ERC FUNDED PROJECTS

Quantum Chaos is an emerging discipline which is crossing over from Physics into Pure Mathematics. The recent crossover is driven in part by a connection with Number Theory. This project explores several aspects of this interrelationship and is composed of a number of sub-projects. The sub-projects deal with: statistics of energy levels and wave functions of pseudo-integrable systems, a hitherto unexplored subject in the mathematical community which is not well understood in the physics community; with statistics of zeros of zeta functions over function fields, a purely number theoretic topic which is linked to the subproject on Quantum Chaos through the mysterious connections to Random Matrix Theory and an analogy between energy levels and zeta zeros; and with spatial statistics in arithmetic.

1 714 000 €

Start date: 2013-02-01, End date: 2019-01-31

NK cells that are well known by their ability to recognize and eliminate virus infected and tumor cells were also implicated in the defence against bacteria. However, the recognition of bacteria by NK cells is only poorly understood. we do not know how bacteria are recognized and the functional consequences of such recognition are also weakly understood. In the current proposal we aimed at determining the “NK cell receptor-bacterial interactome”. We will examine the hypothesis that NK inhibitory and activating receptors are directly involved in bacterial recognition. This ground breaking hypothesis is based on our preliminary results in which we show that several NK cell receptors directly recognize various bacterial strains as well as on a few other publications. We will generate various mice knockouts for NCR1 (a major NK killer receptor) and determine their microbiota to understand the physiological function of NCR1 and whether certain bacterial strains affects its activity. We will use different human and mouse NK killer and inhibitory receptors fused to IgG1 to pull-down bacteria from saliva and fecal samples and then use 16S rRNA analysis and next generation sequencing to determine the nature of the bacteria species isolated. We will identify the bacterial ligands that are recognized by the relevant NK cell receptors, using bacterial random transposon insertion mutagenesis approach. We will end this research with functional assays. In the wake of the emerging threat of bacterial drug resistance and the involvement of bacteria in the pathogenesis of many different chronic diseases and in shaping the immune response, the completion of this study will open a new field of research; the direct recognition of bacteria by NK cell receptors.

2 499 800 €

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

A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size. A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size.

1 445 000 €

Start date: 2010-09-01, End date: 2015-08-31

Autonomous programmable computing devices made of biological molecules hold the promise of interacting with the biological environment in future biological and medical applications. Our laboratory's long-term objective is to develop a 'Doctor in a cell': molecular-sized device that can roam the body, equipped with medical knowledge. It would diagnose a disease by analyzing the data available in its biochemical environment based on the encoded medical knowledge and treat it by releasing the appropriate drug molecule in situ. This kind of device might, in the future, be delivered to all cells in a specific tissue, organ or the whole organism, and cure or kill only those cells diagnosed with a disease. Our laboratory embarked on the attempt to design and build these molecular computing devices and lay the foundation for their future biomedical applications. Several important milestones have already been accomplished towards the realization of the Doctor in a cell vision. The subject of this proposal is a construction of autonomous biomolecular computers that could be delivered into a living cell, interact with endogenous biomolecules that are known to indicate diseases, logically analyze them, make a diagnostic decision and couple it to the production of an active biomolecule capable of influencing cell fate.

2 125 980 €

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

The study of synthetic molecular networks is of fundamental importance for understanding the organizational principles of biological systems and may well be the key to unraveling the origins of life. In addition, such systems may be useful for parallel synthesis of molecules, implementation of catalysis via multi-step pathways, and as media for various applications in nano-medicine and nano-electronics. We have been involved recently in developing peptide-based replicating networks and revealed their dynamic characteristics. We argue here that the structural information embedded in the polypeptide chains is sufficiently rich to allow the construction of peptide 'Systems Chemistry', namely, to facilitate the use of replicating networks as cell-mimetics, featuring complex dynamic behavior. To bring this novel idea to reality, we plan to take a unique holistic approach by studying such networks both experimentally and via simulations, for elucidating basic-principles and towards applications in adjacent fields, such as molecular electronics. Towards realizing these aims, we will study three separate but inter-related objectives: (i) design and characterization of networks that react and rewire in response to external triggers, such as light, (ii) design of networks that operate via new dynamic rules of product formation that lead to oscillations, and (iii) exploitation of the molecular information gathered from the networks as means to control switching and gating in molecular electronic devices. We believe that achieving the project's objectives will be highly significant for the development of the arising field of Systems Chemistry, and in addition will provide valuable tools for studying related scientific fields, such as systems biology and molecular electronics.

1 500 000 €

Start date: 2010-10-01, End date: 2015-09-30

My lab's work ranges from basic science, querying brain plasticity and sensory integration, to technological developments, allowing the blind to be more independent and even “see” using sounds and touch similar to bats and dolphins (a.k.a. Sensory Substitution Devices, SSDs), and back to applying these devices in research. We propose that, with proper training, any brain area or network can change the type of sensory input it uses to retrieve behaviorally task-relevant information within a matter of days. If this is true, it can have far reaching implications also for clinical rehabilitation. To achieve this, we are developing several innovative SSDs which encode the most crucial aspects of vision and increase their accessibility the blind, along with targeted, structured training protocols both in virtual environments and in real life. For instance, the “EyeMusic”, encodes colored complex images using pleasant musical scales and instruments, and the “EyeCane”, a palm-size cane, which encodes distance and depth in several directions accurately and efficiently. We provide preliminary but compelling evidence that following such training, SSDs can enable almost blind to recognize daily objects, colors, faces and facial expressions, read street signs, and aiding mobility and navigation. SSDs can also be used in conjunction with (any) invasive approach for visual rehabilitation. We are developing a novel hybrid Visual Rehabilitation Device which combines SSD and bionic eyes. In this set up, the SSDs is used in training the brain to “see” prior to surgery, in providing explanatory signal after surgery and in augmenting the capabilities of the bionic-eyes using information arriving from the same image. We will chart the dynamics of the plastic changes in the brain by performing unprecedented longitudinal Neuroimaging, Electrophysiological and Neurodisruptive approaches while individuals learn to ‘see’ using each of the visual rehabilitation approaches suggested here.

1 499 900 €

Start date: 2013-09-01, End date: 2018-08-31

The metabolism of cancer cells is altered to meet cellular requirements for growth, providing novel means to selectively target tumorigenesis. While extensively studied, our current view of cancer cellular metabolism is fundamentally limited by lack of information on variability in metabolic activity between distinct subcellular compartments and cells. We propose to develop a spatio-temporal fluxomics approach for quantifying metabolic fluxes in the cytoplasm vs. mitochondria as well as their cell-cycle dynamics, combining mass-spectrometry based isotope tracing with cell synchronization, rapid cellular fractionation, and computational metabolic network modelling. Spatio-temporal fluxomics will be used to revisit and challenge our current understanding of central metabolism and its induced adaptation to oncogenic events – an important endeavour considering that mitochondrial bioenergetics and biosynthesis are required for tumorigenesis and accumulating evidences for metabolic alterations throughout the cell-cycle. Our preliminary results show intriguing oscillations between oxidative and reductive TCA cycle flux throughout the cell-cycle. We will explore the extent to which cells adapt their metabolism to fulfil the changing energetic and anabolic demands throughout the cell-cycle, how metabolic oscillations are regulated, and their benefit to cells in terms of thermodynamic efficiency. Spatial flux analysis will be instrumental for investigating glutaminolysis - a ‘hallmark’ metabolic adaptation in cancer involving shuttling of metabolic intermediates and cofactors between mitochondria and cytoplasm. On a clinical front, our spatio-temporal fluxomics analysis will enable to disentangle oncogene-induced flux alterations, having an important tumorigenic role, from artefacts originating from population averaging. A comprehensive view of how cells adapt their metabolism due to oncogenic mutations will reveal novel targets for anti-cancer drugs.

