photosynthesis, host, symbiont and holobiont respiration, biomineralization rates and patterns, including colony architecture, and reproduction to temperature and pH gradients and combinations. Integration of molecular aspects of potential replacement of symbiont clades, changes in skeletal crystallography, with biochemical and physiological aspects of temperature response, will lead to a novel mechanistic model predicting changes in coral ecology and survival prospect. High-temperature tolerant clades and species will be revealed, allowing future bioremediation actions and establishment of coral refuges, saving corals and coral reefs for future generations.

3 332 032 €

Start date: 2010-06-01, End date: 2016-05-31

Coupling of atoms is the basis of chemistry, yielding the beauty and richness of molecules and materials. Herein I introduce nanocrystal chemistry: the use of semiconductor nanocrystals (NCs) as artificial atoms to form NC molecules that are chemically, structurally and physically coupled. The unique emergent quantum mechanical consequences of the NCs coupling will be studied and tailored to yield a chemical-quantum palette: coherent coupling of NC exciton states; dual color single photon emitters functional also as photo-switchable chromophores in super-resolution fluorescence microscopy; electrically switchable single NC photon emitters for utilization as taggants for neuronal activity and as chromophores in displays; new NC structures for lasing; and coupled quasi-1D NC chains manifesting mini-band formation, and tailored for a quantum-cascade effect for IR photon emission. A novel methodology of controlled oriented attachment of NC building blocks (in particular of core/shell NCs) will be presented to realize the coupled NCs molecules. For this a new type of Janus NC building block will be developed, and used as an element in a Lego-type construction of double quantum dots (dimers), heterodimers coupling two different types of NCs, and more complex NC coupled quantum structures. To realize this NC chemistry approach, surface control is essential, which will be achieved via investigation of the chemical and dynamical properties of the NCs surface ligands layer. As outcome I can expect to decipher NCs surface chemistry and dynamics, including its size dependence, and to introduce Janus NCs with chemically distinct and selectively modified surface faces. From this I will develop a new step-wise approach for synthesis of coupled NCs molecules and reveal the consequences of quantum coupling in them. This will inspire theoretical and further experimental work and will set the stage for the development of the diverse potential applications of coupled NC molecules.

2 499 750 €

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

CRISPR-Cas systems are microbial defense systems that provide prokaryotes with acquired and heritable DNA-based immunity against selfish genetic elements, primarily viruses. However, the full scope of benefits that these systems can provide, as well as their costs remain unknown. Specifically, it is unclear whether the benefits against viral infection outweigh the continual costs incurred even in the absence of parasitic elements, and whether CRISPR-Cas systems affect microbial genome diversity in nature. Since CRISPR-Cas systems can impede lateral gene transfer, it is often assumed that they reduce genetic diversity. Conversely, our recent results suggest the exact opposite: that these systems generate a high level of genomic diversity within populations. We have recently combined genomics of environmental strains and experimental genetics to show that archaea frequently acquire CRISPR immune memory, known as spacers, from chromosomes of related species in the environment. The presence of these spacers reduces gene exchange between lineages, indicating that CRISPR-Cas contributes to diversification. We have also shown that such inter-species mating events induce the acquisition of spacers against a strain's own replicons, supporting a role for CRISPR-Cas systems in generating deletions in natural plasmids and unessential genomic loci, again increasing genome diversity within populations. Here we aim to test our hypothesis that CRISPR-Cas systems increase within-population diversity, and quantify their benefits to both cells and populations, using large-scale genomics and experimental evolution. We will explore how these systems alter the patterns of recombination within and between species, and explore the potential involvement of CRISPR-associated proteins in cellular DNA repair. This work will reveal the eco-evolutionary role of CRISPR-Cas systems in shaping microbial populations, and open new research avenues regarding additional roles beyond anti-viral defense

2 495 625 €

Start date: 2018-05-01, End date: 2023-04-30

The severe combined immunodeficiencies (SCIDs) are a set of life threatening genetic diseases in which patients are born with mutations in single genes and are unable to develop functional immune systems. While allogeneic bone marrow transplantation can be curative for these diseases, there remain significant limitations to this approach. Gene therapy using viral vectors containing a corrective transgene is being developed for some of these disorders, most successfully for ADA-SCID. However, for other SCID disorders, such as those caused by genetic mutations in RAG1 and RAG2, the transgene needs to be expressed in a precise, developmental and lineage specific manner to achieve functional gene correction and to avoid the risks of cellular transformation. In contrast to using viral vectors to deliver transgenes in an uncontrolled fashion, we are working towards using genome editing by homologous recombination (HR) to correct the disease causing mutation by precisely modifying the genome. We have shown that by using clustered, regularly interspaced, short palindromic repeats (CRISPR) and the CRISPR-associated protein 9 (Cas9) system we can stimulate genome editing by HR at frequencies that should be therapeutically beneficial (>10%) in hematopoietic stem and progenitor cells (HSPCs). The overall focus of the proposal is to translate our basic science studies to use in RAG-SCID patient-derived HSPCs in methodical, careful and pre-clinically relevant fashion. The fundamental approach is to develop a highly active functional genome editing system using CRISPR-Cas9 for RAG-SCIDs and complete pre-clinical efficacy and safety studies to show the approach has a clear path towards future clinical trials. Our goal with this proposal is to develop the next wave of curative therapies for SCIDs and other hematopoietic disorders using genome editing.

1 372 839 €

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

Several organisms have evolved specialized ice binding proteins (IBPs) that prevent their body fluids from freezing (antifreeze proteins, AFPs), inhibit recrystallization of ice in frozen tissues, or initiate freezing at moderate supercooling temperatures (ice nucleating proteins, INPs). These proteins have many potential applications in agriculture, food preservation, cryobiology, and biomedical science. The ubiquitous presence of IBPs in such organisms indicates the power of these molecules to enable survival under cold conditions. Despite this key role in nature, however, IBPs have been effectively exploited in only one cryopreservation application, namely, recrystallization inhibition in ice cream. Several terrestrial organisms, including insects, have developed very active forms of AFPs. These hyperactive AFPs (hypAFPs) have not been utilized significantly thus far in cryopreservation techniques. The gap between the obvious potential of IBPs and their actual applications stems from a lack of knowledge regarding the mechanisms by which IBPs interact with ice surfaces and how these proteins can assist in cryoprotection. I propose to investigate the mechanism by which IBPs inhibit ice crystallization and the use of such proteins for cryopreserving cells, tissues, and organisms. My group has a strong record in the study of the interactions between IBPs and ice using novel methods that we have developed, including fluorescence microscopy techniques combined with cooled microfluidic devices. We will investigate the interactions of AFPs with ice and the use of hypAFPs in cryopreservation procedures. This research will contribute to an understanding of the mechanisms by which IBPs act, and apply the acquired knowledge to cryopreservation. The successful implementation of IBPs in cryopreservation would revolutionize the field of cryobiology, with enormous implications for cryopreservation applications in general and the frozen and chilled food industry in particular.

1 500 000 €

Start date: 2011-11-01, End date: 2016-10-31

The major causes of death in the Western world are cardiovascular diseases and cancer. More accurate detection of these diseases will improve clinical outcomes. Thus, we will develop unique X-ray contrast reagents for use in spectral computerized tomography (CT) that bind active proteases to reveal the exact location and stage of cancer and atherosclerosis. Activity-based probes (ABPs) are small molecules that covalently bind to active proteases. Based on our success in developing optical ABPs for non-invasive optical detection of cancer and atherosclerosis, we will focus on two novel types of reagents: (1) ABPs conjugated to the various contrast elements that can be visualized by x-rays. (2) “smart probes” conjugated to different contrast reagents on each side of the molecule to overcome clearance limitations. Protease found in diseased tissue will selectively bind and remove a part of the molecule, changing the physical properties of the bound probe. Thus, different signals from bound and unbound probes could be detected by photon counting spectral CT scanners. Our initial target, cysteine cathepsin proteases, are overexpressed and activated in cancer and arthrosclerosis. The level of active cathepsins correlates with progression of both diseases, thereby serving as a promising biomarker for these pathologies. The “smart probes” are an innovative type of spectral CT agent that will enable high-resolution rapid imaging in humans before probe clearance. Our probes increase imaging sensitivity since the contrast element remains at the desired site. Moreover, the levels of active cathepsins will reveal critical information regarding disease progression, yielding more accurate diagnoses and improved personalized treatment. For example, these reagents can distinguish between a vulnerable and stable atherosclerotic plaque. Thus, our novel probes will directly reduce cancer and cardiovascular disease mortality by enabling earlier and more accurate disease detection.

