ERC FUNDED PROJECTS

This proposal will determine the technical-economic viability of scaling-up ultra-thin, ink-jet printed films based on liquid-phase exfoliated single atomic layers of a range of nanomaterials. The PI has developed methods to produce in liquid nanosheets of a range of layered materials such as graphene, transition metal oxides, etc. These 2D-materials have immediate and far-reaching potential in several high-impact technological applications such as microelectronics, composites and energy harvesting and storage. 2DNanoCaps (ERC ref: 278516) has demonstrated that lab-scale ultra-thin graphene-based supercapacitor electrodes result in unusually high-power and extremely long device life-time (100% capacitance retention for 5000 charge-discharge cycles at the high power scan rate of 10,000 mV/s). This performance is an order of magnitude better than similar systems produced with conventional methods which cause materials restacking and aggregation. A following ERC PoC grant (2D-USD, Project-Number 620189) is currently focussed on up-scaling the production of thin-films deposition methods based on ultrasonic spray for the production of large-area electrodes for supercapacitors applications. In this proposal we want to explore the new concept of manufacturing conductive, robust, thin, easily assembled electrode and solid electrolytes to realize highly-flexible and all-solid-state supercapacitors by ink-jet printing. This opportunity is particularly relevant to the electronics and portable-device industry and offers the possibility to solve flammability issues, maintaining light weight, flexibility, transparency and portability. In order to do so it will be imperative to develop ink-jet printing methods and techniques. We believe our combination of unique materials and cost-effective, robust and production-scalable process of ultra- thin ink-jet printing will enable us to compete for significant global market opportunities in the energy-storage space.

149 774 €

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

Climate change and the decreasing availability of fossil fuels require society to move towards sustainable and renewable resources. 2DNanoCaps will focus on electrochemical energy storage, specifically supercapacitors. In terms of performance supercapacitors fill up the gap between batteries and the classical capacitors. Whereas batteries possess a high energy density but low power density, supercapacitors possess high power density but low energy density. Efforts are currently dedicated to move supercapacitors towards high energy density and high power density performance. Improvements have been achieved in the last few years due to the use of new electrode nanomaterials and the design of new hybrid faradic/capacitive systems. We recognize, however, that we are reaching a newer limit beyond which we will only see small incremental improvements. The main reason for this being the intrinsic difficulty in handling and processing materials at the nano-scale and the lack of communication across different scientific disciplines. I plan to use a multidisciplinary approach, where novel nanomaterials, existing knowledge on nano-scale processing and established expertise in device fabrication and testing will be brought together to focus on creating more efficient supercapacitor technologies. 2DNanoCaps will exploit liquid phase exfoliated two-dimensional nanomaterials such as transition metal oxides, layered metal chalcogenides and graphene as electrode materials. Electrodes will be ultra-thin (capacitance and thickness of the electrodes are inversely proportional), conductive, with high dielectric constants. Intercalation of ions between the assembled 2D flakes will be also achievable, providing pseudo-capacitance. The research here proposed will be initially based on fundamental laboratory studies, recognising that this holds the key to achieving step-change in supercapacitors, but also includes scaling-up and hybridisation as final objectives.

1 501 296 €

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

My vision is to establish, within the framework of an ERC CoG, a multidisciplinary group which will work in concert towards pioneering the integration of novel 2-Dimensional nanomaterials with novel additive fabrication techniques to develop a unique class of energy storage devices. Batteries and supercapacitors are two very complementary types of energy storage devices. Batteries store much higher energy densities; supercapacitors, on the other hand, hold one tenth of the electricity per unit of volume or weight as compared to batteries but can achieve much higher power densities. Technology is currently striving to improve the power density of batteries and the energy density of supercapacitors. To do so it is imperative to develop new materials, chemistries and manufacturing strategies. 3D2DPrint aims to develop micro-energy devices (both supercapacitors and batteries), technologies particularly relevant in the context of the emergent industry of micro-electro-mechanical systems and constantly downsized electronics. We plan to use novel two-dimensional (2D) nanomaterials obtained by liquid-phase exfoliation. This method offers a new, economic and easy way to prepare ink of a variety of 2D systems, allowing to produce wide device performance window through elegant and simple constituent control at the point of fabrication. 3D2DPrint will use our expertise and know-how to allow development of advanced AM methods to integrate dissimilar nanomaterial blends and/or “hybrids” into fully embedded 3D printed energy storage devices, with the ultimate objective to realise a range of products that contain the above described nanomaterials subcomponent devices, electrical connections and traditional micro-fabricated subcomponents (if needed) ideally using a single tool.