1 481 250 €

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

Clouds and precipitation play a crucial role in the Earth's energy balance, global atmospheric circulation and the water cycle. Despite their importance, clouds still pose the largest uncertainty in climate research. I propose a new approach for studying anthropogenic effects on cloud fields and rain, tackling the challenge from both scientific ends: reductionism and systems approach. We will develop a novel research approach using observations and models interactively that will allow us to “peel apart” detailed physical processes. In parallel we will develop a systems view of cloud fields looking for Emergent Behavior rising out of the complexity, as the end result of all of the coupled processes. Better understanding of key processes on a detailed (reductionist) manner will enable us to formulate the important basic rules that control the field and to look for emergence of the overall effects. We will merge ideas and methods from four different disciplines: remote sensing and radiative transfer, cloud physics, pattern recognition and computer vision and ideas developed in systems approach. All of this will be done against the backdrop of natural variability of meteorological systems. The outcomes of this work will include fundamental new understanding of the coupled surface-aerosol-cloud-precipitation system. More importantly this work will emphasize the consequences of human actions on the environment, and how we change our climate and hydrological cycle as we input pollutants and transform the Earth’s surface. This work will open new horizons in cloud research by developing novel methods and employing the bulk knowledge of pattern recognition, complexity, networking and self organization to cloud and climate studies. We are proposing a long-term, open-ended program of study that will have scientific and societal relevance as long as human-caused influences continue, evolve and change.

1 428 169 €

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

Can we exploit insights from the remarkably lubricated surfaces of articular cartilage, to create lubricants that may alleviate osteoarthritis (OA), the most widespread joint disease, affecting millions? These, succinctly, are the challenges of the present proposal. They are driven by our recent finding that lubrication of destabilised joints leads to changes in gene-regulation of the cartilage-embedded chondrocytes to protect against development of the disease. OA alleviation is known to arise through orthopedically suppressing shear-stresses on the cartilage, and a central premise of this project is that, by reducing friction at the articulating cartilage through suitable lubrication, we may achieve the same beneficial effect on the disease. The objectives of this project are to better understand the origins of cartilage boundary lubrication through examination of friction-reduction by its main molecular components, and exploit that understanding to create lubricants that, on intra-articular injection, will lubricate cartilage sufficiently well to achieve alleviation of OA via gene regulation. The project will examine, via both nanotribometric and macroscopic measurements, how the main molecular species implicated in cartilage lubrication, lipids, hyaluronan and lubricin, and their combinations, act together to form optimally lubricating boundary layers on model surfaces as well as on excised cartilage. Based on this, we shall develop suitable materials to lubricate cartilage in joints, using mouse models. Lubricants will further be optimized with respect to their retention in the joint and cartilage targeting, both in model studies and in vivo. The effect of the lubricants in regulating gene expression, in reducing pain and cartilage degradation, and in promoting stem-cell adhesion to the cartilage will be studied in a mouse model in which OA has been induced. Our results will have implications for treatment of a common, debilitating disease.

2 499 944 €

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

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

2 000 000 €

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

"Communication between the nervous and the immune system is pivotal for maintaining homeostasis and ensuring rapid and efficient reaction to stress and infection insults. The emergence of microRNAs (miRs) as regulators of gene expression and of acetylcholine (ACh) signalling as regulator of anxiety and inflammation provides a model for studying this interaction. My hypothesis is that 1) a specific sub-group of miRs, designated ""CholinomiRs"", may silence multiple target genes in the neuro-immune interface; 2) these miRs compete with each other on the interaction with their targets, and 3) mutations interfering with miR binding lead to inherited susceptibility to anxiety and inflammation disorders by modifying these interactions. Our preliminary findings have shown that by targeting acetylcholinesterase (AChE), CholinomiR-132 can intensify acute stress, resolve intestinal inflammation and change post-ischemic stroke responses. Further, we have identified clustered single nucleotide polymorphisms (SNPs) interfering with AChE silencing by several miRs which associate with elevated trait anxiety, blood pressure and inflammation. To further study miR regulators of ACh signalling, I plan to: (1) Identify anxiety and inflammation-induced changes in CholinomiRs and their targets in challenged brain and immune cells. (2) Establish the roles of these targets for one selected CholinomiR by tissue-specific manipulations. (3) Study primate-specific CholinomiRs by continued human DNA screens to identify SNPs and in ""humanized"" mice with knocked-in human AChE and transgenic CholinomiR-608. (4) Test if therapeutic modulation of aberrant CholinomiR expression can restore homeostasis. This research will clarify how miRs interact with each other in health and disease, introduce the dimension of complexity of multi-target competition and miR interactions and make a conceptual change in miRs research while enhancing the ability to intervene with diseases involving impaired ACh signalling."

2 375 600 €

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

Computational cameras go beyond 2D images and allow the extraction of more dimensions from the visual world such as depth, multiple viewpoints and multiple illumination conditions. They also allow us to overcome some of the traditional photography challenges such as defocus blur, motion blur, noise and resolution. The increasing variety of computational cameras is raising the need for a meaningful comparison across camera types. We would like to understand which cameras are better for specific tasks, which aspects of a camera make it better than others and what is the best performance we can hope to achieve. Our 2008 paper introduced a general framework to address the design and analysis of computational cameras. A camera is modeled as a linear projection in ray space. Decoding the camera data then deals with inverting the linear projection. Since the number of sensor measurements is usually much smaller than the number of rays, the inversion must be treated as a Bayesian inference problem accounting for prior knowledge on the world. Despite significant progress which has been made in the recent years, the space of computational cameras is still far from being understood. Computational camera analysis raises the following research challenges: 1) What is a good way to model prior knowledge on ray space? 2) Seeking efficient inference algorithms and robust ways to decode the world from the camera measurements. 3) Evaluating the expected reconstruction accuracy of a given camera. 4) Using the expected reconstruction performance for evaluating and comparing camera types. 5) What is the best camera? Can we derive upper bounds on the optimal performance? We propose research on all aspects of computational camera design and analysis. We propose new prior models which will significantly simplify the inference and evaluation tasks. We also propose new ways to bound and evaluate computational cameras with existing priors.