1 499 780 €

Start date: 2013-12-01, End date: 2018-11-30

The Inflammatory Bowel Diseases (IBD), Crohn’s Disease (CD) and Ulcerative Colitis (UC) are chronic/relapsing disorders that affect over six million individuals worldwide. Mucosal ulcers, the hallmark of CD, are the result of a complex interaction between microbiota, immune cells, and gut epithelia. Healing of mucosal ulcers is associated with better outcomes, but is achieved in less than half of cases. Past attempts to suppress central and conserved nodes of the immune system failed due to opposing off-target deleterious effects on epithelial renewal. Therefore, there is a critical need to identify more tissue specific targets that lead to mucosal healing and to improved outcomes. Using mRNAseq of intestinal biopsies, we identified a widespread dysregulation of long non-coding RNAs (lncRNA) in the ileum of treatment naïve pediatric CD patients. Importently, we identified significant correlations between lncRNA and mucosal ulcers. CD lncRNA, after carful mechanistic exploration, are highly promising targets for potential future intervention as they regulate diverse cellular functions and exhibit a more tissue specific expression in comparison to protein coding genes. The core goal of this proposal is to understand the role of CD lncRNA in ulcer pathogenesis focusing on granulocytes and epithelial functions in the contexts of their interactions with the microbiota. I plan to utilize state of the art informatics, RNAseq and microbiome profiles together with advanced and novel experimental lab model and co-culture systems, patients-derived prospectively collected tissues, and gut microbiota to explore the role of CD lncRNA function in mediating healing of mucosal ulcers. This work carries the potential to guide new novel therapeutic strategies for mucosal healing with minimal off-targets effects. In a broader prospective, this work will expand our relative limited understanding regarding the role of lncRNA in mediating human diseases.

1 500 000 €

Start date: 2018-05-01, End date: 2023-04-30

We target a frontier in nanocrystal science of combining disparate materials into a single hybrid nanosystem. This offers an intriguing route to engineer nanomaterials with multiple functionalities in ways that are not accessible in bulk materials or in molecules. Such control of novel material combinations on a single nanoparticle or in a super-structure of assembled nanoparticles, presents alongside with the synthesis challenges, fundamental questions concerning the physical attributes of nanoscale systems. My goals are to create new highly controlled hybrid nanoparticle systems, focusing on combinations of semiconductors and metals, and to decipher the fundamental principles governing doping in nanoparticles and charge and energy transfer processes among components of the hybrid systems. The research addresses several key challenges: First, in synthesis, combining disparate material components into one hybrid nanoparticle system. Second, in self assembly, organizing a combination of semiconductor (SC) and metal nanoparticle building blocks into hybrid systems with controlled architecture. Third in fundamental physico-chemical questions pertaining to the unique attributes of the hybrid systems, constituting a key component of the research. A first aspect concerns doping of SC nanoparticles with metal atoms. A second aspect concerns light-induced charge transfer between the SC part and metal parts of the hybrid constructs. A third related aspect concerns energy transfer processes between the SC and metal components and the interplay between near-field enhancement and fluorescence quenching effects. Due to the new properties, significant impact on nanocrystal applications in solar energy harvesting, biological tagging, sensing, optics and electropotics is expected.

2 499 000 €

Start date: 2010-06-01, End date: 2015-05-31

This project aims to explore the effects of human settlement intensity on desert ecological community structure, focusing on the hitherto unstudied phenomenon of trophic cascades in antiquity. Its key research question is whether human-induced changes in arid land biodiversity can feedback to affect natural resources important for human subsistence, such as pasture and wood. The role of such feedback effects in ecological systems is increasingly acknowledged in recent years in the biological literature but has not been addressed in the study of human past. The research question will be approached using bioarchaeological methods applied to the uniquely-preserved material record from the middle and late Holocene settlement sequence (approximately 4,500 BCE to 700 CE) of the Dead Sea Ein Gedi Oasis, and to the contemporary palaeontological assemblages from caves located in the surrounding Judean Desert. The proposed research is expected to bridge between aspects of current thinking on ecosystem dynamics and the study of human past by exploring the role of trophic cascades as an invisible dimension of Anthropocene life in marginal environments. The study of the history of human impact on such environments is important to resource management planning across a rapidly expanding ecological frontier on Earth, as climate deterioration brings more people in contact with life-sustaining and sensitive arid land ecosystems.

1 499 563 €

Start date: 2019-01-01, End date: 2023-12-31

Bacterial pathogens remain a significant threat to global health, necessitating a better understanding of host-pathogen biology. While various evidence point to early infection as a key event in the eventual progression to disease, our recent preliminary data show that during this stage, highly adaptable and dynamic host cells and bacteria engage in complex, diverse interactions that contribute to well-documented heterogeneous outcomes of infection. However, current methodologies rely on measurements of bulk populations, thereby overlooking this diversity that can trigger different outcomes. This application focuses on understanding heterogeneity during the first stages of infection in order to reduce the complexity of these interactions into informative readouts of population physiology and predictors of infection outcome. We will apply multiparametric single-cell analysis to obtain an accurate and complete description of infection with the enteric intracellular pathogen Salmonella of macrophages in vitro, and in early stages of mice colonization. We will characterize the molecular details that underlie distinct infection outcomes of individual encounters, to reconstruct the repertoire of host and pathogen strategies that prevail at critical stages of early infection. We propose the following three objectives: (1) Develop methodologies to simultaneously profile host and pathogen transcriptional changes on a single cell level; 2) Characterizing the molecular details that underlie the formation of subpopulations during macrophage infection; and (3) Determine how host and pathogen encounters in vivo result in emergence of specialized subpopulations, recruitment of immune cells and pathogen dissemination. We anticipate that this work will fundamentally shift our paradigms of infectious disease pathogenesis and lay the groundwork for the development of a new generation of therapeutic agents targeting the specific host-pathogen interactions ultimately driving disease.

1 499 999 €

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

Unsupervised visual inference can often be performed by exploiting the internal redundancy inside a single visual datum (an image or a video). The strong repetition of patches inside a single image/video provides a powerful data-specific prior for solving a variety of vision tasks in a “blind” manner: (i) Blind in the sense that sophisticated unsupervised inferences can be made with no prior examples or training; (ii) Blind in the sense that complex ill-posed Inverse-Problems can be solved, even when the forward degradation is unknown. While the above fully unsupervised approach achieved impressive results, it relies on internal data alone, hence cannot enjoy the “wisdom of the crowd” which Deep-Learning (DL) so wisely extracts from external collections of images, yielding state-of-the-art (SOTA) results. Nevertheless, DL requires huge amounts of training data, which restricts its applicability. Moreover, some internal image-specific information, which is clearly visible, remains unexploited by today's DL methods. One such example is shown in Fig.1. We propose to combine the power of these two complementary approaches – unsupervised Internal Data Recurrence, with Deep Learning, to obtain the best of both worlds. If successful, this will have several important outcomes including: • A wide range of low-level & high-level inferences (image & video). • A continuum between Internal & External training – a platform to explore theoretical and practical tradeoffs between amount of available training data and optimal Internal-vs-External training. • Enable totally unsupervised DL when no training data are available. • Enable supervised DL with modest amounts of training data. • New applications, disciplines and domains, which are enabled by the unified approach. • A platform for substantial progress in video analysis (which has been lagging behind so far due to the strong reliance on exhaustive supervised training data).

2 466 940 €

Start date: 2018-05-01, End date: 2023-04-30

Model theory deals with general classes of structures (called models). Specific examples of such classes are: the class of rings or the class of algebraically closed fields. It turns out that counting the so-called complete types over models in the class has an important role in the development of model theory in general and stability theory in particular. Stable classes are those with relatively few complete types (over structures from the class); understanding stable classes has been central in model theory and its applications. Recently, I have proved a new dichotomy among the unstable classes: Instead of counting all the complete types, they are counted up to conjugacy. Classes which have few types up to conjugacy are proved to be so-called ``dependent'' classes (which have also been called NIP classes). I have developed (under reasonable restrictions) a ``recounting theorem'', parallel to the basic theorems of stability theory. I have started to develop some of the basic properties of this new approach. The goal of the current project is to develop systematically the theory of dependent classes. The above mentioned results give strong indication that this new theory can be eventually as useful as the (by now the classical) stability theory. In particular, it covers many well known classes which stability theory cannot treat.

