ERC FUNDED PROJECTS

Serotonin (5-HT) is a central neuromodulator and a major target of therapeutic psychoactive drugs, but relatively little is known about how it modulates information processing in neural circuits. The theory of predictive coding postulates that the brain combines raw bottom-up sensory information with top-down information from internal models to make perceptual inferences about the world. We hypothesize, based on preliminary data and prior literature, that a role of 5-HT in this process is to report prediction errors and promote the suppression and weakening of erroneous internal models. We propose that it does this by inhibiting top-down relative to bottom-up cortical information flow. To test this hypothesis, we propose a set of experiments in mice performing olfactory perceptual tasks. Our specific aims are: (1) We will test whether 5-HT neurons encode sensory prediction errors. (2) We will test their causal role in using predictive cues to guide perceptual decisions. (3) We will characterize how 5-HT influences the encoding of sensory information by neuronal populations in the olfactory cortex and identify the underlying circuitry. (4) Finally, we will map the effects of 5-HT across the whole brain and use this information to target further causal manipulations to specific 5-HT projections. We accomplish these aims using state-of-the-art optogenetic, electrophysiological and imaging techniques (including 9.4T small-animal functional magnetic resonance imaging) as well as psychophysical tasks amenable to quantitative analysis and computational theory. Together, these experiments will tackle multiple facets of an important general computational question, bringing to bear an array of cutting-edge technologies to address with unprecedented mechanistic detail how 5-HT impacts neural coding and perceptual decision-making.

2 486 074 €

Start date: 2016-01-01, End date: 2020-12-31

Cytokinesis completes cell division by partitioning the contents of the mother cell to the two daughter cells. This process is accomplished through the assembly and constriction of a contractile ring, a complex actomyosin network that remains poorly understood on the molecular level. Research in cytokinesis has overwhelmingly focused on signaling mechanisms that dictate when and where the contractile ring is assembled. By contrast, the research I propose here addresses fundamental questions about the structural and functional properties of the contractile ring itself. We will use the nematode C. elegans to exploit the power of quantitative live imaging assays in an experimentally tractable metazoan organism. The early C. elegans embryo is uniquely suited to the study of the contractile ring, as cells dividing perpendicularly to the imaging plane provide a full end-on view of the contractile ring throughout constriction. This greatly facilitates accurate measurements of constriction kinetics, ring width and thickness, and levels as well as dynamics of fluorescently-tagged contractile ring components. Combining image-based assays with powerful molecular replacement technology for structure-function studies, we will 1) determine the contribution of branched and non-branched actin filament populations to contractile ring formation; 2) explore its ultra-structural organization in collaboration with a world expert in electron microcopy; 3) investigate how the contractile ring network is dynamically remodeled during constriction with the help of a novel laser microsurgery assay that has uncovered a remarkably robust ring repair mechanism; and 4) use a targeted RNAi screen and phenotype profiling to identify new components of actomyosin contractile networks. The results from this interdisciplinary project will significantly enhance our mechanistic understanding of cytokinesis and other cellular processes that involve actomyosin-based contractility.

1 499 989 €

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

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

New generations of devices for tissue engineering (TE) should rationalize better the physical and biochemical cues operating in tandem during native regeneration, in particular at the scale/organizational-level of the stem cell niche. The understanding and the deconstruction of these factors (e.g. multiple cell types exchanging both paracrine and direct signals, structural and chemical arrangement of the extra-cellular matrix, mechanical signals…) should be then incorporated into the design of truly biomimetic biomaterials. ATLAS proposes rather unique toolboxes combining smart biomaterials and cells for the ground-breaking advances of engineering fully time-self-regulated complex 2D and 3D devices, able to adjust the cascade of processes leading to faster high-quality new tissue formation with minimum pre-processing of cells. Versatile biomaterials based on marine-origin macromolecules will be used, namely in the supramolecular assembly of instructive multilayers as nanostratified building-blocks for engineer such structures. The backbone of these biopolymers will be equipped with a variety of (bio)chemical elements permitting: post-processing chemistry and micro-patterning, specific/non-specific cell attachment, and cell-controlled degradation. Aiming at being applied in bone TE, ATLAS will integrate cells from different units of tissue physiology, namely bone and hematopoietic basic elements and consider the interactions between the immune and skeletal systems. These ingredients will permit to architect innovative films with high-level dialogue control with cells, but in particular sophisticated quasi-closed 3D capsules able to compartmentalise such components in a “globe-like” organization, providing local and long-range order for in vitro microtissue development and function. Such hybrid devices could be used in more generalised front-edge applications, including as disease models for drug discovery or test new therapies in vitro.

2 498 988 €

Start date: 2015-12-01, End date: 2020-11-30

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

The two fundamental challenges of this project are the integration of medieval Jewries and their histories within the framework of European history without undermining their distinct communal status and the creation of a history of everyday medieval Jewish life that includes those who were not part of the learned elite. The study will focus on the Jewish communities of northern Europe (roughly modern Germany, northern France and England) from 1100-1350. From the mid-thirteenth century these medieval Jewish communities were subject to growing persecution. The approaches proposed to access daily praxis seek to highlight tangible dimensions of religious life rather than the more common study of ideologies to date. This task is complex because the extant sources in Hebrew as well as those in Latin and vernacular were written by the learned elite and will require a broad survey of multiple textual and material sources. Four main strands will be examined and combined: 1. An outline of the strata of Jewish society, better defining the elites and other groups. 2. A study of select communal and familial spaces such as the house, the synagogue, the market place have yet to be examined as social spaces. 3. Ritual and urban rhythms especially the annual cycle, connecting between Jewish and Christian environments. 4. Material culture, as objects were used by Jews and Christians alike. Aspects of material culture, the physical environment and urban rhythms are often described as “neutral” yet will be mined to demonstrate how they exemplified difference while being simultaneously ubiquitous in local cultures. The deterioration of relations between Jews and Christians will provide a gauge for examining change during this period. The final stage of the project will include comparative case studies of other Jewish communities. I expect my findings will inform scholars of medieval culture at large and promote comparative methodologies for studying other minority ethnic groups