756 845 €

Start date: 2010-12-01, End date: 2015-11-30

Cosmic explosions, the violent deaths of stars, play a crucial role in many of the most interesting open questions in physics today. These events serve as “cosmic accelerators” for ultra-high-energy particles that are beyond reach for even to most powerful terrestrial accelerators, as well as distant sources for elusive neutrinos. Explosions leave behind compact neutron stars and black hole remnants, natural laboratories to study strong gravity. Acting as cosmic furnaces, these explosions driven the chemical evolution of the Universe Cosmic explosions trigger and inhibit star formation processes, and drive galactic evolution (“feedback”). Distances measured using supernova explosions as standard candles brought about the modern revolution in our view of the accelerating Universe, driven by enigmatic “dark energy”. Understanding the nature of cosmic explosions of all types is thus an extremely well-motivated endeavour. I have been studying cosmic explosions for over a decade, and since the earliest stages of my career, have followed an ambition to figure out the nature of cosmic explosions of all types, and to search for new types of explosions. Having already made several key discoveries, I now propose to undertake a comprehensive program to systematically tackle this problem.I review below the progress made in this field and the breakthrough results we have achieved so far, and propose to climb the next step in this scientific and technological ladder, combining new powerful surveys with comprehensive multi-wavelength and multi-disciplinary (observational and theoretical) analysis. My strategy is based on a combination of two main approaches: detailed studies of single objects which serve as keys to specific questions; and systematic studies of large samples, some that I have, for the first time, been able to assemble and analyze, and those expected from forthcoming efforts. Both approaches have already yielded tantalizing results.

1 499 302 €

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

Over 100 types of distinct modifications are catalyzed on RNA molecules post-transcriptionally. In an analogous manner to well-studied chemical modifications on proteins or DNA, modifications on RNA - and particularly on mRNA - harbor the exciting potential of regulating the complex and interlinked life cycle of these molecules. The most abundant modification in mammalian and yeast mRNA is N6-methyladenosine (m6A). We have pioneered approaches for mapping m6A in a transcriptome wide manner, and we and others have identified factors involved in encoding and decoding m6A. While experimental disruption of these factors is associated with severe phenotypes, the role of m6A remains enigmatic. No single methylated site has been shown to causally underlie any physiological or molecular function. This proposal aims to establish a framework for systematically deciphering the molecular function of a modification and its underlying mechanisms and to uncover the physiological role of the modification in regulation of a cellular response. We will apply this framework to m6A in the context of meiosis in budding yeast, as m6A dynamically accumulates on meiotic mRNAs and as the methyltransferase catalyzing m6A is essential for meiosis. We will (1) aim to elucidate the physiological targets of methylation governing entry into meiosis (2) seek to elucidate the function of m6A at the molecular level, and understand its impact on the various steps of the mRNA life cycle, (3) seek to understand the mechanisms underlying its effects. These aims will provide a comprehensive framework for understanding how the epitranscriptome, an emerging post-transcriptional layer of regulation, fine-tunes gene regulation and impacts cellular decision making in a dynamic response, and will set the stage towards dissecting the roles of m6A and of an expanding set of mRNA modifications in more complex and disease related systems.

1 402 666 €

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

A cell’s decision to die is governed by multiple input signals received from a complex network of programmed cell death (PCD) pathways, including apoptosis and programmed necrosis. Additionally, under some conditions, autophagy, whose function is mainly pro-survival, may act as a back-up death pathway. We propose to apply new approaches to study the molecular basis of two important questions that await resolution in the field: a) how the cell switches from a pro-survival autophagic response to an apoptotic response and b) whether and how pro-survival autophagy is converted to a death mechanism when apoptosis is blocked. To address the first issue, we will screen for direct physical interactions between autophagic and apoptotic proteins, using the protein fragment complementation assay. Validated pairs will be studied in depth to identify built-in molecular switches that activate apoptosis when autophagy fails to restore homeostasis. As a pilot case to address the concept of molecular ‘sensors’ and ‘switches’, we will focus on the previously identified Atg12/Bcl-2 interaction. In the second line of research we will categorize autophagy-dependent cell death triggers into those that directly result from autophagy-dependent degradation, either by excessive self-digestion or by selective protein degradation, and those that utilize the autophagy machinery to activate programmed necrosis. We will identify the genes regulating these scenarios by whole genome RNAi screens for increased cell survival. In parallel, we will use a cell library of annotated fluorescent-tagged proteins for measuring selective protein degradation. These will be the starting point for identification of the molecular pathways that convert survival autophagy to a death program. Finally, we will explore the physiological relevance of back-up death mechanisms and the newly identified molecular mechanisms to developmental PCD during the cavitation process in early stages of embryogenesis.

2 500 000 €

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

Cancer is rapidly becoming the greatest health hazard of our days. The most widespread cancers, are lung cancer (LC), breast cancer (BC), colorectal cancer (CC), and prostate cancer (PC). The impact of the various techniques used for diagnosis, screening and monitoring these cancers is either uncertain and/or inconvenient for the patients. This proposal aims to create a low-cost, easy-to-use and noninvasive screening method for LC, BC, CC, and PC based on breath testing with a novel nanosensors approach. With this in mind, we propose to: (a) modify an array of nanosensors based on Au nanoparticles for obtaining highly-sensitive detection levels of breath biomarkers of cancer; and (b) investigate the use of the developed array in a clinical study. Towards this end, we will collect suitable breath samples from patients and healthy controls in a clinical trial and test the feasibility of the device to detect LC, BC, CC, and PC, also in the presence of other diseases. We will then investigate possible ways to identify the stage of the disease, monitor the response to cancer treatment, and to identify cancer subtypes. Further, we propose that the device can be used for monitoring of cancer patients during and after treatment. The chemical nature of the cancer biomarkers will be identified through spectrometry techniques. The proposed approach would be used outside specialist settings and could considerably lessen the burden on the health budgets, both through the low cost of the proposed all-inclusive cancer test, and through earlier and, hence, more cost-effective cancer treatment.

1 200 000 €

Start date: 2011-01-01, End date: 2014-12-31

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

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

The asset management industry is a 60 trillion euros industry world wide, with a ratio of assets under management by asset managers to GDP around 100 percent. Despite the prominence of financial intermediaries in financial markets, our understanding of the portfolio delegation relationship, and its equilibrium asset pricing and contracting implications is at its infancy. The recent financial crisis has further underscored the importance of better understanding the incentives of financial intermediaries, the distortions induced by these incentives, the contracts that can help mitigate these distortions, and the impact of their trading on asset pricing dynamics. One key feature that is at the core of the asset management relationship is its dynamic nature: investors can, and do, periodically re-allocate funds between managers and between funds and other investment vehicles. The magnitude of fund flows, both over time and accross funds at a given point in time, have been shown to be quantitatively large relative to assets under management. The ability of investors to quickly pull money out of funds at a time of crisis can have significant ramifications for the stability of the financial system. Understanding implications of the dynamic nature of the delegation relationship is imperative in order to understand multiple aspects related to delegation and financial markets at large, including: risk taking behavior by funds; welfare implications for investors who invest in funds; what regulatory restrictions should be imposed on contracts; the evolution, past and future, of the asset management industry; securities return dynamics. The objective is to develope models that will incorporate dynamic flows in settings that will allow studying implications and deriving empirical predictions on multiple dimensions: portfolio choice; optimal contracting; distribution of assets across funds; equilibrium asset pricing dynamics.