1 748 000 €

Start date: 2014-03-01, End date: 2019-02-28

Measurement based quantum computing is one of the most fault-tolerant architectures proposed for quantum information processing. It opens the possibility of performing quantum computing tasks using linear optical systems. An efficient route for measurement based quantum computing utilizes highly entangled states of photons, called cluster states. Propagation and processing quantum information is made possible this way using only single qubit measurements. It is highly resilient to qubit losses. In addition, single qubit measurements of polarization qubits is easily performed with high fidelity using standard optical tools. These features make photonic clusters excellent platforms for quantum information processing. Constructing photonic cluster states, however, is a formidable challenge, attracting vast amounts of research efforts. While in principle it is possible to build up cluster states using interferometry, such a method is of a probabilistic nature and entails a large overhead of resources. The use of entangled photon pairs reduces this overhead by a small factor only. We outline a novel route for constructing a deterministic source of photonic cluster states using a device based on semiconductor quantum dot. Our proposal follows a suggestion by Lindner and Rudolph. We use repeated optical excitations of a long lived coherent spin confined in a single semiconductor quantum dot and demonstrate for the first time practical realization of their proposal. Our preliminary demonstration presents a breakthrough in quantum technology since deterministic source of photonic cluster, reduces the resources needed quantum information processing. It may have revolutionary prospects for technological applications as well as to our fundamental understanding of quantum systems. We propose to capitalize on this recent breakthrough and concentrate on R&D which will further advance this forefront field of science and technology by utilizing the horizons that it opens.

2 502 974 €

Start date: 2016-06-01, End date: 2021-05-31

The communities of the Western Sephardic Diaspora were founded in the 16th and 17th centuries by New Christians from Iberia who returned to Judaism that had been abandoned by their ancestors in the late Middle Ages. This project will concentrate on the changes in the religious conceptions and behavior as well as the cultural patterns of the communities of Amsterdam, Hamburg, Leghorn, London, and Bordeaux. We will analyze the vigorous activity of their leaders to set the boundaries of their new religious identity in comparison to the policy of several Christian “communities of belief,” which went into exile following religious persecution in their homelands. We will also examine the changes in the attitude toward Judaism during the 17th century in certain segments of the Sephardic Diaspora: rather than a normative system covering every area of life, Judaism came to be seen as a system of faith restricted to the religious sphere. We will seek to explain the extent to which this significant change influenced their institutions and social behaviour. This study will provide us with better understanding of the place of the Jews in European society. At the same time, we will subject a central series of concepts in the historiographical discourse of the Early Modern Period to critical analysis: confessionalization, disciplinary revolution, civilizing process, affective individualism, etc. This phase of the research will be based on qualitative and quantitative analysis of many hundreds of documents, texts and the material remains of these communities. Using sociological and anthropological models, we will analyze ceremonies and rituals described at length in the sources, the social and cultural meaning of the architecture of the Sephardic synagogues of that time, and of other visual symbols.

1 671 200 €

Start date: 2012-03-01, End date: 2018-02-28

The goal of this research initiative is to construct large-scale computational modeling of how knowledge of the world emerges from the combination of innate mechanisms and visual experience. The ultimate goal is a ‘digital baby’ model which, through perception and interaction with the world, develops on its own representations of complex concepts that allow it to understand the world around it, in terms of objects, object categories, events, agents, actions, goals, social interactions, etc. A wealth of empirical research in the cognitive sciences have studied how natural concepts in these domains are acquired spontaneously and efficiently from perceptual experience, but a major open challenge is an understating of the processes and computations involved by rigorous testable models. To deal with this challenge we propose a novel methodology based on two components. The first, ‘computational Nativism’, is a computational theory of cognitively and biologically plausible innate structures , which guide the system along specific paths through its acquisition of knowledge, to continuously acquire meaningful concepts, which can be significant to the observer, but statistically inconspicuous in the sensory input. The second, ‘embedded interpretation’ is a new way of acquiring extended learning and interpretation processes. This is obtained by placing perceptual inference mechanisms within a broader perception-action loop, where the actions in the loop are not overt actions, but internal operation over internal representation. The results will provide new modeling and understanding of the age-old problem of how innate mechanisms and perception are combined in human cognition, and may lay foundation for a major research direction dealing with computational cognitive development.

1 647 175 €

Start date: 2011-06-01, End date: 2016-05-31

High-dimensional problems with a geometric flavor appear in quite a few branches of mathematics, mathematical physics and theoretical computer science. A priori, one would think that the diversity and the rapid increase of the number of configurations would make it impossible to formulate general, interesting theorems that apply to large classes of high-dimensional geometric objects. The underlying theme of the proposed project is that the contrary is often true. Mathematical developments of the last decades indicate that high dimensionality, when viewed correctly, may create remarkable order and simplicity, rather than complication. For example, Dvoretzky's theorem demonstrates that any high-dimensional convex body has nearly-Euclidean sections of a high dimension. Another example is the central limit theorem for convex bodies due to the PI, according to which any high-dimensional convex body has approximately Gaussian marginals. There are a number of strong motifs in high-dimensional geometry, such as the concentration of measure, which seem to compensate for the vast amount of different possibilities. Convexity is one of the ways in which to harness these motifs and thereby formulate clean, non-trivial theorems. The scientific goals of the project are to develop new methods for the study of convexity in high dimensions beyond the concentration of measure, to explore emerging connections with other fields of mathematics, and to solve the outstanding problems related to the distribution of volume in high-dimensional convex sets.

998 000 €

Start date: 2013-01-01, End date: 2018-12-31

There are many parallels between Lie group actions on homogeneous spaces and the action of $\SL_2(\R)$ and its subgroups on strata of translation or half-translation surfaces. I propose to investigate these two spaces in parallel, focusing on the dynamical behavior, and more specifically, the description of orbit-closures. I intend to utilize existing and emerging measure rigidity results, and to develop new topological approaches. These should also shed light on the geometry and topology of the spaces. I propose to apply results concerning these spaces to the study of diophantine approximations (approximation on fractals), geometry of numbers (Minkowski's conjecture), interval exchanges, and rational billiards.

850 000 €

Start date: 2011-10-01, End date: 2016-09-30

Transcription factors (TF) regulate genome function by controlling gene expression. Comprehensive characterization of the in vivo binding of TF to the DNA in relevant primary models is a critical step towards a global understanding of the human genome. Recent advances in high-throughput genomic technologies provide an extraordinary opportunity to develop and apply systematic approaches to learn the underline principles and mechanisms of mammalian transcriptional networks. The premise of this proposal is that a tractable set of rules govern how cells commit to a specific cell type or respond to the environment, and that these rules are coded in regulatory elements in the genome. Currently our understanding of the mammalian regulatory code is hampered by the difficulty of directly measuring in vivo binding of large numbers of TFs to DNA across multiple primary cell types and their natural response to physiological stimuli. Here, we overcome this bottleneck by systematically exploring the genomic binding network of 1. All relevant TFs of key hematopoietic cells in both steady state and under relevant stimuli. 2. Follow the changes in TF networks as cells differentiate 3. Use these models to engineer cell states and responses. To achieve these goals, we developed a new method for automated high throughput ChIP coupled to sequencing (HT-ChIP-Seq). We used this method to measure binding of 40 TFs in 4 time points following stimulation of dendritic cells with pathogen components. We find that TFs vary substantially in their binding dynamics, genomic localization, number of binding events, and degree of interaction with other TFs. The analysis of this data suggests that the TF network is hierarchically organized, and composed of different types of TFs, cell differentiation factors, factors that prime for gene induction, and factors that bind more specifically and dynamically. This proposal revisits and challenges the current understanding of the mammalian regulatory code.

1 500 000 €

Start date: 2012-10-01, End date: 2017-09-30

Deep packet inspection (DPI) lies at the core of contemporary Network Intrusion Detection/Prevention Systems and Web Application Firewall. DPI aims to identify various malware (including spam and viruses), by inspecting both the header and the payload of each packet and comparing it to a known set of patterns. DPI are often performed on the critical path of the packet processing, thus the overall performance of the security tools is dominated by the speed of DPI. Traditionally, DPI considered only exact string patterns. However, in modern network devices patterns are often represented by regular expressions due to their superior expressiveness. Matching both exact string and regular expressions are well-studied area in Computer Science; however all well-known solutions are not sufficient for current network demands: First, current solutions do not scale in terms of speed, memory and power requirements. While current network devices work at 10-100 Gbps and have thousands of patterns, traditional solutions suffer from exponential memory size or exponential time and induce prohibitive power consumption. Second, non clear-text traffic, such as compressed traffic, becomes a dominant portion of the Internet and is clearly harder to inspect. In this research we design new algorithms and schemes that cope with today demand. This is evolving area both in the Academia and Industry, where currently there is no adequate solution. We intend to use recent advances in hardware to cope with these demanding requirements. More specifically, we plan to use Ternary Content-Addressable Memories (TCAMs), which become standard commodity in contemporary network devices. TCAMs can compare a key against all rules in a memory in parallel and thus provide high throughput. We believ

990 400 €

Start date: 2010-11-01, End date: 2016-10-31

Optical microscopy, perhaps the most important tool in biomedical investigation and clinical diagnostics, is currently held back by the assumption that it is not possible to noninvasively image microscopic structures more than a fraction of a millimeter deep inside tissue. The governing paradigm is that high-resolution information carried by light is lost due to random scattering in complex samples such as tissue. While non-optical imaging techniques, employing non-ionizing radiation such as ultrasound, allow deeper investigations, they possess drastically inferior resolution and do not permit microscopic studies of cellular structures, crucial for accurate diagnosis of cancer and other diseases. I propose a new kind of microscope, one that can peer deep inside visually opaque samples, combining the sub-micron resolution of light with the penetration depth of ultrasound. My novel approach is based on our discovery that information on microscopic structures is contained in random scattered-light patterns. It breaks current limits by exploiting the randomness of scattered light rather than struggling to fight it. We will transform this concept into a breakthrough imaging platform by combining ultrasonic probing and modulation of light with advanced digital signal processing algorithms, extracting the hidden microscopic structure by two complementary approaches: 1) By exploiting the stochastic dynamics of scattered light using methods developed to surpass the diffraction limit in optical nanoscopy and for compressive sampling, harnessing nonlinear effects. 2) Through the analysis of intrinsic correlations in scattered light that persist deep inside scattering tissue. This proposal is formed by bringing together novel insights on the physics of light in complex media, advanced microscopy techniques, and ultrasound-mediated imaging. It is made possible by the new ability to digitally process vast amounts of scattering data, and has the potential to impact many fields.