2 499 942 €

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

In the coming few decades, two major global grand challenges will continue to attract the attention of scientists and engineers in academia and industry: achieving clean water and clean energy. This PoC establishes the development of two prototypes, water oxidation catalyst and water purification filter, by creating inexpensive, abundant and versatile hierarchical structures of inorganic nanomaterials (HSINs). The formation of HSINs has been one of the major obstacles toward achieving a technological progress in various applications. Presently, fabrication of well-defined 3-D structures can be achieved either by photo/electro lithography, assembly, 3D printing or template-mediated methods. Various structures with high quality/yield can be obtained through those techniques, however, these methods suffer from high cost, difficulty of fabrication of free-standing structures, and sometime the throughput is limited. On the other hand, the templated approaches usually are facile, low cost and offer several and complex structures in particular the ones obtained from nature. Our invention is based on forming the HSINs using fossil templates from nature. We propose to harness the naturally designed morphologies of the fossil templates to rationally form hierarchical structures of nanomaterials. These structures have many advantageous, compared to the current state-of-the-art catalyst and filter, for example high surface area, high porosity, confined space (nano-reactor) and divers functionalities obtained by controlling the chemical composition of the inorganic material shell. Since these properties are important for achieving high performance, we propose HSINs as next generation water oxidation electrocatalyst and water purification filter.

150 000 €

Start date: 2017-03-01, End date: 2018-08-31

The sub-cellular processes that control the most critical aspects of life occur in three-dimensions (3D), and are intrinsically dynamic. While super-resolution microscopy has revolutionized cellular imaging in recent years, our current capability to observe the dynamics of life on the nanoscale is still extremely limited, due to inherent trade-offs between spatial, temporal and spectral resolution using existing approaches. We propose to develop and demonstrate an optical microscopy methodology that would enable live sub-cellular observation in unprecedented detail. Making use of multicolor 3D point-spread-function (PSF) engineering, a technique I have recently developed, we will be able to simultaneously track multiple markers inside live cells, at high speed and in five-dimensions (3D, time, and color). Multicolor 3D PSF engineering holds the potential of being a uniquely powerful method for 5D tracking. However, it is not yet applicable to live-cell imaging, due to significant bottlenecks in optical engineering and signal processing, which we plan to overcome in this project. Importantly, we will also demonstrate the efficacy of our method using a challenging biological application: real-time visualization of chromatin dynamics - the spatiotemporal organization of DNA. This is a highly suitable problem due to its fundamental importance, its role in a variety of cellular processes, and the lack of appropriate tools for studying it. The project is divided into 3 aims: 1. Technology development: diffractive-element design for multicolor 3D PSFs. 2. System design: volumetric tracking of dense emitters. 3. Live-cell measurements: chromatin dynamics. Looking ahead, here we create the imaging tools that pave the way towards the holy grail of chromatin visualization: dynamic observation of the 3D positions of the ~3 billion DNA base-pairs in a live human cell. Beyond that, our results will be applicable to numerous 3D micro/nanoscale tracking applications.

1 802 500 €

Start date: 2018-11-01, End date: 2023-10-31

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

When faced with a threat, an animal must decide whether to freeze, reducing its chances of being noticed, or to flee to the safety of a refuge. Animals from fish to primates choose between these two alternatives when confronted by an attacking predator, a choice that largely depends on the context in which the threat occurs. Recent work has made strides identifying the pre-motor circuits, and their inputs, which control freezing behavior in rodents, but how contextual information is integrated to guide this choice is still far from understood. We recently found that fruit flies in response to visual looming stimuli, simulating a large object on collision course, make rapid freeze/flee choices that depend on the social and spatial environment, and the fly’s internal state. Further, identification of looming detector neurons was recently reported and we identified the descending command neurons, DNp09, responsible for freezing in the fly. Knowing the sensory input and descending output for looming-evoked freezing, two environmental factors that modulate its expression, and using a genetically tractable system affording the use of large sample sizes, places us in an unique position to understand how a information about a threat is integrated with cues from the environment to guide the choice of whether to freeze (our goal). To assess how social information impinges on the circuit for freezing, we will examine the sensory inputs and neuromodulators that mediate this process, mapping their connections to DNp09 neurons (Aim 1). We ask whether learning is required for the spatial modulation of freezing, which cues flies are using to discriminate different places and which brain circuits mediate this process (Aim 2). Finally, we will study how activity of DNp09 neurons drives freezing (Aim 3). This project will provide a comprehensive understanding of the mechanism of freezing and its modulation by the environment, from single neurons to behaviour.