728 436 €

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

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

The pioneering enterprise I propose is the study of a particular type of linguistic discontinuity – language revival – inspired by the revival of Hebrew at the end of the 19th century. The historical and sociocultural dimensions the revival have been studied before, but not its linguistic dimensions. My main aim is to construct a model of the linguistic factors which have shaped the revival of Hebrew. I expect this model to provide clues for the understanding of the process of language revival in general. For a language to be revived, a new grammar must be created by its native speakers. I hypothesize that the new grammar is formed by some of the general principles which also govern other better known cases of linguistic discontinuity (creoles, mixed languages, emergent sign languages etc.). The model I will develop will lay the foundation for a new subfield within the study of discontinuity – the study of language revival. I will start with careful work of documenting the development of the grammar of Modern Hebrew, in particular its syntax, something which has not been done systematically before. One product of the project will be a linguistic application for the documentation and annotation of the novel syntactic constructions of Modern Hebrew, their sources in previous stages of Hebrew and in the languages with which Modern Hebrew was in contact at the time of the revival, and the development of these constructions since the beginning of the revival until the present time. The linguistic application will be made available on the web for other linguists to use and to contribute to. The institution of an expanding data-base of the syntactic innovations of Modern Hebrew which comprises both documentation/ annotation and theoretical modeling which could be applied to other languages makes this an extremely ambitious proposal with potentially wide-reaching ramifications for the revival and revitalization of the languages of ethno-linguistic minorities world wide.

2 498 750 €

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

"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

The biological response to stress is concerned with the maintenance of homeostasis in the presence of real or perceived challenges. This process requires numerous adaptive responses involving changes in the central nervous and neuroendocrine systems. When a situation is perceived as stressful, the brain activates many neuronal circuits linking centers involved in sensory, motor, autonomic, neuroendocrine, cognitive, and emotional functions in order to adapt to the demand. However, the details of the pathways by which the brain translates stressful stimuli into the final, integrated biological response are presently incompletely understood. Nevertheless, it is clear that dysregulation of these physiological responses to stress can have severe psychological and physiological consequences, and there is much evidence to suggest that inappropriate regulation, disproportional intensity, or chronic and/or irreversible activation of the stress response is linked to the etiology and pathophysiology of anxiety disorders and depression. Understanding the neurobiology of stress by focusing on the brain circuits and genes, which are associated with, or altered by, the stress response will provide important insights into the brain mechanisms by which stress affects psychological and physiological disorders. This is an integrated multidisciplinary project from gene to behavior using state-of-the-art moue genetics and animal models. We will employ integrated molecular, biochemical, physiological and behavioral methods, focusing on the generation of mice genetic models as an in vivo tool, in order to study the central pathways and molecular mechanisms mediating the stress response. Defining the contributions of known and novel gene products to the maintenance of stress-linked homeostasis may improve our ability to design therapeutic interventions for, and thus manage, stress-related disorders.

1 500 000 €

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

Our working hypothesis is that tumorigenesis is an evolutionary process that fundamentally couples few major driving events (point mutations, rearrangements) with a complex flux of minor aberrations, many of which are epigenetic. We believe that these minor events are critical factors in the emergence of the cancer phenotype, and that understanding them is essential to the characterization of the disease. In particular, we hypothesize that a quantitative and principled evolutionary model for carcinogenesis is imperative for understanding the heterogeneity within tumor cell populations and predicting the effects of cancer therapies. We will therefore develop an interdisciplinary scheme that combines theoretical models of cancer evolution with in vitro evolutionary experiments and new methods for assaying the population heterogeneity of epigenomic organization. By developing techniques to interrogate DNA methylation and its interaction with other key epigenetic marks at the single-cell level, we will allow quantitative theoretical predictions to be scrutinized and refined. By combining models describing epigenetic aberrations with direct measurements of chromatin organization using Hi-C and 4C-seq, we shall revisit fundamental questions on the causative nature of epigenetic changes during carcinogenesis. Ultimately, we will apply both theoretical and experimental methodologies to assay and characterize the evolutionary histories of tumor cell populations from multiple mouse models and clinical patient samples.

1 499 998 €

Start date: 2012-12-01, End date: 2017-11-30

Expander graphs are finite graphs which play a fundamental role in many areas of computer science such as: communication networks, algorithms and more. Several areas of deep mathematics have been used in order to give explicit constructions of such graphs e.g. Kazhdan property (T) from representation theory of semisimple Lie groups, Ramanujan conjecture from the theory of automorphic forms and more. In recent years, computer science has started to pay its debt to mathematics: expander graphs are playing an increasing role in several areas of pure mathematics. The goal of the current research plan is to deepen these connections in both directions with special emphasis of the more recent and surprising application of expanders to group theory, the geometry of 3-manifolds and number theory.

1 082 504 €

Start date: 2008-10-01, End date: 2014-09-30

"I propose to combine analytical studies and simulations to explore fundamental open questions in the dynamics and statistical mechanics of stars near massive black holes. These directly affect key issues such as the rate of supply of single and binary stars to the black hole, the growth and evolution of single and binary massive black holes and the connections to the evolution of the host galaxy, capture of stars around the black hole, the rate and modes of gravitational wave emission from captured compact objects, stellar tidal heating and destruction, and the emergence of ""exotic"" stellar populations around massive black holes. These processes have immediate observational implications and relevance in view of the huge amounts of data on massive black holes and galactic nuclei coming from earth-bound and space-borne telescopes, from across the electromagnetic spectrum, from cosmic rays, and in the near future also from neutrinos and gravitational waves."

880 000 €

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

Experimental time-domain astrophysics is on the verge of a new era as technological, computational, and operational progress combine to revolutionise the manner in which we study the time-variable sky. This proposal consolidates previous breakthrough work on wide-field surveys into a coherent program to advance our study of the variable sky on ever decreasing time-scales: from days, through hours, to minutes. We will watch how stars explode in real time in order to study the complex physics of stellar death, build new tools to handle and analyse the uniquely new data sets we are collecting, and shed light on some of the most fundamental questions in modern astrophysics: from the origin of the elements, via the explosions mechanism of supernova explosions, to the feedback processes that drive star formation and galaxy evolution.

2 461 111 €

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

We propose to study the fractal geometry of invariant sets for endomorphisms of compact abelian groups, specifically a family of conjectures by Furstenberg on the dimensions of orbit closures under such dynamics, and on the size of sums and intersections of invariant sets. These conjectures are related to problems on expansion in integer bases, in Diophantine approximation, measure rigidity, analysis and equidistribution. The project focuses on the conjectures themselves and some related problems, e.g. Bernoulli convolutions, and on applications to equidistribution on tori. Our approach combines tools from ergodic theory, geometric measure theory and additive combinatorics, building on recent progress in these fields and recent partial results towards the main conjectures.