1 500 000 €

Start date: 2016-04-01, End date: 2021-03-31

A novel type of defense system was recently identified in bacteria: the CRISPR array and its associated gene products (Cas). The system inserts short DNA sequences, called spacers, derived from foreign nucleic acid molecules in between direct repeats, thus forming the CRISPR array. The transcribed spacers eventually serve as molecular guides for Cas proteins that monitor and destroy nucleic acids having sequences similar to those spacers. Thorough mapping of the functional components and regulators of the system in a single model organism will be extremely valuable for understanding its mechanism of action. Studying the interactions between bacteria and phages should highlight the evolutionary role of the system and its consequences for shaping ecological systems. These insights will lead to novel ways of exploiting the system to improve molecular biology tools, to protect fermenting bacteria from phage spoilage, to equip phages with anti-CRISPR warfare to fight bacteria, and to prevent horizontal gene transfer between pathogens. Here, I intend to systematically seek out new roles of the system and to identify fundamental mechanisms and components that allow the system to function efficiently. I will address fundamental questions such as how the system avoids sampling self DNA into the CRISPR array. In addition, I will pursue two revolutionary possibilities. One, that the CRISPR/Cas system is not merely an adaptive defense system against phages, but that one of its roles is to serve as molecular machinery for silencing specific harmful genes by generating small silencing RNAs without the need for Cas proteins. The other is to test the system’s ability to prevent horizontal gene transfer of antibiotic resistance genes in an effort to study the system’s ecological value, potentially for applicative uses. My proposed studies will allow deeper understanding of the system, and enable breakthroughs from both basic and applicative aspects of the CRISPR field studies.

1 499 000 €

Start date: 2013-12-01, End date: 2018-11-30

This proposal aims to advance a new general theory that links plasticity in prey responses to predation and biogeochemical processes to explain context-dependent variations in ecosystem functioning. The physiological reaction of prey to predation involves allocating resources from production to support emergency functions. An example of such a reaction is an increase in maintenance respiration concomitant with higher carbohydrate and lower N demand. Such changes in prey energy and elemental budget should alter the role prey play in regulating the quality of detrital inputs to soils. Nutrient content of detritus is an important determinant of the way soil communities regulate ecosystem processes. Thus, the physiological reaction of prey to predation can potentially explicate changes in ecosystem functioning. My first empirical examination of a few selected mechanisms of this theory has yielded very promising insights. The main objectives of this proposal are: (1) To systematically test whether prey reactions to predation are consistent with the proposed theory’s predictions across species and ecosystems; (2) to examine the interface between stress physiology and anti-predatory behaviors in explaining predator induced diet shift, and (3) to evaluate how predator induced responses at the individual level regulate ecosystem processes. To address these objectives, I propose combining manipulative field experiments, highly controlled laboratory and garden experiments, and stable-isotopes pulse chase approaches. I will examine individual prey responses and the emerging patterns across five food-chains that represent phylogenetically distant taxa and disparate ecosystems. The proposed study is expected to revolutionize our understanding of the mechanisms by which aboveground predators regulate ecosystem processes. Promoting such a mechanistic understanding is crucial to predict how human-induced changes in biodiversity will affect life-supporting ecosystem services.

1 379 600 €

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

The vast majority of published research on the impact of school interventions has examined their effects on short-run outcomes, primarily test scores. While important, a possibly deeper question of interest to society is the impact of such interventions on long-run life outcomes. This is a critical question because the ultimate goal of education is to improve lifetime well-being. Recent research has begun to look at this issue but much work remains to be done, particularly with regard to the long-term effects of interventions explicitly targeting improvement in general quality and students’ educational attainment. This proposal examines the impact of seven different schooling interventions – teachers’ quality, school quality, remedial education, school choice, teacher incentive payments, students' conditional cash transfers and an experiment with an increase in the return to schooling – on long-run life outcomes, including educational attainment, employment, income, marriage and fertility, crime and welfare dependency. To address this important question I will exploit unique data from seven experimental programs and natural experiments implemented simultaneously at different schools in Israel. All programs were successful in achieving their short-term objectives, though the cost of the programs varied. This undertaking presents a unique context with unusual data and very compelling empirical settings. I will examine whether these programs also achieved a longer-term measure of success by improving students’ life outcomes. Another unique feature of the proposed study is that the interventions vary widely and touch on some emergent educational trends. The body of empirical evidence from this study will provide a more complete picture of the individual and social returns from these educational interventions, and will allow policymakers to make more informed decisions when deciding which educational programs lead to the most beneficial use of limited school resources.

1 519 000 €

Start date: 2013-05-01, End date: 2019-04-30

Membrane fusion is a universal process essential inside cells (endoplasmic) and between cells in fertilization and organ formation (exoplasmic). With the exception of SNARE-mediated endoplasmic fusion the proteins that mediate cellular fusion (fusogens) are unknown. Despite many years of research, little is known about the mechanism of cell-cell fusion. Our studies of developmental cell fusion in the nematode C. elegans have led to the discovery of the first family of eukaryotic fusogens (FF). These fusogens, EFF-1 and AFF-1, are type I membrane glycoproteins that are essential for cell fusion and can fuse cells when ectopically expressed on the membranes of C. elegans and heterologous cells. Our main goals are: (1) To determine the physicochemical mechanism of cell membrane fusion mediated by FF proteins. (2) To find the missing fusogens that act in cell fusion events across all kingdoms of life. We hypothesize that FF proteins fuse membranes by a mechanism analogous to viral or endoplasmic fusogens and that unidentified fusogens fuse cells following the same principles as FF proteins. Our specific aims are: AIM 1 Determine the mechanism of FF-mediated cell fusion: A paradigm for cell membrane fusion AIM 2 Find the sperm-egg fusion proteins (fusogens) in C. elegans AIM 3 Identify the myoblast fusogens in mammals AIM 4 Test fusogens using functional cell fusion assays in heterologous systems Identifying critical domains required for FF fusion, intermediates in membrane remodeling, and atomic structures of FF proteins will advance the fundamental understanding of the mechanisms of eukaryotic cell fusion. We propose to find the Holy Grail of fertilization and mammalian myoblast fusion. We estimate that this project, if successful, will bring a breakthrough to the sperm-egg and muscle fusion fields with potential applications in basic and applied biomedical sciences.

2 380 000 €

Start date: 2011-05-01, End date: 2016-04-30

Cellular senescence, which is a terminal cell cycle arrest, is a potent tumor suppressor mechanism that limits cancer initiation and progression; it also limits tissue damage response. While senescence is protective in the cell autonomous manner, senescent cells secrete a variety of factors that lead to inflammation, tissue destruction and promote tumorigenesis and metastasis in the sites of their presence. Here we propose a unique approach – to eliminate senescent cells from tissues in order to prevent the deleterious cell non-autonomous effects of these cells. We will use our understanding in immune surveillance of senescent cells, and in cell-intrinsic molecular pathways regulating cell viability, to identify the molecular “Achilles’ heal” of senescent cells. We will identify the mechanisms of interaction of senescent cells with NK cells and other immune cells, and harness these mechanisms for elimination of senescent cells. The impact of components of the main pathways regulating cell viability, apoptosis and autophagy, will then be evaluated for their specific contribution to the viability of senescent cells. The molecular players identified by all these approaches will be readily implemented for the elimination of senescent cells in vivo. We will consequently be able to evaluate the impact of the elimination of senescent cells on tumor progression, in mouse models, where these cells are present during initial stages of tumorigenesis. Additionally, we will develop a novel mouse model that will allow identification of senescent cells in vivo in real time. This model is particularly challenging and valuable due to absence of single molecular marker for senescent cells. The ability to eliminate senescent cells will lead to the understanding of the role of presence of senescent cells in tissues and the mechanisms regulating their viability. This might suggest novel ways of cancer prevention and treatment.