1 941 688 €

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

Peptide building blocks serve as very attractive bio-inspired elements in nanotechnology owing to their controlled self-assembly, inherent biocompatibility, chemical versatility, biological recognition abilities and facile synthesis. We have demonstrated the ability of remarkably simple aromatic peptides to form well-ordered nanostructures of exceptional physical properties. By taking inspiration from the minimal recognition modules used by nature to mediate coordinated processes of self-assembly, we have developed building blocks that form well-ordered nanostructures. The compact design of the building blocks, and therefore, the unique structural organization, resulted in metallic-like Young's modulus, blue luminescence due to quantum confinement, and notable piezoelectric properties. The goal of this proposal is to develop two new fronts for bio-inspired building block repertoire along with co-assembly to provide new avenues for organic nanotechnology. This will combine our vast experience in the assembly of aromatic peptides together with additional structural modules from nature. The new entities will be developed by exploiting the design principles of small aromatic building blocks to arrive at the smallest possible module that form super helical assembly based on the coiled coil motifs and establishing peptide nucleic acids based systems to combine the worlds of peptide and DNA nanotechnologies. The proposed research will combine extensive design and synthesis effort to provide a very diverse collection of novel buildings blocks and determination of their self-assembly process, followed by broad chemical, physical, and biological characterization of the nanostructures. Furthermore, effort will be made to establish supramolecular co-polymer systems to extend the morphological control of the assembly process. The result of the project will be a large and defined collection of novel chemical entities that will help reshape the field of bioorganic nanotechnology.

3 003 125 €

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

Tight regulation of RNA metabolism is essential for normal brain function. This includes co and post-transcriptional regulation, which are extremely prevalent in neurons. Recently, circular RNAs (circRNAs), a highly abundant new type of regulatory non-coding RNA have been found across the animal kingdom. Two of these RNAs have been shown to act as miRNA sponges but no function is known for the thousands of other circRNAs, indicating the existence of a widespread layer of previously unknown gene regulation. The present proposal aims to comprehensively determine the role and mode of actions of circRNAs in gene expression and RNA metabolism in the fly brain. We will do so by studying their biogenesis, transport, and mechanism of action, as well as by determining the roles of circRNAs in neuronal function and behaviour. Briefly, we will: 1) identify factors involved in the biogenesis, localization, and stabilization of circRNAs; 2) determine neuro-developmental, molecular, neural and behavioural phenotypes associated with down or up regulation of specific circRNAs; 3) study the molecular mechanisms of action of circRNAs: identify circRNAs that work as miRNA sponges and determine whether circRNAs can encode proteins or act as signalling molecules and 4) perform mechanistic studies in order to determine cause-effect relationships between circRNA function and brain physiology and behaviour. The present proposal will reveal the key pathways by which circRNAs control gene expression and influence neuronal function and behaviour. Therefore it will be one of the pioneer works in the study of this new and important area of research, which we predict will fundamentally transform the study of gene expression regulation in the brain

1 971 750 €

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

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

Cancer is caused by a series of genetic alterations that confer an advantage to cancer cells, leading to uncontrolled growth. However, each tumor exhibits distinct molecular changes, making each patient’s malignancy unique. Hence, in the personalized medicine era, cancer treatment aims to tailor the most suitable treatment for each patient according to his/her genetic background, tumor acquired mutations and clinical indications. The p53 tumor suppressor is the most frequently mutated gene in human cancers, with thousands of different tumor-associated mutations reported. Many such cancer-associated mutations in p53 lead to loss of its tumor suppressive activity and in some cases, to gain of new oncogenic functions, resulting in tumor recurrence and enhanced patient mortality. Importantly, tumors with different p53 mutations exhibit specific cancerous phenotypes and do not respond to particular treatments. Based on our ERC-funded breakthrough technology, where we made a library of ~10,000 distinct p53 variants, and based on our strong IPR offering and competitive advantages, here we propose to develop three products for determining which treatment (or combination) would be most effective for treating a patient’s tumor according to his specific p53 sequence, reducing excruciating side effects and improving treatment outcomes: 1) Offering patients/physicians a list of treatments ranked by their efficacy in treating cells of similar origin and p53 mutations to those present in the patient’s tumor, allowing them to make more informed treatment decisions. 2) Offering companies in the personalized cancer treatment field access to our existing proprietary data regarding treatment efficacies towards p53 genetic variants. 3) A service to drug developing companies that applies our technology for testing the efficacy of a client-supplied drug of interest over all ~10,000 p53 mutations in our library in a cell-line of choice.

150 000 €

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

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

Social-science explanations for rising wage inequality have reached a dead end. Most economists argue that computerization has been primarily responsible, while on the other side of the argument are sociologists and political scientists who stress the role of political forces in the evolution process of wages. I would like to use my knowledge and experience to come up with an original theory on the complex dynamics between technology and politics in order to solve two unsettled questions regarding the role of computerization in rising wage inequality: First, how can computerization, which diffused simultaneously in rich countries, explain the divergent inequality trends in Europe and the United States? Second, what are the mechanisms behind the well-known observed positive correlation between computers and earnings? To answer the first question, I develop a new institutional agenda stating that politics, broadly defined, mitigates the effects of technological change on wages by stimulating norms of fair pay and equity. To answer the second question, I propose a truly novel perspective that conceptualizes the earnings advantage that derives from computerization around access to and control of information on the production process. Capitalizing on this new perspective, I develop a new approach to measuring computerization to capture the form of workers’ interaction with computers at work, and build a research strategy for analysing the effect of computerization on wages across countries and workplaces, and over time. This research project challenges the common understanding of technology’s role in producing economic inequality, and would thereby significantly impact all of the abovementioned disciplines, which are debating over the upswing in wage inequality, as well as public policy, which discusses what should be done to confront the resurgence of income inequality.

1 495 091 €

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

"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

The efficiency of cryptographic constructions is a fundamental question. Theoretically, it is important to understand how much computational resources are needed to guarantee strong notions of security. Practically, highly efficient schemes are always desirable for real-world applications. More generally, the possibility of cryptography with low complexity has wide applications for problems in computational complexity, combinatorial optimization, and computational learning theory. In this proposal we aim to understand what are the minimal computational resources needed to perform basic cryptographic tasks. In a nutshell, we suggest to focus on three main objectives. First, we would like to get better understanding of the cryptographic hardness of random local functions. Such functions can be computed by highly-efficient circuits and their cryptographic hardness provides a strong and clean formulation for the conjectured average-case hardness of constraint satisfaction problems - a fundamental subject which lies at the core of the theory of computer science. Our second objective is to harness our insights into the hardness of local functions to improve the efficiency of basic cryptographic building blocks such as pseudorandom functions. Finally, our third objective is to expand our theoretical understanding of garbled circuits, study their limitations, and improve their efficiency. The suggested project can bridge across different regions of computer science such as random combinatorial structures, cryptography, and circuit complexity. It is expected to impact central problems in cryptography, while enriching the general landscape of theoretical computer science.