1 107 000 €

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

"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

The proposed research contains two main directions in group theory and geometry: Independence of Group Elements and Geometric Rigidity. The first consists of problems related to the existence of free subgroups, uniform and effective ways of producing such, and analogous questions for finite groups where the analog of independent elements are elements for which the Cayley graph has a large girth, or non-small expanding constant. This line of research began almost a century ago and contains many important works including works of Hausdorff, Banach and Tarski on paradoxical decompositions, works of Margulis, Sullivan and Drinfeld on the Banach-Ruziewicz problem, the classical Tits Alternative, Margulis-Soifer result on maximal subgroups, the recent works of Eskin-Mozes-Oh and Bourgain-Gamburd, etc. Among the famous questions is Milnor's problem on the exponential verses polynomial growth for f.p. groups, originally stated for f.g. groups but reformulated after Grigorchuk's counterexample. Related works of the PI includes a joint work with Breuillard on the topological Tits alternative, where several well known conjectures were solved, e.g. the foliated version of Milnor's problem conjectured by Carriere, and on the uniform Tits alternative which significantly improved Tits' and EMO theorems. A joint work with Glasner on primitive groups where in particular a conjecture of Higman and Neumann was solved. A paper on the deformation varieties where a conjecture of Margulis and Soifer and a conjecture of Goldman were proved. The second involves extensions of Margulis' and Mostow's rigidity theorems to actions of lattices in general topological groups on metric spaces, and extensions of Kazhdan's property (T) for group actions on Banach and metric spaces. This area is very active today. Related work of the PI includes his joint work with Karlsson and Margulis on generalized harmonic maps, and his joint work with Bader, Furman and Monod on actions on Banach spaces.

750 000 €

Start date: 2008-07-01, End date: 2013-12-31

"Live-cell imaging combined with kinetic analyses has provided new biological insights on the gene expression pathway. However, such studies in mammalian cells typically require use of exogenous over-expressed gene constructs, which often form large tandem gene arrays and usually lack the complete endogenous regulatory sequences. It is therefore imperative to design methodology for analyzing gene expression kinetics of single alleles of endogenous genes. While certain steps have been taken in this direction, there are many experimental obstacles standing in the way of a robust genome-wide system for the in vivo examination of endogenous gene expression within the natural nuclear environment. GENEXP sets out to provide such a system. It will start with methodology for robust tagging of a multitude of endogenous genes and their transcribed mRNAs in human cells using the ""CD tagging"" approach. Thereby, in vivo mRNA synthesis at the nuclear site of RNA birth will be explored in a unique manner. A high-resolution study of gene expression, in particular mRNA transcription and mRNA export, under endogenous cellular context and using a genome-wide live-cell approach will be performed. GENEXP will specifically focus on the: i) Transcriptional kinetics of endogenous genes in single cells and cell populations; ii) Kinetics of mRNA export on the single molecule level; iii) Examination of the protein composition of endogenous mRNPs; iv) High throughput scan for drugs that affect gene expression and mRNA export. Altogether, GENEXP will provide breakthrough capability in kinetically quantifying the gene expression pathway of a large variety of endogenous genes, and the ability to examine the generated molecules on the single-molecule level. This will be done within their normal genomic and biological environment, at the single-allele level."

1 498 510 €

Start date: 2010-12-01, End date: 2015-11-30

We consider the dynamics of actions on homogeneous spaces of algebraic groups, We propose to tackle the central open problems in the area, including understanding actions of diagonal groups on homogeneous spaces without an entropy assumption, a related conjecture of Furstenberg about measures on R / Z invariant under multiplication by 2 and 3, and obtaining a quantitative understanding of equidistribution properties of unipotent flows and groups generated by unipotents. This has applications in arithmetic, Diophantine approximations, the spectral theory of homogeneous spaces, mathematical physics, and other fields. Connections to arithmetic combinatorics will be pursued.

1 229 714 €

Start date: 2011-01-01, End date: 2016-12-31

Gamma-Ray Bursts (GRBs), short and intense bursts of gamma-rays originating from random directions in the sky, are the brightest explosions in our Universe. They involve ultra-relativistic motion, huge magnetic fields, the strongest gravitational fields, acceleration of photons, neutrinos and cosmic rays to ultra high energies, the collapse of massive stars, mergers of neutron star binaries and formation of newborn black holes. They are at the focal point of relativistic high energy astrophysics and they serve as the best laboratory for extreme physics. The internal-external shocks model was formulated to explain their inner working. This model had impressive successes in interpreting and predicting GRB properties. Still it had left many fundamental questions unanswered. Furthermore, recently it has been confronted with puzzling Swift observations of the early afterglow and it is not clear if it needs minor revisions or a drastic overhaul. I describe here an extensive research program that deals with practically all aspects of GRB. From a technical point of view this program involves sophisticated state of the art computations on one hand, fundamental theory and phenomenological analysis of observations and data analysis on the other one. My goal is to address both old and new open question, considering, among other options the possibility that the current model has to be drastically revised. My long term goal, beyond understanding the inner working of GRBs, is to create a unified theory of accretion acceleration and collimation and of emission of high energy gamma-rays and relativistic particles that will synergize our understanding of GRBs, AGNs, Microquasars, galactic binary black holes SNRs and other high energy astrophysics phenomena. A second hope is to find ways to utilize GRBs to reveal new physics that cannot be explored otherwise.

1 933 460 €

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

Hematopoiesis is an important model for stem cell differentiation with great medical significance. Heterogeneity within hematopoietic progenitor populations has considerably limited characterization and molecular understanding of lineage commitment in both health and disease. Advances in single-cell genomic technologies provide an extraordinary opportunity for unbiased and high resolution mapping of biological function and regulation. Recently we have developed an experimental and analytical method, termed massively parallel single-cell RNA-Seq (MARS-Seq), for unbiased classification of individual cells from their native context and successfully applied it for characterization of immune and hematopoietic progenitors. Here, we propose to uncover the hierarchy and regulatory mechanisms controlling hematopoiesis by combining comprehensive single-cell RNA-Seq analyses, modelling approaches, advanced functional assays, single-cell CRISPR screens, knockout models and epigenetic profiling. Exciting preliminary result show that indeed our approach is starting to uncover the complexity of hematopoietic progenitors and the regulatory circuits driving hematopoietic decisions. We will pursue the following aims: (i) Generate a refined model of hematopoiesis by comprehensive single-cell RNA-Seq profiling of hematopoietic progenitors, (ii) validate the predicted model by in vivo functional developmental assays and then (iii) test candidate transcription and chromatin factors uncovered by our model for their role in controlling progression towards various lineages using single-cell measurements combined with CRISPR screens. Together, our study is expected to generate a revised and high-resolution hematopoietic model and decipher the regulatory networks that control hematopoiesis. Our methods and models may provide a platform for future medical advancements including a large-scale European collaborative project to discover a comprehensive human hematopoietic tree.