1 500 000 €

Start date: 2012-11-01, End date: 2017-10-31

Understanding how the Milky Way arrived at its present state requires a large volume of precision measurements of our Galaxy’s current makeup, as well as an empirically based understanding of the main processes involved in the Galaxy’s evolution. Such data are now about to arrive in the flood of quality information from Gaia and SDSS-V. The demography of the stars and of the compact stellar remnants in our Galaxy, in terms of phase-space location, mass, age, metallicity, and multiplicity are data products that will come directly from these surveys. I propose to integrate this information into a comprehensive picture of the Milky Way’s present state. In parallel, I will build a Galactic chemical evolution model, with input parameters that are as empirically based as possible, that will reproduce and explain the observations. To get those input parameters, I will measure the rates of supernovae (SNe) in nearby galaxies (using data from past and ongoing surveys) and in high-redshift proto-clusters (by conducting a SN search with JWST), to bring into sharp focus the element yields of SNe and the distribution of delay times (the DTD) between star formation and SN explosion. These empirically determined SN metal-production parameters will be used to find the observationally based reconstruction of the Galaxy’s stellar formation history and chemical evolution that reproduces the observed present-day Milky Way stellar population. The population census of stellar multiplicity with Gaia+SDSS-V, and particularly of short-orbit compact-object binaries, will hark back to the rates and the element yields of the various types of SNe, revealing the connections between various progenitor systems, their explosions, and their rates. The plan, while ambitious, is feasible, thanks to the data from these truly game-changing observational projects. My team will perform all steps of the analysis and will combine the results to obtain the clearest picture of how our Galaxy came to be.

1 859 375 €

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

Intractable conflicts are one of the gravest challenges to both humanity and science. These conflicts are initiated and perpetuated by people; therefore changing people's hearts and minds constitutes a huge step towards resolution. Research on emotions in conflicts has led to the realization that intergroup emotions are critical to conflict dynamics. This project’s intrinsic question is whether and how intergroup emotions can be regulated to alter attitudes and behavior towards peace. I offer an innovative path, using two strategies of emotion regulation. The first is Direct Emotion Regulation, where traditional, effective emotion regulation strategies can be used to change intergroup emotional experiences and subsequently political positions in conflict situations. The second, Indirect Emotion Regulation, serves to implicitly alter concrete cognitive appraisals, thus changing attitudes by changing discrete emotions. This is the first attempt ever to integrate psychological aggregated knowledge on emotion regulation with conflict resolution. I propose 16 studies, conducted in the context of the intractable Israeli-Palestinian conflict. Seven studies will focus on direct emotion regulation, reducing intergroup anger and hatred, while 9 studies will focus on indirect regulation, aspiring to reduce fear and despair. In both paths, correlational and in-lab experimental studies will be used to refine adequate strategies of down regulating destructive emotions, the results of which will be used to develop innovative, theory-driven education and media interventions that will be tested utilizing wide scale experience sampling methodology. This project aspires to bridge the gap between basic and applied science, creating a pioneering, interdisciplinary framework which contributes to existing knowledge on emotion regulation in conflict and implements ways to apply it in real-world circumstances.

1 499 344 €

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

Vascularization, the process in which new blood vessels assemble, is fundamental to tissue vitality. Vessel network assembly within 3D tissues can be induced in-vitro by means of multicellular culturing of endothelial cells (EC), fibroblasts and cells specific to the tissue of interest. This approach supports formation of endothelial vessels and promotes EC and tissue-specific cell interactions. Such EC-dependent tube-like openings may also form the basis for improved media penetration to the inner regions of thick 3D constructs, allowing for enhanced construct survival and for effective engineering of large complex tissues in the lab. Moreover, our own breakthrough results describe the beneficial impact of in vitro prevascularization of engineered muscle tissue on its survival and vascularization upon implantation. These studies have also demonstrated that implanted vascular networks of in vitro engineered constructs, can anastomose with host vasculature and form functional blood vessels in vivo. However, the mechanisms underlying enhanced vascularization of endothelialized engineered constructs and implant-host vessel integration remain unclear. In this proposal, our research objectives are (1) to uncover the mechanisms governing in vitro vessel network formation in engineered 3D tissues and (2) to elucidate the process of graft-host vessel network integration and implant vessel-stimulated promotion of neovascularization in vivo. In addition, the impact of construct prevascularization on implant survival and function will be explored in animal disease models. While there are still many challenges ahead, should we succeed, our research could lay the foundation for significantly enhanced tissue construct vascularization procedures and for their application in regenerative medicine. In addition, it may provide alternative models for studying the vascularization processes in embryogenesis and disease.

1 500 000 €

Start date: 2012-10-01, End date: 2017-09-30

The last decade has witnessed a new spring for dynamical systems. The field - initiated by Poincare in the study of the N-body problem - has become essential in the understanding of seemingly far off fields such as combinatorics, number theory and theoretical computer science. In particular, ideas from ergodic theory played an important role in the resolution of long standing open problems in combinatorics and number theory. A striking example is the role of dynamics on nilmanifolds in the recent proof of Hardy-Littlewood estimates for the number of solutions to systems of linear equations of finite complexity in the prime numbers. The interplay between ergodic theory, number theory and additive combinatorics has proved very fruitful; it is a fast growing area in mathematics attracting many young researchers. We propose to tackle central open problems in the area.

1 342 500 €

Start date: 2016-05-01, End date: 2021-04-30

"Gene expression in living cells is a most intricate molecular process, occurring in stages, each of which is regulated by a diversity of mechanisms. Among the various stages leading to gene expression, only transcription is relatively well understood, thanks to Genomics and bioinformatics. In contrast to the vast amounts of genome-wide data and a growing understanding of the structure of networks controlling transcription, we still lack quantitative, genome-wide knowledge of the mechanisms underlying regulation of mRNA degradation and translation. Among the unknowns are the identity of the regulators, their kinetic modes of action, and their means of interaction with the sequence features that make-up their targets; how these target combine to produce a higher level ""grammar"" is also unknown. An important part of the project is dedicated to generating genome-wide experimental data that will form the basis for quantitative and more comprehensive analysis of gene expression. Specifically, the primary objectives of our proposed research plan are: 1) to advance our understanding of the transcriptome, by deciphering the code regulating mRNA decay 2) to break the code which controls protein translation efficiency 3) to understand how mRNA degradation and translation efficiency determine noise in protein expression levels. The proposed strategy is based on an innovative combination of computational prediction, synthetic gene design, and genome-wide data acquisition, all culminating in extensive data analysis, mathematical modeling and focused experiments. This highly challenging, multidisciplinary project is likely to greatly enhance our knowledge of the various modes by which organisms regulate expression of their genomes, how these regulatory mechanisms are interrelated, how they generate precise response to environmental challenges and how they have evolved over time."

1 320 000 €

Start date: 2008-09-01, End date: 2013-08-31

ETASECS aims at making a breakthrough in the development of photoelectrochemical (PEC) cells for solar-powered water splitting that can be readily integrated with PV cells to provide storage capacity in the form of hydrogen. It builds upon our recent invention for resonant light trapping in ultrathin films of iron oxide (a-Fe2O3), which enables overcoming the deleterious trade-off between light absorption and charge carrier collection efficiency. Although we recently broke the water photo-oxidation record by any a-Fe2O3 photoanode reported to date, the losses are still high and there is plenty of room for further improvements that will lead to a remakable enhancement in the performance of our photoanodes, reaching quantum efficiency level similar to state-of-the-art PV cells. ETASECS aims at reaching this ambitious goal, which is essential for demonstrating the competitiveness of PEC+PV tandem systems for solar energy conversion and storage. Towards this end WP1 will combine theory, modelling and simulations, state-of-the-art experimental methods and advanced diagnostic techniques in order to identify and quantify the different losses in our devices. This work will guide the optimization work in WP2 that will suppress the losses at the photoanode and insure optimal electrical and optical coupling of the PEC and PV cells. We will also explore advanced photon management schemes that will go beyond our current light trapping scheme by combining synergic optical and nanophotonics effects. WP3 will integrate the PEC and PV cells and test their properties and performance. WP4 will disseminate our progress and achievements in professional and public forums. The innovations that will emerge from this frontier research will be further pursued in proof of concept follow up investigations that will demonstrate the feasibility of this technology. Success along these lines holds exciting promises for ground breaking progress towards large scale deployment of solar energy.