1 265 750 €

Start date: 2015-05-01, End date: 2021-04-30

In this project, the basal ganglia are defined as actor-critic reinforcement learning networks that aim at an optimal tradeoff between the maximization of future cumulative rewards and the minimization of the cost (the reinforcement driven multi objective optimization RDMOO model). This computational model will be tested by multiple neuron recordings in the major basal ganglia structures of monkeys engaged in a similar behavioral task. We will further validate the RMDOO computational model of the basal ganglia by extending our previous studies of neural activity in the MPTP primate model of Parkinson's disease to a primate model of central serotonin depletion and emotional dysregulation disorders. The findings in the primate model of emotional dysregulation will then be compared to electrophysiological recordings carried out in human patients with treatment-resistant major depression and obsessive compulsive disorder during deep brain stimulation (DBS) procedures. I aim to find neural signatures (e.g., synchronous gamma oscillations in the actor part of the basal ganglia as predicted by the RMDOO model) characterizing these emotional disorders and to use them as triggers for closed loop adaptive DBS. Our working hypothesis holds that, as for the MPTP model of Parkinson's disease, closed loop DBS will lead to greater amelioration of the emotional deficits in serotonin depleted monkeys. This project incorporates extensive collaborations with a team of neurosurgeons, neurologists, psychiatrists, and computer science/ neural network researchers. If successful, the findings will provide a firm understanding of the computational physiology of the basal ganglia networks and their disorders. Importantly, they will pave the way to better treatment of human patients with severe mental disorders.

2 476 922 €

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

During the human lifetime 10000 trillion cell divisions take place to ensure tissue homeostasis and several vital functions in the organism. Mitosis is the process that ensures that dividing cells preserve the chromosome number of their progenitors, while deviation from this, a condition known as aneuploidy, represents the most common feature in human cancers. Here we will test two original concepts with strong implications for chromosome segregation fidelity. The first concept is based on the “tubulin code” hypothesis, which predicts that molecular motors “read” tubulin post-translational modifications on spindle microtubules. Our proof-of-concept experiments demonstrate that tubulin detyrosination works as a navigation system that guides chromosomes towards the cell equator. Thus, in addition to regulating the motors required for chromosome motion, the cell might regulate the tracks in which they move on. We will combine proteomic, super-resolution and live-cell microscopy, with in vitro reconstitutions, to perform a comprehensive survey of the tubulin code and the respective implications for motors involved in chromosome motion, mitotic spindle assembly and correction of kinetochore-microtubule attachments. The second concept is centered on the recently uncovered chromosome separation checkpoint mediated by a midzone-associated Aurora B gradient, which delays nuclear envelope reformation in response to incompletely separated chromosomes. We aim to identify Aurora B targets involved in the spatiotemporal regulation of the anaphase-telophase transition. We will establish powerful live-cell microscopy assays and a novel mammalian model system to dissect how this checkpoint allows the detection and correction of lagging/long chromosomes and DNA bridges that would otherwise contribute to genomic instability. Overall, this work will establish a paradigm shift in our understanding of how spatial information is conveyed to faithfully segregate chromosomes during mitosis.

2 323 468 €

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

This project is about the racialization of migrant labourers across political boundaries, with a main focus on impoverished Europeans who served in huge numbers as indentured labourers in nineteenth-century Guianese, Caribbean and Hawaiian sugar plantations and in the workforce of late nineteenth and early twentieth century New England cotton mills. With this project I aim to provide major, innovative contributions on three fronts: (i) theory-making, by working the concepts of race, racism, racialization, embodiment and memory in association with migrant work across political boundaries and imperial classifications; (ii) social relevance of basic research, by linking an issue of pressing urgency in contemporary Europe to substantive, broad-scope, and multi-sited anthropological/historical research on the wider structures of domination, rather than to targeted problem-solving research of immediate applicability; (iii) disciplinary scope, by proposing to unsettle historical anthropology and ethnographic history from within the boundaries of a single empire, and to overcome the limitations of existing comparative studies, by inquiring into the flows and interactions between competing empires. I will also: (iv) strengthen the methodology for multi-sited, multi-period research in anthropology; (v) contribute to an anthropology of global connections and trans-local approaches; (vi) promote the multidisciplinary and combined-methods approach to complex subjects; (vii) narrate a poorly known set of historical situations of labour racializations involving Europeans and document the ways they reverberate through generations; and (viii) make the analysis available to both academic audiences and the different communities involved in the research.

2 161 397 €

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

The project focuses on the interface between computational and combinatorial geometry. Geometric problems emerge in a variety of computational fields that interact with the physical world. The performance of geometric algorithms is determined by the description complexity of their underlying combinatorial structures. Hence, most theoretical challenges faced by computational geometry are of a distinctly combinatorial nature. In the past two decades, computational geometry has been revolutionized by the powerful combination of random sampling techniques with the abstract machinery of geometric arrangements. These insights were used, in turn, to establish state-of-the-art results in combinatorial geometry. Nevertheless, a number of fundamental problems remained open and resisted numerous attempts to solve them. Motivated by the recent breakthrough results, in which the PI played a central role, we propose two exciting lines of study with the potential to change the landscape of this field. The first research direction concerns the complexity of Voronoi diagrams -- arguably the most common structures in computational geometry. The second direction concerns combinatorial and algorithmic aspects of geometric intersection structures, including some fundamental open problems in geometric transversal theory. Many of these questions are motivated by geometric variants of general covering and packing problems, and all efficient approximation schemes for them must rely on the intrinsic properties of geometric graphs and hypergraphs. Any progress in responding to these challenges will constitute a major breakthrough in both computational and combinatorial geometry.