2 000 000 €

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

Until recently it was believed to be impossible to produce hydrogen through water electrolysis systems, without an electrochemical oxygen production process and without a membrane. However, in the past few years, our team was able to develop a new technological configuration which divides the water splitting process into two phases : (1) an efficient electrochemical hydrogen production followed by a (2) spontaneous chemical oxygen production phase. By eliminating the inefficient electrochemical water oxidation reaction (OER) we achieve a significant increase in hydrogen production efficiency. Furthermore, reducing the danger of mixing hydrogen and oxygen eliminates the need for a membrane. A membrane-free system enables high pressure hydrogen production without the risk of gas mixture or membrane failure. Moreover, as the membrane failure is the main cause for malfunctions and offline times of alkaline and PEM electrolyzer, our technology improves system reliability and energy efficiency. The purpose of this PoC is to further develop our basic lab prototype to demonstrate two potential commercial applications:(1)Power to Gas (P2G) storage of renewable energy (demonstrating the ability to produce hydrogen with high efficiency and under high peaks) and (2) On-site hydrogen production for hydrogen refuelling stations (demonstrating purity and durability under high-pressure). Furthermore, HYMEFCECS, will include an in-depth user requirements analysis (combining business, economic and technical inputs); devising a proper business model and business plan per two target markets, financial forecasting, Intellectual Property and an Investor Toolkit.

150 000 €

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

With increased life expectancy, there has been a critical growth in the portion of the population that suffers from age-related cognitive decline and dementia. Attempts are therefore being made to find ways to slow brain-aging processes; successful therapies would have a significant impact on the quality of life of individuals, and decrease healthcare expenditures. Aging of the immune system has never been suggested as a factor in memory loss. My group formulated the concept of protective autoimmunity , suggesting a linkage between immunity and self-maintenance in the context of the brain in health and disease. Recently, we showed that T lymphocytes recognizing brain-self antigens have a pivotal role in maintaining hippocampal plasticity, as manifested by reduced neurogenesis and impaired cognitive abilities in T-cell deficient mice. Taken together, our novel observations that T cell immunity contributes to hippocampal plasticity, and the fact that T cell immunity decreases with progressive aging create the basis for the present proposal. We will focus on the following questions: (a) Which aspects of cognition are supported by the immune system- learning, memory or both; (b) whether aging of the immune system is sufficient to induce aging of the brain; (c) whether activation of the immune system is sufficient to reverse age-related cognitive decline; (d) the mechanism underlying the effect of peripheral immunity on brain cognition; and (e) potential therapeutic implications of our findings. Our preliminary results demonstrate that the immune system contributes to spatial memory, and that imposing an immune deficiency is sufficient to cause a reversible memory deficit. These findings give strong reason for optimism that memory loss in the elderly is preventable and perhaps reversible by immune-based therapies; we hope that, in the not too distant future, our studies will enable development of a vaccine to prevent CNS aging and cognitive loss in elderly.

1 650 000 €

Start date: 2009-01-01, End date: 2012-12-31

The importance of information asymmetry in financial markets has long been recognized in financial economics. Most existing models focus on the role of privately informed investors who influence prices through their trades. But in many cases the agents who have the biggest information advantage are insiders or the firms themselves; they are precluded from trading but can affect the information flow to the market. This endogenous information flow and its effect on financial market is the focus of the proposed project. By the term information flow we refer to a wide range of channels through which firms can communicate. The information can be part of a mandatory disclosure or a voluntary one. It can be verifiable or non-verifiable information. In addition there can be an implicit information transmission. A firm may choose certain actions to convey its private information (i.e. signaling) without any explicit announcements. The way firms convey this information may provide key insights into the behavior of financial markets and in particular the development of financial crises. The project combines theoretical and empirical work. In the theory part I plan to examine the channels mentioned above and develop testable implications. In the empirical part I plan to test these implications.

1 500 000 €

Start date: 2010-10-01, End date: 2016-09-30

Melanoma is the most aggressive, treatment-resistant and lethal type of skin cancer. Its increasing incidence worldwide emphasizes the need for new treatment strategies. Major recent breakthroughs in melanoma therapy have highlighted the role of immune T cell-mediated responses against tumor cells, showing that immune-system recognition of neo-antigens on cancer cells serves as a distinctive immunological signature. However, current strategies to identify neo-antigens are biased, costly and time-consuming. Directly addressing this major therapeutic limitation, this PoC project is aimed at commercializing an innovative tool, called INTACt, for designing highly personalized therapies for melanoma patients, ones that efficiently target the composition of patient-specific neo-antigens that arise as a consequence of mutations in a patient’s melanoma genome. INTACt is designed to identify neo-antigens in a high-throughput, systematic and cost-effective manner in cell lines, fresh tumors, patient-derived xenografts and plasma. INTACt will further identify the patient neo-antigen-reactive T cells to then be returned to the patient, using neo-antigen-specific T cells or RNA vaccines. Such personalized targeting of the patient’s melanoma genetic landscape is key to a significantly improved mortality. Unlike existing therapeutic strategies, INTACt may be considered the ultimate personalized immune therapy for the treatment of melanoma patients to be expended to other cancer types. This patient-specific tool will significantly lower patients’ economic and psychological burden caused by unnecessary chemotherapy and targeted therapy. INTACt also holds the promise of realizing value from enormous past investments in drug candidates that were eliminated due to person-specific toxicities or lack of efficacy as these can be combined with the neo-antigen-based immunotherapy. INTACt will thus enable the creation of new business models for the highly pressured pharmaceutical industry.

150 000 €

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

The central purpose of this project is to bring down interdisciplinary barriers by showing how the Slavic and the Jewish heritage can each be approached as a unique repository of the unknown texts, traditions, and sensibilities of the other. By focusing on previously unexplored or under-explored medieval texts, I aim to reconstruct the Jewish and Slavic legacies, some of whose materials have been considered lost, while others were misinterpreted or neglected. This research project will resort to historical and philological techniques hitherto considered mutually incompatible in this field. The study intends to use methods of cultural archaeology to explore medieval Judeo-Slavic transparency. By cultural transparency we understand the mutual permeability of different cultures, which facilitates the exchange of ideas and genres of creativity between them. Cultural archeology involves methods of multi-disciplinary research based on the assumption that Eastern Europe constituted a melting pot characterized by an intensive cross-fertilization of cultural legacies. Cultural archaeology studies different historical, religious, and literary texts by looking at them as a palimpsest in which earlier texts and types of discourse come to the fore as shaped by their contemporary socio-cultural settings. The proposed theme has far-reaching methodological implications beyond the Judeo-Slavic cultural realm. This project will build a model of cross-cultural interaction to achieve a better understanding of the situations in which different faith-based ethnic cultures cohabit.