2 150 000 €

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

"The first part of this project is about employment in Europe, including the new members of the European Union. Both the level of employment and the type of jobs created will be examined. A thorough study of institutional structures and policies is proposed, with a view to arriving at conclusions about their influence on job creation and about the best policy needed to achieve national or European-level employment objectives. Job creation is investigated at the two-digit level and male and female employment, wage inequality and the role of policy will be studied in depth. The research will build on solid theoretical microfoundations taking into account the choices available to firms and workers/consumers about working at home or in the market and buying domestic or foreign goods. The project has a second part about unemployment, with special emphasis on recession. The same emphasis on institutions and policies as for employment is given to this part. A key component of the project is new theory on the evolution of institutions and policies in markets with friction, and on the impact that the policy changes that took place after the recession of the 1980s have had on the responses of European labour markets to the recent recession. Special attention will be given to the formerly planned economies and the reasons for their slow convergence to the western economies."

2 200 143 €

Start date: 2013-06-01, End date: 2018-05-31

Bacterial cooperation underlies many bacterial traits of practical interest. Many social traits of bacteria are regulated by inter-cellular signalling pathways, generally known as quorum sensing (QS). QS has been proposed as novel target for anti-virulence treatment. To this aim, there is a need to better understand the mechanisms of QS and their social and evolutionary impact. While the basic schemes of a single quorum sensing pathway acting in homogenous conditions are well understood, the system’s level function of QS regulatory networks can only be appreciated by considering the role phenotypic and genetic variability has on shaping the network’s structure and function. Phenotypic variability in complex communities may arise from division of labour between cells and environmental gradients and substantially impact the way cells secrete and interpret QS signals. Genetic variability in QS networks may lead to multiple social relations between cells of different genotypes including cross-talks, interception, manipulation and quenching of signals. This will affect the population structure and performance. The proposed project will study the function of QS signalling in heterogeneous communities. Phenotypic variability and its impact on QS function will be studied in a spatially inhomogeneous cooperating system. Genetic variability will be studied at the macro and micro-scales in a bacterial species showing rapid diversification of their QS networks. Finally, we will rationally design strains with superior ‘cheating’ strategies that can invade and eliminate a cooperative population. Throughout this project, we will use a combination of experimental techniques from microbiology, socio-biology, genetics and microscopy together with mathematical analysis tools from systems biology, population genetics and game theory, to study bacterial cooperation and its dependence on the underlying communication network, social complexity and environmental variation.

1 497 996 €

Start date: 2012-01-01, End date: 2016-12-31

Soon after new antibiotics are introduced, bacterial strains resistant to their action emerge. Recently, non-specific factors that promote the later appearance of specific mechanisms of resistance have been found. Some of these so-called global factors (as opposed to specific resistance mechanisms) emerge as major players in shaping the rate of evolution of resistance. For example, a mutation in the mismatch repair system is a global genetic factor that increases the mutation rate and therefore leads to an increased probability to evolve resistance. In addition to global genetic factors, it is becoming clear that global phenotypic factors play a crucial role in resistance evolution. For example, activation of stress responses can also result in an elevated mutation rate and accelerated evolution of drug resistance. A natural question which arises in this context is how sub-populations of phenotypic variants differ in their evolutionary potential, and how that, in turn, affects the rate at which an entire population adapts to antibiotic stress. I propose a multidisciplinary approach to the systematic and quantitative study of the non-specific factors that affect the mode and tempo of evolution towards antibiotic resistance. Our preliminary results indicate that the presence of dormant bacteria that survive antibiotic treatment affects the rate of resistance evolution in bacterial populations. I will exploit the established expertise of my lab using microfluidic devices for single cell analyses to track the emergence of resistance at the single-cell level, in real-time, and to study the correlation between the phenotype of single bacteria and the probability to evolve resistance. My second approach will take advantage of the recent developments in experimental evolution and high throughput sequencing and combine those with single cells observations for the systematic search of E.coli genes that affect the rate of resistance evolution. We will study replicate populations of E.coli, founded by either laboratory strains or clinical isolates, as they evolve in parallel, under antibiotic stress. Evolved populations will be compared with ancestral populations in order to identify genes and phenotypes that have changed during the evolution of antibiotic resistance. Finally, in silico evolution that simulates the experimental conditions will be developed to analyze the contribution of global factors on resistance evolution. The evolution of antibiotic resistance is not only a fascinating demonstration of the power of evolution but also represents one of the major health threats today. I anticipate that this multidisciplinary study of the global factors that influence the evolution of resistance, from the single cell to the population level, will shed light on the mechanisms used by bacteria to accelerate evolution in general, as well as provide clues as to how to prevent the emergence of antibiotic resistance.

1 458 200 €

Start date: 2010-11-01, End date: 2015-10-31

How embryonic stem cells (ESCs) maintain their dual capacity to self-renew and to differentiate into all cell types is one of the fundamental questions in biology. Although this question remains largely open, there is growing evidence suggesting that chromatin plasticity is a fundamental hallmark of ESCs, providing their necessary flexibility. Previously we found that ESCs possess a relatively open chromatin conformation, giving rise to permissive transcriptional program. Here I propose to investigate the mechanisms that support chromatin plasticity and pluripotency in ESCs. Using a simple biochemical assay which I developed (DCAP: Differential Chromatin Associated Proteins), based on micrococcal nuclease (MNase) digestion combined with multi-dimensional protein identification technology (MudPIT), I seek to identify ESC-specific chromatin proteins. Selected proteins will be knocked-down (or out) and their ESC function will be evaluated. In addition, I will conduct a hypothesis-driven research using mutant ESCs and epigenetic-related drugs to search for potential mechanisms, (i.e. histone modifications, DNA methylation), that may support chromatin plasticity in ESCs. Based on our intriguing preliminary data, I will also focus on the link between the nuclear lamina and ESC plasticity. Thirdly, we will analyze non-polyadenylated transcription using genome-wide tiling arrays and RNA-seq. We will design custom microarrays containing the identified sequences, which will allow us to reveal, using ChIP-chip experiments, the mechanistic regulation of the non-polyadenylated transcripts. Finally, we will knockout, using zinc-finger nuclease technology, selected highly conserved candidates in search of their function. Understanding chromatin regulation, plasticity and function will enable one to intelligently manipulate ESCs to transition between the pluripotent, multipotent and unipotent states and to expedite their use in the clinic.

1 500 000 €

Start date: 2011-12-01, End date: 2016-11-30

Combinatorics is an extremely fast growing mathematical discipline. While it started as a collection of isolated problems that were tackled using ad-hoc arguments it has since grown into a mature discipline which both incorporated into it deep tools from other mathematical areas, and has also found applications in other mathematical areas such as Additive Number Theory, Theoretical Computer Science, Computational Biology and Information Theory. The PI will work on a variety of problems in Extremal Combinatorics which is one of the most active subareas within Combinatorics with spectacular recent developments. A typical problem in this area asks to minimize (or maximize) a certain parameter attached to a discrete structure given several other constrains. One of the most powerful tools used in attacking problems in this area uses the so called Structure vs Randomness phenomenon. This roughly means that any {\em deterministic} object can be partitioned into smaller quasi-random objects, that is, objects that have properties we expect to find in truly random ones. The PI has already made significant contributions in this area and our goal in this proposal is to obtain further results of this caliber by tackling some of the hardest open problems at the forefront of current research. Some of these problems are related to the celebrated Hypergraph and Arithmetic Regularity Lemmas, to Super-saturation problems in Additive Combinatorics and Graph Theory, to problems in Ramsey Theory, as well as to applications of Extremal Combinatorics to problems in Theoretical Computer Science. Another major goal of this proposal is to develop new approaches and techniques for tackling problems in Extremal Combinatorics. The support by means of a 5-year research grant will enable the PI to further establish himself as a leading researcher in Extremal Combinatorics and to build a vibrant research group in Extremal Combinatorics.

1 221 921 €

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

Standard spacecraft designs comprise modules assembled in a single monolithic structure. When unexpected situations occur, the spacecraft are unable to adequately respond, and significant functional and financial losses are unavoidable. For instance, if the payload of a spacecraft fails, the whole system becomes unserviceable and substitution of the entire spacecraft is required. It would be much easier to replace the payload module only than launch a completely new satellite. This idea gives rise to an emerging concept in space engineering termed disaggregated spacecraft. Disaggregated space architectures (DSA) consist of several physically-separated modules, interacting through wireless communication links to form a single virtual platform. Each module has one or more pre-determined functions: Navigation, attitude control, power generation and payload operation. The free-flying modules, capable of resource sharing, do not have to operate in a tightly-controlled formation, but are rather required to remain in bounded relative position and attitude, termed cluster flying. DSA enables novel space system architectures, which are expected to be much more efficient, adaptable, robust and responsive. The main goal of the proposed research is to develop beyond the state-of-the-art technologies in order to enable operational flight of DSA, by (i) developing algorithms for semi-autonomous long-duration maintenance of a cluster and cluster network, capable of adding and removing spacecraft modules to/from the cluster and cluster network; (ii) finding methods so as to autonomously reconfigure the cluster to retain safety- and mission-critical functionality in the face of network degradation or component failures; (iii) designing semi-autonomous cluster scatter and re-gather maneuvesr to rapidly evade a debris-like threat; and (iv) validating the said algorithms and methods in the Distributed Space Systems Laboratory in which the PI serves as a Principal Investigator.