1 303 750 €

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

"In recent years, the importance of superimposing the contribution of the measure to that of the metric, in determining the underlying space's (generalized Ricci) curvature, has been clarified in the works of Lott, Sturm, Villani and others, following the definition of Curvature-Dimension introduced by Bakry and Emery. We wish to systematically incorporate this important idea of considering the measure and metric in tandem, in the study of questions pertaining to isoperimetric and concentration properties of convex domains in high-dimensional Euclidean space, where a-priori there is only a trivial metric (Euclidean) and trivial measure (Lebesgue). The first step of enriching the class of uniform measures on convex domains to that of non-negatively curved (""log-concave"") measures in Euclidean space has been very successfully implemented in the last decades, leading to substantial progress in our understanding of volumetric properties of convex domains, mostly regarding concentration of linear functionals. However, the potential advantages of altering the Euclidean metric into a more general Riemannian one or exploiting related Riemannian structures have not been systematically explored. Our main paradigm is that in order to progress in non-linear questions pertaining to concentration in Euclidean space, it is imperative to cast and study these problems in the more general Riemannian context. As witnessed by our own work over the last years, we expect that broadening the scope and incorporating tools from the Riemannian world will lead to significant progress in our understanding of the qualitative and quantitative structure of isoperimetric minimizers in the purely Euclidean setting. Such progress would have dramatic impact on long-standing fundamental conjectures regarding concentration of measure on high-dimensional convex domains, as well as other closely related fields such as Probability Theory, Learning Theory, Random Matrix Theory and Algorithmic Geometry."

1 194 190 €

Start date: 2015-10-01, End date: 2020-09-30

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

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

T lymphocytes display potent pro- or anti-inflammatory properties, which typically associate with distinct effector (Teff) versus regulatory (Treg) cell subsets. Based on published and our preliminary data showing a major impact of microRNAs on T cell differentiation and (auto)immune pathology, my proposal aims to dissect the miRNA networks that control the balance between Teff and Treg subsets in vivo, in various experimental models of infection and autoimmunity. We will focus on three critical mediators of T cell functions: interferon-gamma (IFN-g) and interleukin-17A (IL-17), highly pro-inflammatory Teff cytokines; and Foxp3, the transcription factor that confers Treg suppressive properties. To track the activity of these key genes, we will generate a new Ifng/ Il17/ Foxp3 triple reporter mouse, from which we will isolate Teff and Treg subsets to determine their genome-wide miRNA profiles and specific signatures in vivo. We will investigate both natural (thymic-derived and present in naïve mice) and induced (in the periphery upon challenge) Teff and Treg subsets, as they make distinct contributions to the immune response. We will identify miRNAs selectively expressed in Teff (Ifng+ or Il17+) versus Treg (Foxp3+) subsets of various lineages (CD4+, CD8+, gamma-delta or NKT) in each in vivo model; assess whether they are induced during thymic development or upon peripheral activation; and determine the robustness of subset-specific miRNA profiles across various in vivo challenges. We will then use loss- and gain-of-function strategies to define the individual miRNAs that impact Teff or Treg differentiation and disease pathogenesis; dissect the external cues and intracellular mechanisms that regulate miRNA expression; and identify the mRNA networks controlled by key miRNAs in Teff and Treg differentiation. I expect this project to provide major conceptual and experimental advances towards manipulating miRNAs either to boost immunity or to treat autoimmunity.

2 000 000 €

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

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

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

Understanding behavior is still one of the holy grails in the natural and social sciences. Behavior is often utterly complex because it is a result of an extremely rich set of past experiences, the present state of the animal and the animal’s predictions about the future; all of which affect learning, decision making and consequently behavior. Given the complexity of behavior, most researchers work in the realm of highly simplified learning tasks but these only test very basic attributes of learning and are constraining discovery of more sophisticated behavior. To date, there are only few available platforms for rigorous study of complex behavioral paradigms in experimental animals; not in basic science nor in biomedical research. Our goal is to bring to completion (and potential commercialization) a novel platform for analyzing complex animal behavior named “The Educage” to allow fully automatic, hands free assessment of higher cognitive functions in freely behaving animals. Potential customers are research labs, and the biomedical industry. The Educage will allow researchers to study behavior at unprecedented resolution, 24/7, for any duration of time. The learning paradigms can be tailored to the specific task of interest. The Educage has many advantages that outperform existing technologies by allowing rigorous statistical assessment of complex behaviors in laboratory animals. The Educage allows researchers the flexibility to monitor, analyze and manipulate the experiment during the behavior. Our system can be reliably used to analyze perceptual learning in mice and is well suited for being a new and rigorous behavioral platform. It has great potential to become a central tool to fuel discovery in animal research both in biology and biomedical research.

150 000 €

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

Flows of complex fluids, such as many biological fluids and most synthetic fluids, are common in our daily life and are very important from an industrial perspective. Because of their inherent nonlinearity, the flow of complex viscoelastic fluids often leads to counterintuitive and complex behaviour and, above critical conditions, can prompt flow instabilities even under low Reynolds number conditions which are entirely absent in the corresponding Newtonian fluid flows. The primary goal of this project is to substantially expand the frontiers of our current knowledge regarding the mechanisms that lead to the development of such purely-elastic flow instabilities, and ultimately to understand the transition to so-called “elastic turbulence”, a turbulent-like phenomenon which can arise even under inertialess flow conditions. This is an extremely challenging problem, and to significantly advance our knowledge in such important flows these instabilities will be investigated in a combined manner encompassing experiments, theory and numerical simulations. Such a holistic approach will enable us to understand the underlying mechanisms of those instabilities and to develop accurate criteria for their prediction far in advance of what we could achieve with either approach separately. A deep understanding of the mechanisms generating elastic instabilities and subsequent transition to elastic turbulence is crucial from a fundamental point of view and for many important practical applications involving engineered complex fluids, such as the design of microfluidic mixers for efficient operation under inertialess flow conditions, or the development of highly efficient micron-sized energy management and mass transfer systems. This research proposal will create a solid basis for the establishment of an internationally-leading research group led by the PI studying flow instabilities and elastic turbulence in complex fluid flows.