1 044 000 €

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

The focus of our proposal is on arithmetic circuit complexity. Arithmetic circuits are the most common model for computing polynomials, over arbitrary fields. This model was studied by many researchers in the past 40 years but still not much is known on many of the basic problems concerning this model. In this research we propose to study some of the most exciting fundamental open problems in theoretical computer science: Proving lower bounds on the size of arithmetic circuits and finding efficient deterministic algorithms for checking identity of arithmetic circuits. Proving a strong lower bound or finding efficient deterministic algorithms to the polynomial identity testing problem are the most important problems in algebraic complexity and solving either of them will be a dramatic breakthrough in theoretical computer science. The two problems that we intend to study are closely related to each other - there are several known results showing that a solution to one of the problems may lead to a solution to the other. Thus, we propose to study strongly related problems that lie in the frontier of algebraic complexity. Any advance will be a significant contributions to the field of theoretical computer science.

1 427 485 €

Start date: 2011-03-01, End date: 2017-02-28

We propose to provide the theoretical, algorithmic and methodological foundations, and build the supporting tools, to bring about a major, paradigmatic, revolutionary change in the way software and systems are programmed and executed, based on the idea of liberated programming, a sweeping extension of the scenario-based play-in/play-out approach to program design and execution that I and my group have done around the language of live sequence charts (LSCs). Play-in is a new way of software programming, combining the ideas of showing and teaching, instead of telling, relying on friendly advanced user interfaces, and using intuitive yet formal and expressive visual languages. Play-out is a general name for the technologies of executing played-in programs using powerful tools such as model-checking and synthesis. Our proposed work is divided into four main threads: (1) play-in, the development of new languages and interaction techniques; (2) play-out, the development of new execution technologies; (3) domain specific adaptations and applications; and (4) integration and tools. The play-in techniques proposed include the translation of systems requirements given in natural language into an executable artifact, the use of novel and dynamic human machine interaction techniques, relying on visual languages as target languages. The play-out execution methods proposed include the use of model-checking and synthesis algorithms, compilation, and execution environments that learn. Domain specific applications proposed include web services, tactical simulators, embedded systems, and biological modeling. Finally, we propose to build prototype tools that will allow the evaluation of the new technologies and their dissemination into the academic community and industry.

2 102 958 €

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

Reversible epigenetic modifications regulate gene expression to define cell fate and response to environmental stimuli. Gene expression tuning by DNA and chromatin modifications is well studied, yet the effect of RNA modifications on gene expression is only starting to be revealed. More than a hundred chemical modifications decorate RNAs, mainly non-coding ones, expanding their nucleotide vocabulary and mediating their diverse functions. Several modifications were globally mapped in mRNA. Only two, N6-methyladenosine (m6A) and N1-methyladenosine (m1A) exhibit a distinct topology alluding to a functional role. We pioneered the identification of m6A that is located preferentially in distinct transcript landmarks, mostly around stop codons and mediates transcript localization, splicing, decay and translation. We now identified m1A which decorates thousands of genes mainly in the start codon vicinity, upstream to the first splice site. Our preliminary results indicate that m1A dynamically responds to environmental stimuli and plays a central role in translation regulation. The regulation and functions of m1A are still terra incognita. Our objectives are to identify m1A writers and erasers, elucidate m1A readers and the mechanisms whereby m1A dictates downstream outcomes, particularly translation regulation. We will study m1A functions in response to physiologic stimuli and stress conditions in cells and animal models by manipulation of the m1A deposition machinery. As epigenetic marks operate in a context-dependent concerted way we will map m1A marks concomitantly with m6A to decipher their interplay in regulating gene expression via a putative “epigenetic RNA code”. The data obtained from parallel mapping of m1A and m6A at a single nucleotide and a single transcript resolution, will expose the interplay between these two mRNA modifications in the context of multilayer epigenetics. The study of m1A circuits may identify targets amenable to therapeutic manipulations.

2 457 500 €

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

This proposal is aimed at developing and applying novel ultra-sensitive methods for studying the structure and dynamics of surfaces on an atomic scale, focusing on water surfaces in particular. The proposal consists of two main instrument development projects which are based on magnetic manipulation of molecular beams: (1) Developing a ground-breaking apparatus which uses a pre-polarized H2O molecular beam in order to perform NMR measurements on dilute surface science systems, measurements which were impossible using conventional NMR approaches. (2) Developing a unique second-generation helium spin echo spectrometer which is sensitive to motion on an unprecedentedly wide time scale range. This instrument will be capable of measuring atomic scale surface dynamics of systems which were previously beyond the realm of experimentalists. Both of these novel instruments will be primarily used to study the atomic scale structure and dynamics of water surfaces. Studying these systems is particularly challenging due to the delicate and complex nature of the surface, nevertheless, there is an extensive interest in studying water surfaces due to the key role they play in a wide range of research fields and applications. Examples include atmospheric chemistry, where ozone depleting reactions are catalyzed on ice surfaces, Material sciences and nano-technology, where the interaction and reactivity of a surface with water can determine the performance of novel miniature devices and even astrophysics where star birth reactions take place on ice surfaces. We intend to exploit the new contrast mechanisms and the unique time scales made available by the novel instruments we will develop, in order to obtain new experimental insights into this exciting research field.

1 850 000 €

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

The way data science algorithms and techniques, central to the Internet and on-line media, are designed need to be revolutionized. Current designs ignore participants' strategic incentives. Our vision is the establishment of an entirely new repertoire of incentive-compatible data science algorithms and techniques, obtained through pioneering the application of game-theoretic mechanism design for data science. Game theory is the branch of mathematics dealing with the modeling and analysis of multi-agent interactions. Mechanism design is the part of game theory that deals with the design of protocols/algorithms for environments consisting of self-motivated participants. Mechanism design has been central to bridging computer science and game theory. It has been widely applied to electronic commerce, advertising and routing networks, and led to significant contributions. On the other hand, data science is flowering, with major applications in search and information retrieval, on-line recommendation systems, clustering and segmentation, and social networks analysis. Quite surprisingly, although the incentives of publishers/firms/customers in such data science contexts are of great importance, mechanism design in the related settings has been almost completely neglected. The proposal aims at building theoretical foundations, providing algorithms, as well as validating through experiments, a fundamental bridge between mechanism design and data science. The ultimate success of this research would be the replacement of classical relevance ranking, segmentation, on-line explore \& exploit, and influencers' detection algorithms by incentive-compatible ones, creating the next generation of data science algorithms..

2 493 705 €

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

The physiology and behavior of mammals are subject to daily oscillations that are driven by an endogenous circadian clock. The mammalian circadian timing system is composed of a central pacemaker in the brain that is entrained by daily light-dark cycles and in turn synchronizes subsidiary oscillators in virtually all cells of the body. The core clock molecular circuitry is based on interlocked negative transcription-translation feedback loops that generate daily oscillations of gene expression in cultured cells and living animals. Circadian clocks play a major role in orchestrating daily metabolism and their disruption can lead to metabolic diseases such as diabetes and obesity. Concomitantly, circadian clocks are tightly coupled to cellular metabolism and respond to feeding cycles. The molecular mechanisms through which metabolism regulates clocks’ function are just starting to emerge. Recent work of ours and others revealed that NAD+/NADH are implicated in the function of circadian clocks, yet the molecular mechanisms involved are largely unknown. We propose to intensively study the role of NAD+/NADH in the function of circadian clocks and to reveal the underlying mechanisms. The functional interplay between circadian clocks and metabolism raises the question whether there are daily cycles in cellular metabolism and intracellular metabolites. Hitherto, direct measurements of daily changes in cellular metabolism and intracellular metabolite levels are still in their infancy. Our overarching goal is to identify metabolic cycles in mammals and mechanistically address their interplay with circadian clocks. We will monitor metabolic outputs in intact cells and living animals and systemically measure daily changes in intracellular metabolites. Our findings are expected to push forward a paradigm shift in the circadian field from the current “transcriptional-translational clocks” to “metabolic clocks”.