1 500 000 €

Start date: 2011-10-01, End date: 2016-09-30

Anxiety and stress-related conditions represent a significant health burden in modern society. Anxiety disorders are currently treated with a variety of agents targeting synaptic mechanisms. These agents either directly affect neurotransmitter receptor systems or modulate neurotransmitter levels or availability, but their long-term use is limited by problematic side effects and suboptimal efficacy. The development of new anxiolytic drugs has been fraught with difficulty, hence there is a need for new targets and new avenues for therapeutic development. Importin-dependent transport mechanisms link synapse to nucleus in a diversity of physiological contexts, rendering them potentially interesting targets for behavioural control. However importins and related molecules have not been evaluated for roles in anxiolysis to date. We discovered the roles of importins in axonal injury signaling and in cell size sensing. During the course of our current ERC Advanced grant, and as part of one of the aims, we have conducted comprehensive phenotyping of importin mouse mutants to identify in vivo consequences of the deregulation of size control pathways. One importin mutant line presented a specific phenotype in anxiety tests, and follow-up analyses identified a new molecular pathway for anxiety regulation, and approved drugs affecting this pathway that can be repositioned for anxiety treatment. In this PoC, we will (1) carry out IP protection on our initial identifications of anxiolytic drugs; (2) further validate the anxiolytic activities of these drugs and their closely related structural or functional analogs; and (3) devise an HTS-compatible assay for targeting the importin involved and conduct a pilot screen of ~200,000 compounds in this assay to identify new drug leads for anxiety treatment. As a final step, we will carry out (4) additional IP protection and pre-commercialisation tasks for maximizing the commercialisation potential of our discovery.

150 000 €

Start date: 2017-11-01, End date: 2019-04-30

"The emergence of networked embedded systems and sensor/actuator networks has facilitated the development of advanced monitoring and control applications, where a large amount of sensor data is collected and processed in real-time in order to activate the appropriate actuators and achieve the desired control objectives. However, in situations where a fault arises in some of the components (e.g., sensors, actuators, communication links), or an unexpected event occurs in the environment, this may lead to a serious degradation in performance or, even worse, to an overall system failure. There is a need to develop a systematic framework to enhance the reliability, fault-tolerance and sustainability of complex distributed dynamical systems through the use of fault-adaptive monitoring and control methods. The work proposed here will contribute to the development of such a framework with emphasis on applications related to critical infrastructure systems (e.g., power, water, telecommunications and transportation systems). It will provide an innovative approach based on the use of networked intelligent agent systems, where the state of the infrastructure is monitored and controlled by a network of sensors and actuators with cooperating agents for fault diagnosis and fault tolerant control. A hierarchical fault diagnosis architecture will be developed, with neighbouring fault diagnosis agents cooperating at a local level, while transmitting their information, as needed, to a regional monitoring agent, responsible for integrating in real-time local information into a large-scale “picture” of the health of the infrastructure. A key motivation is to exploit spatial and temporal correlations between measured variables using learning methods, and to develop the tools and design methodologies that will prevent relatively “small” faults or unexpected events from causing significant disruption or complete system failures in complex distributed dynamical systems."

2 035 200 €

Start date: 2012-04-01, End date: 2018-03-31

We will study phase transitions and chemical and biological reactions in liquid mixtures in electric field gradients. These new phase transitions are essential in statistical physics and thermodynamics. We will examine theoretically the complex and yet unexplored phase ordering dynamics in which droplets nucleate and move under the external nonuniform force. We will look in detail at the interfacial instabilities which develop when the field is increased. We will investigate how time-varying potentials produce electromagnetic waves and how their spatial decay in the bistable liquid leads to phase changes. These transitions open a new and general way to control the spatio-temporal behaviour of chemical reactions by directly manipulating the solvents' concentrations. When two or more reagents are preferentially soluble in one of the mixture's components, field-induced phase separation leads to acceleration of the reaction. When the reagents are soluble in different solvents, field-induced demixing will lead to the reaction taking place at a slow rate and at a two-dimensional surface. Additionally, the electric field allows us to turn the reaction on or off. The numerical study and simulations will be complemented by experiments. We will study theoretically and experimentally biochemical reactions. We will find how actin-related structures are affected by field gradients. Using an electric field as a tool we will control the rate of actin polymerisation. We will investigate if an external field can damage cancer cells by disrupting their actin-related activity. The above phenomena will be studied in a microfluidics environment. We will elucidate the separation hydrodynamics occurring when thermodynamically miscible liquids flow in a channel and how electric fields can reversibly create and destroy optical interfaces, as is relevant in optofluidics. Chemical and biological reactions will be examined in the context of lab-on-a-chip.

1 482 200 €

Start date: 2010-08-01, End date: 2015-07-31

Fatty Liver disease (FLD) is a widespread disease which can often progress to Nonalcoholic steatohepatitis, cirrhosis and liver cancer. At present FLD disease affects a huge perportion of the population and prompt treatment will be of major health benefits to the general population. We have developed a specific therapeutic targeting a microRNA we and others have shown to be involved in the pathogenesis of FLD. This therapeutic agent can dramatically reduce FLD in a mouse model. We would like to extend the pre-clinical studies in order to encourage interest of a pharmaceutical company who will license the technology and pursue clinical trials.

149 800 €

Start date: 2015-01-01, End date: 2016-06-30

Anomalies in surface temperatures, winds, and precipitation can significantly alter energy supply and demand, cause flooding, and cripple transportation networks. Better management of these impacts can be achieved by extending the duration of reliable predictions of the atmospheric circulation. Polar stratospheric variability can impact surface weather for well over a month, and this proposed research presents a novel approach towards understanding the fundamentals of how this coupling occurs. Specifically, we are interested in: 1) how predictable are anomalies in the stratospheric circulation? 2) why do only some stratospheric events modify surface weather? and 3) what is the mechanism whereby stratospheric anomalies reach the surface? While this last question may appear academic, several studies indicate that stratosphere-troposphere coupling drives the midlatitude tropospheric response to climate change; therefore, a clearer understanding of the mechanisms will aid in the interpretation of the upcoming changes in the surface climate. I propose a multi-pronged effort aimed at addressing these questions and improving monthly forecasting. First, carefully designed modelling experiments using a novel modelling framework will be used to clarify how, and under what conditions, stratospheric variability couples to tropospheric variability. Second, novel linkages between variability external to the stratospheric polar vortex and the stratospheric polar vortex will be pursued, thus improving our ability to forecast polar vortex variability itself. To these ends, my group will develop 1) an analytic model for Rossby wave propagation on the sphere, and 2) a simplified general circulation model, which captures the essential processes underlying stratosphere-troposphere coupling. By combining output from the new models, observational data, and output from comprehensive climate models, the connections between the stratosphere and surface climate will be elucidated.

1 808 000 €

Start date: 2016-05-01, End date: 2021-04-30

The discovery of the fractional quantum Hall effect created a revolution in solid state research by introducing a new state of matter resulting from strong electron interactions. The new state is characterized by excitations (quasi-particles) that carry fractional charge, which are expected to obey fractional statistics. While odd denominator fractional states are expected to have an abelian statistics, the newly discovered 5/2 even denominator fractional state is expected to have a non-abelian statistics. Moreover, a large number of emerging proposals predict that the latter state can be employed for topological quantum computing ( Station Q was founded by Microsoft Corp. in order to pursue this goal). This proposal aims at studying the abelian and non-abelian fractional charges, and in particular to observe their peculiar statistics. While charges are preferably determined by measuring quantum shot noise, their statistics must be determined via interference experiments, where one particle goes around another. The experiments are very demanding since the even denominator fractions turn to be very fragile and thus can be observed only in the purest possible two dimensional electron gas and at the lowest temperatures. While until very recently such high quality samples were available only by a single grower (in the USA), we have the capability now to grow extremely pure samples with profound even denominator states. As will be detailed in the proposal, we have all the necessary tools to study charge and statistics of these fascinating excitations, due to our experience in crystal growth, shot noise and interferometry measurements.