994 110 €

Start date: 2012-10-01, End date: 2018-01-31

Cancer is a global epidemic that affects all ages and socio-economic groups. In turn, tremendous resources are being invested in prevention, diagnosis, and treatment of cancer. For instance, over 1,000 anticancer drugs are currently in various phases of development and pre-approval testing, more than the number for heart disease, stroke, and mental illness combined. Finding multi-drug combinations for cancer is an increasingly pressing therapeutic challenge. However, screening all possible drug combinations is an impossible task because the number of experiments grows exponentially with the number of different drugs and doses. Therefore, highly effective combinations of already approved drugs may likely exist that have never been tested before at the appropriate doses, due the astronomical number of wet lab tests required to find these combinations. Motivated by this challenge, we have developed a novel method for computing the effects of high order combinations of drugs on cancer cells and predicting the best drug for a given tumor based only on a very small number of experiments. In turn, the goals of our PoC project are to further validate the potential of our formula by means of numerous rigorous tests and to establish the business potential of our idea. If successful, this PoC project will pave the way to the development and adoption of highly personalized drug cocktails that are designed based only on a limited number of measurements performed on patient-derived tumor material.

150 000 €

Start date: 2016-11-01, End date: 2018-04-30

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

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

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

A fundamental research challenge in modern cryptography is understanding the necessary hardness assumptions required to build different cryptographic primitives. Attempts to answer this question have gained tremendous success in the last 20-30 years. Most notably, it was shown that many highly complicated primitives can be based on the mere existence of one-way functions (i.e., easy to compute and hard to invert), while other primitives cannot be based on such functions. This research has yielded fundamental tools and concepts such as randomness extractors and computational notions of entropy. Yet many of the most fundamental questions remain unanswered. Our first goal is to answer the fundamental question of whether cryptography can be based on the assumption that P not equal NP. Our second and third goals are to build a more efficient symmetric-key cryptographic primitives from one-way functions, and to establish effective methods for security amplification of cryptographic primitives. Succeeding in the second and last goals is likely to have great bearing on the way that we construct the very basic cryptographic primitives. A positive answer for the first question will be considered a dramatic result in the cryptography and computational complexity communities. To address these goals, it is very useful to understand the relationship between different types and quantities of cryptographic hardness. Such understanding typically involves defining and manipulating different types of computational entropy, and comprehending the power of security reductions. We believe that this research will yield new concepts and techniques, with ramification beyond the realm of foundational cryptography.

1 239 838 €

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

One of the greatest challenges facing society is treating patients afflicted with degenerative and age-related disorders, such as multiple sclerosis, Parkinson’s disease and diabetes. For all of these, stem cell therapy represents a novel treatment approach and a great hope for the millions of patients worldwide. In my ERC-funded research project, we successfully managed to generate Extracellular-signal-Regulated Kinases (ERK) signalling independent human naïve Pluripotent Stem Cells (PSCs), a new category of human stem cells that retrain features that are characteristic of earlier developmental stages, i.e. they are more “primitive” than typical/conventional human PSCs. We managed to do so by employing a novel medium that allows the acquisition of many apparent naïve features that were previously observed only in rodent pluripotent stem cells. Importantly, this new pluripotent configuration, not only comes in different molecular flavours, but also has different functional properties. In turn, the first goal of our PoC project is to establish the technical feasibility of our novel medium by carrying out a series of molecular and functional tests. Such tests would enable us to further improve the existing medium conditions and create a commercial-like platform for enhanced expansion and derivation of human naïve induced PSCs. The second goal of FORMAT project is to establish the commercialization potential of our novel medium as a means to maintain standardized cells that can in turn be used to replenish, regenerate and repair damaged human tissues.

150 000 €

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

"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

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

DNA methylation, the covalent binding of a methyl group (CH3) to cytosine base, regulates the genome activity and plays a fundamental developmental role in eukaryotes. Its epigenetic characteristics of regulating transcription without changing the genetic code together with the ability to be transmitted through DNA replication allow organisms to memorize cellular events for many generations. DNA methylation is mostly known for its role in transcriptional silencing; however, its functional output is more complex and is influenced in part by its DNA context. Recent genomic studies, have found DNA methylation to be targeted inside sequences of actively transcribed genes, thus termed gene body methylation. Despite being an evolutionary conserved and a robust methylation pathway targeted to thousands of genes in animal and plant genomes, the function of gene body methylation is still poorly understood at both the molecular and functional level. Similar to the chicken and egg conundrum, because we do not know what gene body methylation does, therefore scientists could not apply its function to discover its regulators either. Gene body methylation is targeted to a very specific subset and subregions of genes, thus we strongly believe that specific factors exist and are missing simply because that no one has ever searched for them before. Hence, to make major breakthroughs in the field, our approach is to artificially generate gene-body-specific hypomethylated plants that together with customized genetic and biochemical systems will allow us to discover regulators and interpreters of gene body methylation. Using these unique genetic tools and novel molecular factors, we will be able to ultimately explore the particular biological roles of gene body methylation. These findings will fill the gap towards a full comprehension of the entire functional array of DNA methylation, and to its more precise exploitation in yielding better crops and in treating human diseases.

1 500 000 €

Start date: 2016-10-01, End date: 2021-09-30

The interplay between intestinal microbes and immune cells ensures vital functions of the organism. However, inadequate host-microbe relationships lead to inflammatory diseases that are major public health concerns. Innate lymphoid cells (ILC) are an emergent family of effectors abundantly present at mucosal sites. Group 3 ILC (ILC3) produce pro-inflammatory cytokines and regulate mucosal homeostasis, anti-microbial defence and adaptive immune responses. ILC development and function have been widely perceived to be programmed. However, recent evidence indicates that ILC are also controlled by dietary signals. Nevertheless, how ILC3 perceive, integrate and respond to environmental cues remains utterly unexplored. We hypothesise that ILC3 sense their environment and exert their function as part of a novel epithelial-glial-ILC unit orchestrated by neurotrophic factors. Thus, we propose to employ genetic, cellular and molecular approaches to decipher how this unconventional multi-cellular unit is controlled and how glial-derived factors set ILC3 function and intestinal homeostasis. In order to achieve this, we will assess ILC3-autonomous functions of neurotrophic factor receptors. ILC3-specific loss and gain of function mutant mice for neuroregulatory receptors will be used to define the role of these molecules in ILC3 function, mucosal homeostasis, gut defence and microbial ecology. Sequentially we propose to decipher the anatomical and functional basis for the enteric epithelial-glial-ILC unit. To this end we will employ high-resolution imaging, genome-wide expression analysis and tissue-specific mutants for define target genes. Our ground-breaking research will establish a novel sensing program by which ILC3 integrate environmental cues and will define a key multi-cellular unit at the core of intestinal homeostasis and defence. Finally, our work will reveal new pathways that may be targeted in inflammatory diseases that are major Public Health concerns.