1 499 980 €

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

The purpose of this project is to write a long-term regional history of medicine in the Middle East and North Africa from a transnational and multi-layered perspective. A regional approach will enable tracing both global influences and local specificities, while a long-term perspective (1830-1960) will allow tracing continuity and change from the late Ottoman Middle East through the colonial to the post-colonial periods. Combining archival and published sources in Arabic, French, English, Hebrew, English, German and Ottoman Turkish, it will offer a unique perspective into the formation of the modern Middle East. Research for this project will revolve around five main cores: First, the global context: global vectors of disease transmission, alongside the transmission of medical knowledge and expertise. Second, the international aspect: how international conventions and international bodies affected the region and were affected by it. Third, the regional flow of both health challenges and proposed solutions, the regional spread of epidemics and the formation of regional epistemic communities. Fourth, the colonial aspect, noting both inter- and intra-colonial influences, and the encounter between colonial bodies of knowledge and locally produced ones. Fifth, the role played by doctors in various national projects: the nahda, namely the Arabic literary revival from the mid-nineteenth century onwards; the Zionist project; Egyptian and Syrian interwar nationalism and, later, Arab nationalism. This project will portray an intersection between the corporal, the social, the cultural and the technological and trace these interconnections across time and space. Health, medicine and hygiene will be a prism through which to explore large processes, such as colonization and decolonization, national identity and state-building. The scientific development of medicine and the globalization of health-risks and medical knowledge in this period make medicine an ideal case study.

1 867 181 €

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

Bacteria use various mechanisms to combat competitors and colonize new niches. The Type VI Secretion System (T6SS), a contact-dependent protein delivery apparatus, is a widespread, recently discovered machine used by Gram-negative bacteria to target competitors. Its toxicity is mediated by secreted proteins called effectors, yet the identity of many effectors, the mechanism of secretion of different effector classes, and their toxic activities remain largely unknown. I recently uncovered a widespread class of T6SS effectors that share a domain called MIX. MIX-effectors are polymorphic proteins carrying various toxin domains, many of which with unknown activities. Many bacterial pathogens have acquired resistance to contemporary antibiotic treatments, becoming a public health threat and necessitating the development of novel antibacterial strategies. Thus, as a relatively untapped antibacterial system, studying the T6SS and its MIX-effectors presents a double incentive: 1) previously uncharacterized antibacterial activities of MIX-effectors can illuminate novel cellular targets for antibacterial drug development; 2) the T6SS machinery can be used as a novel toxin delivery platform to combat multi-drug resistant bacterial infections, using polymorphic MIX-effectors. In this proposal, I will focus on T6SS MIX-effectors and elucidate their activities, mechanism of secretion, and utilization as antibacterial agents, by combining microbiology, molecular biology, genetic, biochemical, and proteomic approaches. Specifically, the goal of this proposal is to utilize T6SSs and MIX-effectors to develop a novel T6SS-based, antibacterial therapeutic platform in which a nonpathogenic bacterium will be engineered to carry a T6SS that can secrete a diverse repertoire of polymorphic antibacterial MIX-effectors. This innovative platform has several advantages over current antibacterial strategies, and can be used as an adjustable tool to combat multi-drug resistant bacteria.

1 484 375 €

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

This project seeks to study the Mongol Empire in its full Eurasian context. It combines a world history perspective with close reading in a huge array of primary sources in various languages (mainly Persian, Arabic and Chinese) and different historiographical traditions, and classifies the acquired information into a sophisticated prosopographical database, which records the individuals acting under Mongol rule in the 13th and 14th centuries. On the basis of this unique corpus, the project maps and analyzes mobility patterns, and the far-reaching effects that this mobility generated. More specifically, it aims: (a) to analyze modes of migrations in Mongol Eurasia: why, how, when and into where people- along with their ideas and artefacts - moved across Eurasia, portraying the full spectrum of such populations movements from the coerced to the voluntary. (b) to shed light on the economic and cultural exchange that this mobility engendered, with a stress on the religious, scientific and commercial networks both within and beyond the empire’s frontiers. (c) to reconstruct the new elite of the empire by scrutinizing the personnel of key Mongolian institutions, such as the guard, the judicial and postal systems, the diplomatic corps, and the local administration. These issues will be studied comparatively, in the period of the united Mongol empire (1206-1260) and across its four successor khanates that centred at China, Iran, Central Asia and Russia. The result will be a quantum leap forward in our understanding of the Mongol empire and its impact on world history, and a major contribution to the theoretical study of pre-modern migrations, cross-cultural contacts, nomad-sedentary relations and comparative study of empires. Moreover, the re-conceptualization of the economic and cultural exchange in Mongol Eurasia will lead to a broader and more nuanced understanding of the transition from the Middle Ages to the early modern era.

1 500 000 €

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

The evolution of specificity between interacting biological molecules underlies the diversification and expansion of biological pathways. A shift in specificity poses a serious theoretical problem; it requires coordinated mutations in the interacting partners, but mutation in one partner may lead to loss of interaction and functional failure. While some theoretical suggestions were proposed to solve this 'specificity valley crossing' problem, it remains a challenge to study this problem empirically at the molecular level. In bacteria, there are numerous divergent evolving pathways. Many of these pathways are involved in mediating conflicts between selfish genes, cells and populations. We and others have speculated that such multilevel selection can facilitate pathway divergence. Here we propose to study this link using the Rap-Phr cell-cell communication system, which has diversified to ~100 specific systems in the B. subtilis lineage. These systems consist of a receptor (Rap) and its cognate peptide pheromone (Phr) that influence multiple levels of selection. They promote their own horizontal transfer, modulate core cellular pathways, and manipulate cooperation between cells. Combining modelling with deep mutational scanning, competition assays and time-lapse microscopy we will quantitatively study all these levels of selection and their implication for diversification on a large fitness landscape. Specifically, we will (1) map the Rap-Phr interaction landscape at unprecedented resolution, constructing and screening libraries of ~106 Phr peptide variants and ~104 Rap variants. (2) Quantify the fitness effects of these systems at multiple levels of selection in biofilms. (3) Theoretically generate and experimentally verify predictions about how Rap-Phr co-evolve and diversify. Our work will pioneer the study of fitness landscapes under multilevel selection and provide a direct, quantitative, and predictive framework for understanding the evolution of specificity.

2 000 000 €

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