2 000 000 €

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

FractFrict is a comprehensive study of the space-time dynamics that lead to the failure of both bulk materials and frictionally bound interfaces. In these systems, failure is precipitated by rapidly moving singular fields at the tips of propagating cracks or crack-like fronts that cause material damage at microscopic scales. These generate damage that is macroscopically reflected as characteristic large-scale, modes of material failure. Thus, the structure of the fields that microscopically drive failure is critically important for an overall understanding of how macroscopic failure occurs. The innovative real-time measurements proposed here will provide fundamental understanding of the form of the singular fields, their modes of regularization and their relation to the resultant macroscopic modes of failure. Encompassing different classes of bulk materials and material interfaces. We aim to: [1] To establish a fundamental understanding of the dynamics of the near-tip singular fields, their regularization modes and how they couple to the macroscopic dynamics in both frictional motion and fracture. [2] To determine the types of singular failure processes in different classes of materials and interfaces (e.g. the brittle to ductile transition in amorphous materials, the role of fast fracture processes in frictional motion). [3] To establish local (microscopic) laws of friction/failure and how they evolve into their macroscopic counterparts [4]. To identify the existence and origins of crack instabilities in bulk and interface failure The insights obtained in this research will enable us to manipulate and/or predict material failure modes. The results of this study will shed considerable new light on fundamental open questions in fields as diverse as material design, tribology and geophysics.

2 265 399 €

Start date: 2010-12-01, End date: 2016-11-30

"Much currently deployed cryptography is designed using more “art'” than “science,” and most of the schemes used in practice lack rigorous justification for their security. While theoretically sound designs do exist, they tend to be quite a bit slower to run and hence are not realistic from a practical point of view. This gap is especially evident in “low-level” cryptographic primitives, which are the building blocks that ultimately process the largest quantities of data. Recent years have witnessed dramatic progress in the understanding of highly-parallelizable (local) cryptography, and in the construction of schemes based on the mathematics of geometric objects called lattices. Besides being based on firm theoretical foundations, these schemes also allow for very efficient implementations, especially on modern microprocessors. Yet despite all this recent progress, there has not yet been a major effort specifically focused on bringing the efficiency of such constructions as close as possible to practicality; this project will do exactly that. The main goal of the Fast and Sound Cryptography project is to develop new tools and techniques that would lead to practical and theoretically sound implementations of cryptographic primitives. We plan to draw ideas from both theory and practice, and expect their combination to generate new questions, conjectures, and insights. A considerable fraction of our efforts will be devoted to demonstrating the efficiency of our constructions. This will be achieved by a concrete setting of parameters, allowing for cryptanalysis and direct performance comparison to popular designs. While our initial focus will be on low-level primitives, we expect our research to also have direct impact on the practical efficiency of higher-level cryptographic tasks. Indeed, many of the recent improvements in the efficiency of lattice-based public-key cryptography can be traced back to research on the efficiency of lattice-based hash functions."

1 498 214 €

Start date: 2012-10-01, End date: 2017-09-30

Recent advances in nano technologies provide an exciting new tool-box best suited for stimulating and monitoring neurons at a very high accuracy and with improved bio-compatibility. In this project we propose the development of an innovative nano-material based platform to interface with neurons in-vivo, with unprecedented resolution. In particular we aim to form the building blocks for future sight restoration devices. By doing so we will address one of the most challenging and important applications in the realm of in-vivo neuronal stimulation: high-acuity artificial retina. Existing technologies in the field of artificial retinas offer only very limited acuity and a radically new approach is needed to make the needed leap to achieve high-resolution stimulation. In this project we propose the development of flexible, electrically conducting, optically addressable and vertically aligned carbon nanotube based electrodes as a novel platform for targeting neurons at high fidelity. The morphology and density of the aligned tubes will mimic that of the retina photo-receptors to achieve record-high resolution. The most challenging element of the project is the transduction from an optical signal to electrical activations at high resolution placing this effort at the forefront of nano-science and nano-technology research. To deal with this difficult challenge, vertically aligned carbon nanotubes will be conjugated with additional engineered materials, such as conducting polymers and quantum dots to build a supreme platform allowing unprecedented resolution and bio-compatibility. Ultimately, in this project we will focus on devising materials and processes that will become the building blocks of future devices so high density retinal implants and consequent sight restoration will become a reality in the conceivable future.

1 499 560 €

Start date: 2012-10-01, End date: 2018-09-30

Plants evolved a unique molecular mechanism that spatially regulate auxin, forming finely tuned gradients and local maxima of auxin that inform and direct developmental patterning and adaptive growth processes. Recent findings call into question the uniqueness of polar auxin transport in the sense that more plant hormones seem to be actively transported. Although still lacking many mechanistic details, as well as comprehensive functional connotations, these findings warrant a more thorough investigation into the prospect of a broader scope for plants spatial regulation capacity in the context of additional hormones. Critically, we lack an effective set of tools to directly investigate and dissect the particulars of plant hormones mobility at the molecular level. My long-term goal is to provide a molecular and mechanistic understanding of plant hormones dynamics that will augment our evolving model of how they are regulated and how they convey information. Here, I hypothesize that GA mobility in plants is controlled and directed by an active transport mechanism to form distinct distribution patterns that affect signaling. I will test my hypothesis with a multi-faceted and multi-disciplinary approach, combining: fluorescent labeling of key gibberellins to map their accumulation sites in whole plants and at the sub-cellular level; chemical-biology strategies that facilitate manipulation of GA “origin point” in planta to map and quantify GA flow pathways; probe-based genetic screens and un-biased photo-affinity labeling to identify proteins affecting GA mobility; and genetic and molecular biology techniques to characterize identified proteins’ functions. I expect to offer an exceptional, detailed view into the inner workings of gibberellins dynamics in planta and into the mechanisms driving it. I further anticipate that the strategies developed here to specifically address gibberellins could be straightforwardly re-tailored to investigate additional plant hormones.

1 500 000 €

Start date: 2016-02-01, End date: 2021-01-31

It is generally thought that an organism contains the exactly same genomic information in all its cells and that a genome remains unaltered throughout the organism’s life, with the exception of rare and random somatic mutations that might occur. This genomic information will also serve as a template for exact RNA copies. However, endogenous and powerful means of creating inner genomic diversity are known to exist: (1) RNA editing that leads to alteration of one nucleotide into another, (mainly A-to-I); (2) DNA editing that changes the DNA’s content by shifting C-into-U; (3) active retroelements that can insert copies of their sequences into new locations in a genome. Recently, we and others have found that although considered extremely rare, all three mechanisms are active somatically or at least leave traces of their occurrence in the genome, and are linked together, as most editing events occur in retroelements. However, the magnitude and scope of these mechanisms, which can lead to huge diversity and complexity within an organism and even within a cell, are still a mystery. This explosion of genomic variety can have dramatic effect on diverse biological processes, such as brain complexity, cancer and evolution acceleration. In GENEDVER, we aim to perform the first genome-wide mapping of editing and active retroelements in various genomes using a combination of computational and genomic approaches. Specifically, we will develop a strategy to detect RNA and DNA editing in retroelements, scan for editing events in various genomes, and build the first global editing atlas. In addition, we will exploit the close association between editing and retroelements in to produce a genome-wide approach to detect active retroelements. Finally, we will screen for editing events and retrotranspositions in various biological conditions, in order to expose their involvement in many biological states and evolution.

1 499 249 €

Start date: 2012-10-01, End date: 2017-09-30

In order to fully understand the complexity of biological processes that are reflected by simultaneous occurrences of intra and inter-cellular events, multiplexed imaging platforms are needed. Fluorescent reporter genes, with their “multicolor” imaging capabilities, have revolutionized science and their founders have been awarded the Nobel Prize. Nevertheless, the light signal source of these reporters, which restricts their use in deep tissues and in large animals (and potentially in humans), calls for alternatives. Reporter genes for MRI, although in their infancy, showed several exceptionalities, including the ability to longitudinal study the same subject with unlimited tissue penetration and to coregister information from reporter gene expression with high-resolution anatomical images. Inspired by the multicolor capabilities of optical reporter genes, this proposal aims to develop, optimize, and implement genetically engineered reporter systems for MRI with artificial “multicolor” characteristics. Capitalizing on (i) the Chemical Exchange Saturation Transfer (CEST)-MRI contrast mechanism that allows the use of small bioorganic molecules as MRI sensors, (ii) the frequency encoding, color-like features of CEST, and on (iii) enzyme engineering procedures that allow the optimization of enzymatic activity for a desired substrate, a “multicolor” genetically encoded MRI reporter system is proposed. By (a) synthesizing libraries of non-natural nucleosides (“reporter probes”) to generate artificially “colored” CEST contrast, and (b) performing directed evolution of deoxyribonucleoside kinase (dNK) enzymes (“reporter genes”) to phosphorylate those nucleosides, the “multicolor” genetically encoded MRI “reporter system” will be created. The orthogonally of the obtained pairs of substrate (CEST sensor)/ enzyme (mutant dNK) will allow their simultaneous use as a genetically encoded reporter system for in vivo “multicolor” monitoring of reporter gene expression with MRI.

1 478 284 €

Start date: 2016-05-01, End date: 2021-04-30