2 270 000 €

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

How animals make decisions in the wild is an open key-question in biology. Our lack of knowledge results from a technological gap – the difficulty to track animals over long periods while monitoring their behaviour; and from a conceptual gap – how to identify animals’ decision-points outdoors? We suggest applying our innovative on-board miniature sensors, to study decision making in the wild. We focus on one of the most fundamental contexts of decision making – foraging for food. We will study bats, which constitute over 20% of mammalian species and are extremely diverse, enabling to examine different aspects of decision making. Importantly, echolocating bats emit sound to perceive their environment, allowing us to infer their behavior (attacks on prey and interactions with conspecifics) via sound recording. Our miniature sensors include a GPS and an ultrasonic microphone, which enables us to reveal not only bats’ movements, but also their behavior and accordingly the factors underlying their decisions. We will study three bat species to elucidate different aspects of foraging decisions: (1) How does animal sociality facilitate decision making? We have developed a system to monitor an entire colony including all conspecific-interactions when bats are in the roost or foraging outside. (2) How do animals weigh current input against previous experience? We will study a bat that must nightly search large areas over sea to find food. (3) How flexible are animal decisions? We will manipulate the natural environment of specific individuals to study how they adjust their foraging. Our results will have far-reaching implications in many fields, from animal conservation to robotics. The operational and technical difficulty of performing controlled manipulations in the wild drives most disciplines to perform experiments exclusively in artificial laboratory conditions. Our approach opens new opportunities to conduct controlled studies in the natural environment.

1 928 750 €

Start date: 2016-03-01, End date: 2021-02-28

Inherited variation in the quantity and functionality of immune cells plays a key role in determining phenotypic diversity between individuals. Surprisingly little is known, however, about the specific contribution of immune cell subsets to variation in phenotypes such as susceptibility to infectious diseases and the underlying genetic variation. In many complex diseases, we currently have a poor understanding of the driver cell types that are responsible for inherited variation in disease states. A comprehensive mapping of quantities and functions of immune cell types during the course of disease, in large cohorts, bears the potential to transform genetic research; provides understanding of the genetic and immune basis of phenotypes; and reveals the key driver cell subsets. Here I aim to derive a mechanistic understanding of how variation in quantity and function of immune cell subsets mediates inherited variation in disease states. I propose to develop a computational model that integrates predicted quantities and functions of cell subsets with genotypic and phenotypic information, leading to specific hypotheses on physiological regulation and the particular cell subsets that drive phenotypic diversity. To circumvent the technical difficulty in quantifying a large number of immune cell types, I will profile gene expression and computationally quantify changes in a large number of cell types. I will develop and apply this strategy to dissect Influenza infection in mice. Since changes in immune responses play a key role in complex diseases, our ability to predict variation in immune responses from genotypes would have important clinical implications. This project has far reaching implications as the paradigm developed here will transform quantitative genetics studies as well as systems immunology research of complex disease. This approach will be applicable to any mammalian disease, allowing researchers to dissect their own systems at unprecedented detail.

1 497 000 €

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

"Expander graphs have been playing a fundamental role in many areas of computer science. During the last 15 years they have also found important and unexpected applications in pure mathematics. The goal of the current research is to develop systematically high-dimensional (HD) theory of expanders, i.e., simplicial complexes and hypergraphs which resemble in dimension d, the role of expander graphs for d = 1. There are several motivations for developing such a theory, some from pure mathematics and some from computer science. For example, Ramanujan complexes (the HD versions of the ""optimal"" expanders, the Ramanujan graphs) have already been useful for extremal hypergraph theory. One of the main goals of this research is to use them to solve other problems, such as Gromov's problem: are there bounded degree simplicial complexes with the topological overlapping property (""topological expanders""). Other directions of HD expanders have applications in property testing, a very important subject in theoretical computer science. Moreover they can be a tool for the construction of locally testable codes, an important question of theoretical and practical importance in the theory of error correcting codes. In addition, the study of these simplicial complexes suggests new quantum error correcting codes (QECC). It is hoped that it will lead to such codes which are also low density parity check (LDPC). The huge success and impact of the theory of expander graphs suggests that the high dimensional theory will also bring additional unexpected applications beside those which can be foreseen as of now."

1 592 500 €

Start date: 2016-08-01, End date: 2021-07-31

Histones are the major structural proteins of eukaryotic DNA. Two copies each of the core histones, H2A, H2B, H3 and H4, form the core nucleosome, the basic unit of chromatin. Histone tails protrude from the nucleosome structure and are subject to a variety of post-translational modifications on multiple residues, including methylation, acetylation, phosphorylation, sumoylation, ubiquitination and polyribosylation. These histone modifications dictate local and global structure of chromatin, rendering it active and decondensed (‘euchromatic’) or suppressed and compact (‘heterochromatic’) by the recruitment of chromatin-binding proteins that recognize and associate with specific modifications. Histone modifications are therefore the basic regulatory unit of gene expression, genomic silencing, developmental programs, cell division and essentially all cellular processes. Understanding this so-called ‘epigenetic’ landscape is therefore vital for all biological mechanisms. Currently a Western blot is required in order to determine the state of each of the dozens of different histone modifications. Because of the growing number of histone modifications, this procedure is time consuming and labour intensive. Here I suggest to develop an antibody microarray to monitor the levels of all histone modifications simultaneously. This method will be essentially useful for any tissue or cell type in any biological process, for diagnosis, prognosis and drug screening. In addition to basic research, our platform will enable fast and reliable screening for epigenetic effects of existing and novel drugs. We believe that such a product could serve many drug companies interested in direct and indirect effects of epigenetic and non-epigentic drugs.