1 969 750 €

Start date: 2019-02-01, End date: 2024-01-31

Chronic Obstructive Pulmonary Disease (COPD) is a group of chronic diseases characterized by airflow limitations in the lung. COPD is a critical international health problem. It is estimated to affect up to 600 million people worldwide and by 2020 it will become the third most frequent cause of death. In Europe alone, COPD affects up to 10% of people (i.e. more people than breast cancer and diabetes) and it takes the life of around 300,000 Europeans each year. Up to date, COPD has no cure as current treatments fail to halt the long-term decline in lung function. They are only able to delay its progression. Those treatments however, are associated with a variety of side effects some of which can be acute and even life threatening. Thus, COPD remains a disease with a significant unmet medical need. In this project (acronymed AbCURE_COPD) we intend to carry out a set of necessary activities for the evaluation of a potentially groundbreaking approach for treating COPD. Our approach is focusing on antibody-mediated clearance of senescent cells which accumulate in tissues with age and contribute to multiple age-related diseases, including COPD. The goal of the PoC project is two-fold. (1) The first goal is to establish the technical feasibility of our idea by testing the effect of senescence-specific antibodies on COPD development and progression by implementing COPD mouse model we developed. (2) The second goal is to establish the business feasibility of our revolutionary approach by taking the necessary steps towards its commercialization, focusing on the creation of strategic alliances with key private sector companies. We firmly believe that with our approach we can significantly extend the health span and improve the quality of life of COPD patients. Equally important, our approach will pave the way for the development of novel treatment strategies applicable to other age-related diseases, such as osteoarthritis, cardiovascular, and neurodegenerative diseases.

150 000 €

Start date: 2018-11-01, End date: 2020-04-30

The proliferation of mobile and ubiquitous computing technology is radically changing the ways in which we live our lives: from interacting with friends & family, to how we produce & consume services and engage in business. However, this pervasiveness of technologies, and their increasingly seamless integration and inter-operation, are blurring the boundaries between systems. This poses significant challenges for security engineers who aim to design systems that monitor and control the movement of digital or physical assets across those boundaries. My ERC Advanced Grant on Adaptive Security and Privacy (ASAP) is investigating ways in which security controls can change in response to changes in the context of operation of systems. However, since the monitoring of such elusive and changing boundaries is difficult, we have developed an adaptive security approach that monitors valuable assets that are managed by a system, and changes the means and extent by which those assets are protected in response to changes in assets and their values. This could radically change the way security is designed and implemented in a range of applications because it allows for a choice of appropriate protection, depending on particular requirements. In ASAP, we developed the modelling and computational capabilities of our approach, including some prototype tool fragments that demonstrate the approach in our lab. However, interest from our industrial collaborators, evidenced by direct funding of follow-on research, and the demonstration of our prototypes to senior management and potential customers, has motivated us to pursue a proof of concept (PoC) assessment of our work in a more systematic and targeted way. To this end, this ERC PoC will: 1) Develop a robust prototype demonstrator, instantiated in two application areas (access control & cloud computing); 2) Conduct a market analysis, aided by the demonstrator; 3) Subject to (2), develop a commercialisation strategy and plan