150 000 €

Start date: 2015-10-01, End date: 2017-03-31

Deregulation of signal transduction is a feature of tumor cells and signaling therapies are gaining importance in the growing arsenal against cancer. However, their full potential can only be achieved once we overcome the limited knowledge on how signaling networks are wired in cancer cells. Interleukin 7 (IL7) and its receptor (IL7R) are essential for normal T-cell development and function. However, they can also promote autoimmunity, chronic inflammation and cancer. We showed that patients with T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer, can display IL7R gain-of-function mutations leading to downstream signaling activation and cell transformation. Despite the biological relevance of IL7 and IL7R, the characterization of their signaling effectors remains limited. Here, we propose to move from the single molecule/pathway-centered analysis that has characterized the research on IL7/IL7R signaling, into a ‘holistic’ view of the IL7/IL7R signaling landscape. To do so, we will employ a multidisciplinary strategy, in which data from complementary high throughput analyses, informing on different levels of regulation of the IL7/IL7R signaling network, will be integrated via a systems biology approach, and complemented by cell and molecular biology experimentation and state-of-the-art in vivo models. The knowledge we will generate should have a profound impact on the understanding of the fundamental mechanisms by which IL7/IL7R signaling promotes leukemia and reveal novel targets for fine-tuned therapeutic intervention in T-ALL. Moreover, the scope of insights gained should extend beyond leukemia. Our in-depth, systems-level characterization of IL7/IL7R signaling will constitute a platform with extraordinary potential to illuminate the molecular role of the IL7/IL7R axis in other cancers (e.g. breast and lung) and pathological settings where IL7 has been implicated, such as HIV infection, multiple sclerosis and rheumatoid arthritis.

1 988 125 €

Start date: 2015-09-01, End date: 2020-08-31

How do extreme electromagnetic fields modify the dynamics of matter? Will quantum electrodynamics effects be important at the focus of an ultra intense laser? How are the magnetospheres of compact stellar remnants formed, and can we capture the physics of these environments in the laboratory? These are all longstanding questions with an overarching connection to extreme plasma physics. Electron-positron pair plasmas are pervasive in all these scenarios. Highly nonlinear phenomena such as QED processes, magnetogenesis, radiation, field dynamics in complex geometries, and particle acceleration, are all linked with the collective dynamics of pair plasmas through mechanisms that remain poorly understood. Building on our state-of-the-art models, on the availability of enormous computational power, and on our recent transformative discoveries on ab initio modelling of plasmas under extreme conditions, the time is ripe to answer these questions in silico. InPairs aims to understand the multidimensional dynamics of electron-positron plasmas under extreme laboratory and astrophysical fields, to determine the signatures of the radiative processes on pair plasmas, and to identify the physics of the magnetospheres of compact stellar remnants, focusing on the electrodynamics of pulsars, that can be mimicked in laboratory experiments using ultra high intensity lasers and charged particle beams. This proposal relies on massively parallel simulations to bridge the gap, for the first time, between the pair plasma creation mechanisms, the collective multidimensional microphysics, and their global dynamics in complex geometries associated with laboratory and astrophysical systems. Emphasis will be given to detectable signatures e.g. radiation and accelerated particles, with the ultimate goal of solving some of the central questions in extreme plasma physics, thus opening new connections between computational studies, laboratory experiments, and relativistic plasma astrophysics.

1 951 124 €

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

In the past few decades, the role of judges has changed dramatically and its nature has remained largely unexplored. To date, most cases settle or reach plea-bargaining, and the greater part of judges’ time is spent on managing cases and encouraging parties to reach consensual solutions. Adjudication based on formal rules is a rare phenomenon which judges mostly avoid. The hypothesis underlying JCR is that the various Conflict Resolution methods which are used outside the courtroom, as alternatives to adjudication, could have a strong and positive influence, both theoretical and practical, on judicial activities inside the courts. Judicial activities may be conceptualised along the lines of generic modes of conflict resolution such as mediation and arbitration. Judicial conflict resolution activity is performed in the shadow of authority and in tension with it, and crosses the boundaries between criminal and civil conflicts. It can be evaluated, studied and improved through criteria which go beyond the prevalent search for efficiency in court administration. Empirically, JCR will study judicial activities in promoting settlements comparatively from a quantitative and qualitative perspective, by using statistical analysis, in-depth interviews, mapping and framing legal resources, court observations and narrative analysis. Theoretically, JCR will develop a conflict resolution jurisprudence, which prioritises consent over coercion as a leading value for the administration of justice. Prescriptively, JCR will promote a participatory endeavour to build training programs for judges that implement the research findings regarding the judicial role. Following such findings, JCR will also consider generating recommendations to change legal rules, codes of ethics, measures of evaluation, and policy framings. JCR will increase accountability and access to justice by introducing coherence into a mainstream activity of processing legal conflicts.

1 272 534 €

Start date: 2016-01-01, End date: 2020-12-31

The overarching goal of L2STAT is to understand L2 literacy acquisition by bringing together, for the first time, recent advances in the neurobiology of statistical learning (SL), a detailed statistical characterization of the world’s writing systems, and neurally-plausible general principles of learning, representation, and processing. L2STAT aims to provide a new theoretical framework that considers L2 learning and SL a two-way street: SL, on the one hand, tunes learners to the regularities of a new linguistic environment, and on the other hand, L2 environment shapes learners’ sensitivity to its specific types of statistical properties. The project will focus on the assimilation of reading skills in four novel linguistic environments, and investigate how exposure to their distinct writing systems shape, in turn, SL. L2STAT is an interdisciplinary project that launches in parallel five mutually informative research axes: 1) we employ advanced methods from computational linguistics and machine learning to precisely characterize the statistics of four highly contrasting writing systems (English, Spanish, Hebrew, Chinese). 2) We study the learning that results from biologically-inspired computational models that are exposed to these statistics, to generate a priori predictions regarding what statistical properties can (or cannot) be learned, and how neural mechanisms constrain the representations learned during L2 literacy acquisition. 3) We develop psychometrically reliable behavioral tests of individuals’ capacities to extract regularities in the visual and auditory modalities. 4) We use state of the art neuroimaging techniques including EEG, MEG, fMRI to probe the neurobiological underpinning for detecting regularities in the visual and auditory modalities. 5) We conduct behavioral experimentation in four sites (Israel, Spain, Taiwan to track literacy acquisition longitudinally in the four different languages.