149 977 €

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

Synthetic biology is an emerging discipline that offers powerful tools to control and manipulate fundamental processes in living matter. We propose to develop and apply such tools to modify the genetic code of cultured mammalian cells and bacteria with the aim to study the role of lysine acetylation in the regulation of metabolism and in cancer development. Thousands of lysine acetylation sites were recently discovered on non-histone proteins, suggesting that acetylation is a widespread and evolutionarily conserved post translational modification, similar in scope to phosphorylation and ubiquitination. Specifically, it has been found that most of the enzymes of metabolic processes—including glycolysis—are acetylated, implying that acetylation is key regulator of cellular metabolism in general and in glycolysis in particular. The regulation of metabolic pathways is of particular importance to cancer research, as misregulation of metabolic pathways, especially upregulation of glycolysis, is common to most transformed cells and is now considered a new hallmark of cancer. These data raise an immediate question: what is the role of acetylation in the regulation of glycolysis and in the metabolic reprogramming of cancer cells? While current methods rely on mutational analyses, we will genetically encode the incorporation of acetylated lysine and directly measure the functional role of each acetylation site in cancerous and non-cancerous cell lines. Using this methodology, we will study the structural and functional implications of all the acetylation sites in glycolytic enzymes. We will also decipher the mechanism by which acetylation is regulated by deacetylases and answer a long standing question – how 18 deacetylases recognise their substrates among thousands of acetylated proteins? The developed methodologies can be applied to a wide range of protein families known to be acetylated, thereby making this study relevant to diverse research fields.

1 499 375 €

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

The brain evolves, develops, and operates in the context of animal movements. As a consequence, fundamental brain functions such as spatial perception and motor control critically depend on the precise knowledge of the ongoing body motion. An accurate internal estimate of self-movement is thought to emerge from sensorimotor integration; nonetheless, which circuits perform this internal estimation, and exactly how motor-sensory coordination is implemented within these circuits are basic questions that remain to be poorly understood. There is growing evidence suggesting that, during locomotion, motor-related and visual signals interact at early stages of visual processing. In mammals, however, it is not clear what the function of this interaction is. Recently, we have shown that a population of Drosophila optic-flow processing neurons —neurons that are sensitive to self-generated visual flow, receives convergent visual and walking-related signals to form a faithful representation of the fly’s walking movements. Leveraging from these results, and combining quantitative analysis of behavior with physiology, optogenetics, and modelling, we propose to investigate circuit mechanisms of self-movement estimation during walking. We will:1) use cell specific manipulations to identify what cells are necessary to generate the motor-related activity in the population of visual neurons, 2) record from the identified neurons and correlate their activity with specific locomotor parameters, and 3) perturb the activity of different cell-types within the identified circuits to test their role in the dynamics of the visual neurons, and on the fly’s walking behavior. These experiments will establish unprecedented causal relationships among neural activity, the formation of an internal representation, and locomotor control. The identified sensorimotor principles will establish a framework that can be tested in other scenarios or animal systems with implications both in health and disease.

1 500 000 €

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

Obesity and its metabolic co-morbidities have given rise to a rapidly expanding ‘metabolic syndrome’ pandemic affecting hundreds of millions of individuals worldwide. The integrative genetic and environmental causes of the obesity pandemic remain elusive. White adipose tissue (WAT)-resident immune cells have recently been highlighted as important factors contributing to metabolic complications. However, a comprehensive understanding of the regulatory circuits governing their function and the cell type-specific mechanisms by which they contribute to the development of metabolic syndrome is lacking. Likewise, the gut microbiome has been suggested as a critical regulator of obesity, but the bacterial species and metabolites that influence WAT inflammation are entirely unknown. We propose to use our recently developed high-throughput genomic and gnotobiotic tools, integrated with CRISPR-mediated interrogation of gene function, microbial culturomics, and in-vivo metabolic analysis in newly generated mouse models, in order to achieve a new level of molecular understanding of how WAT immune cells integrate environmental cues into their crosstalk with organismal metabolism, and to explore the microbial contributions to the molecular etiology of WAT inflammation in the pathogenesis of diet-induced obesity. Specifically, we aim to (a) decipher the global regulatory landscape and interaction networks of WAT hematopoietic cells at the single-cell level, (b) identify new mediators of WAT immune cell contributions to metabolic homeostasis, and (c) decode how host-microbiome communication shapes the development of WAT inflammation and obesity. Unraveling the principles of WAT immune cell regulation and their amenability to change by host-microbiota interactions may lead to a conceptual leap forward in our understanding of metabolic physiology and disease. Concomitantly, it may generate a platform for microbiome-based personalized therapy against obesity and its complications.