2 500 000 €

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

"Inflammatory bowel diseases (IBD) is a group of chronic inflammatory conditions of the gastrointestinal tract, including Crohn’s disease (CD) and Ulcerative Colitis (UC) that can impact both the large and small bowel. IBD affects approximately 3.7 million Europeans and its peak onset is in persons of 15 to 30 years of age. IBD imposes a significant burden on Europe with over €3B in annual health care costs and over €3B in indirect cost. The prevalence of IBD is expected to increase by more than 40% over the next decade in many European countries. Therefore, to meet the needs of IBD patients in the European community, we must prepare for the evolving landscape of IBD care in the near future. Although its etiology remains unknown, unregulated immune cells are implicated in the pathogenesis of IBD. As many IBD patients are refractory to conventional medical treatments, there is an urgent need to develop novel therapeutic modalities in combination with real-time imaging in order to manage the disease. I will achieve this goal by generating a ""Trojan horse"" strategy of targeting activated leukocytes that home to the gut in IBD rodent models and reprogram their fate using RNA interference (RNAi) combined with molecular imaging. The primary objective of this proposal is to reprogram in vivo activated leukocytes involved in gut inflammation using advanced RNAi-based therapeutics combined with molecular imaging strategies as the first theranostic modality utilizing leukocytes. The following specific aims include: (i) To develop and characterize unique integrin-targeted nanoparticles (I-tsNPs) targeting a high-affinity (HA) conformation of a4b7 integrin expressed on gut leukocytes; (ii) To study I-tsNPs 3-dimensional (3-D) delivery in colitis models using microPET/CT imaging; (iii) To investigate efficacy and safety profiles using the HA I-tsNPs platform for IBD therapeutics and disease management that will lay the foundation for future clinical trials. "

2 703 125 €

Start date: 2015-11-01, End date: 2020-10-31

The interaction between light and material leads to beautiful visual phenomena that greatly enrich our perception of the world. The ability to measure and model light scattering is central to almost any field of science. However, light transport in rich scenes is a complex process involving a long sequence of scattering events. Computationally modeling, reproducing and acquiring the processes generated so easily by Mother Nature is an extremely challenging task. While several computational models have been proposed, they are all making various simplifying assumptions that cannot capture the full complexity of light transport processes in nature. In the proposed research, we suggest new measurement strategies and new inference algorithms that will allow us to infer more information on light and material interaction. Specifically, the research will focus on the following tasks: (i) Acquiring internal sub-scattering, and recovering the volumetric structure of partially translucent objects using transient imaging data; (ii) Acquiring external illumination from its reflection on diffused objects; (iii) Exploiting illumination for developing digital light sensitive displays, capable of presenting 3D scenes with spatially varying reflectance properties. As light scattering is such a fundamental phenomenon, our envisioned new tools have applications in almost any field of science, from astronomy to microscopy, and in medicine. We plan to push the bound on the penetration depth of medical imaging devices, and allow chemists to infer more information on material decomposition through scattering. In earth science we can infer aerosol density from the scattering of sunlight in the atmosphere and ocean, a central challenge in any study of climate and pollution. In addition, we will pursue new technological developments such as light sensitive displays, offering a novel form of immersive visual experience, and new technologies of coded security cameras.

1 999 825 €

Start date: 2015-12-01, End date: 2021-08-31

Within a decade, advances in single-cell genomics would allow humanity to embark on a coordinated international effort to discover the human cell lineage tree. The goal of LineageDiscovery is to lay the biological, computational and architectural foundations for this envisioned project and demonstrate its feasibility and value. An organismal cell lineage tree is a rooted, labelled binary tree where nodes represent organism cells, edges represent progeny relations and labels capture cell state. The tree of an adult human has about 100 trillion nodes. Many fundamental open questions in biology and medicine are about the structure, dynamics and variance of the human cell lineage tree in development, health, ageing and disease. E.g., which cancer cells give rise to metastases? Do beta cells renew? Which progeny do brain stem cells produce in development, maintenance and ageing? LineageDiscovery is based on a decade of research on this challenge by Shapiro’s lab and others. It will develop an efficient biological-computational cell lineage discovery workflow that starts with sampled cells and ends with knowledge of their cell lineage tree; and a scalable architecture for the collaborative development and the distributed deployment of this workflow. The workflow will be based on emerging single-cell technologies and will include novel algorithms to analyse single-cell data, to reconstruct cell lineage trees, and to infer ancestral cell type and state dynamics. A programmable meta-system will be developed and used for workflow optimization and evaluation. The workflow and architecture will be deployed and tested in a broad range of proof-of-concept human cell lineage discovery experiments with self-funded collaborators. Successful execution of this research plan coupled with expected advances in single-cell genomics would establish both the feasibility and the value of the envisioned large-scale human cell lineage discovery project, ideally leading to its launch.

2 250 000 €

Start date: 2015-09-01, End date: 2020-07-31

Mathematical statistical physics has seen spectacular progress in recent years. Existing problems which were previously unattainable were solved, opening a way to approach some of the classical open questions in the field. The proposed research focuses on phenomena of localization and long-range order in physical systems of large size, identifying several fundamental questions lying at the interface of Statistical Physics, Probability Theory and Combinatorics. One circle of questions concerns the fluctuation behavior of random surfaces, where the PI has recently proved delocalization in two dimensions answering a 1975 question of Brascamp, Lieb and Lebowitz. A main goal of the research is to establish some of the long-standing universality conjectures for random surfaces. This study is also tied to the localization features of random operators, such as random Schrodinger operators and band matrices, as well as those of reinforced random walks. The PI intends to develop this connection further to bring the state-of-the-art to the conjectured thresholds. A second circle of questions regards long-range order in high-dimensional systems. This phenomenon is predicted to encompass many models of statistical physics but rigorous results are quite limited. A notable example is the PI’s proof of Kotecky’s 1985 conjecture on the rigidity of proper 3-colorings in high dimensions. The methods used in this context are not limited to high dimensions and were recently used by the PI to prove the analogue for the loop O(n) model of Polyakov’s 1975 prediction that the 2D Heisenberg model and its higher spin versions exhibit exponential decay of correlations at any temperature. Lastly, statistical physics methods are proposed for solving purely combinatorial problems. The PI has applied this approach successfully to solve questions of existence and asymptotics for combinatorial structures and intends to develop it further to answer some of the tantalizing open questions in the field.

1 136 904 €

Start date: 2016-01-01, End date: 2020-12-31