2 000 000 €

Start date: 2019-03-01, End date: 2024-02-29

The rise of atmospheric O2 ~2,500 million years ago is one of the most profound transitions in Earth's history. Yet, despite its central role in shaping Earth's surface environment, the cause for the rise of O2 remains poorly understood. Tight coupling between the O2 cycle and the biogeochemical cycles of redox-active elements, such as C, Fe and S, implies radical changes in these cycles before, during and after the rise of O2. These changes, too, are incompletely understood, but have left valuable information encoded in the geological record. This information has been qualitatively interpreted, leaving many aspects of the rise of O2, including its causes and constraints on ocean chemistry before and after it, topics of ongoing research and debate. Here, I outline a research program to address this fundamental question in geochemical Earth systems evolution. The inherently interdisciplinary program uniquely integrates laboratory experiments, numerical models, geological observations, and geochemical analyses. Laboratory experiments and geological observations will constrain unknown parameters of the early biogeochemical cycles, and, in combination with field studies, will validate and refine the use of paleoenvironmental proxies. The insight gained will be used to develop detailed models of the coupled biogeochemical cycles, which will themselves be used to quantitatively understand the events surrounding the rise of O2, and to illuminate the dynamics of elemental cycles in the early oceans. This program is expected to yield novel, quantitative insight into these important events in Earth history and to have a major impact on our understanding of early ocean chemistry and the rise of O2. An ERC Starting Grant will enable me to use the excellent experimental and computational facilities at my disposal, to access the outstanding human resource at the Weizmann Institute of Science, and to address one of the major open questions in modern geochemistry.

1 472 690 €

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

In a typical learning problem one tries to approximate an unknown function by a function from a given class using random data, sampled according to an unknown measure. In this project we will be interested in parameters that govern the complexity of a learning problem. It turns out that this complexity is determined by the geometry of certain sets in high dimension that are connected to the given class (random coordinate projections of the class). Thus, one has to understand the structure of these sets as a function of the dimension - which is given by the cardinality of the random sample. The resulting analysis leads to many theoretical questions in Asymptotic Geometric Analysis, Probability (most notably, Empirical Processes Theory) and Combinatorics, which are of independent interest beyond the application to Learning Theory. Our main goal is to describe the role of various complexity parameters involved in a learning problem, to analyze the connections between them and to investigate the way they determine the geometry of the relevant high dimensional sets. Some of the questions we intend to tackle are well known open problems and making progress towards their solution will have a significant theoretical impact. Moreover, this project should lead to a more complete theory of learning and is likely to have some practical impact, for example, in the design of more efficient learning algorithms.

750 000 €

Start date: 2009-03-01, End date: 2014-02-28

Understanding how proteins respond to mutations is of paramount importance to biology and disease. While protein stability and misfolding have been instrumental in rationalizing the impact of mutations, we recently discovered that an alternative route is also frequent, where mutations at the surface of symmetric proteins trigger novel self-interactions that lead to infinite self-assembly. This mechanism can be involved in disease, as in sickle-cell anemia, but may also serve in adaptation. Importantly, it differs fundamentally from aggregation, because misfolding does not drive it. Thus, we term it “agglomeration”. The ease with which agglomeration can occur, even by single point mutations, shifts the paradigm of how quickly new protein assemblies can emerge, both in health and disease. This prompts us to determine the basic principles of protein agglomeration and explore its implications in cell physiology and human disease. We propose an interdisciplinary research program bridging atomic and cellular scales to explore agglomeration in three aims: (i) Map the landscape of protein agglomeration in response to mutation in endogenous yeast proteins; (ii) Characterize how yeast physiology impacts agglomeration by changes in gene expression or cell state, and, conversely, how protein agglomerates impact yeast fitness. (iii) Analyze agglomeration in relation to human disease via two approaches. First, by predicting single nucleotide polymorphisms that trigger agglomeration, prioritizing them using knowledge from Aims 1 & 2, and characterizing them experimentally. Second, by providing a proof-of-concept that agglomeration can be exploited in drug design, whereby drugs induce its formation, like mutations can do. Overall, through this research, we aim to establish agglomeration as a paradigm for protein assembly, with implications for our understanding of evolution, physiology, and disease.

2 574 819 €

Start date: 2019-04-01, End date: 2024-03-31

Europe sits uncomfortably on the idea that there are no political and cultural alternatives credible enough to respond to the current uneasiness or malaise caused by both a world that is more and more non-European and a Europe that increasingly questions what is European about itself. This project will develop a new grounded theoretical paradigm for contemporary Europe based on two key ideas: the understanding of the world by far exceeds the European understanding of the world; social, political and institutional transformation in Europe may benefit from innovations taking place in regions and countries with which Europe is increasingly interdependent. I will pursue this objective focusing on four main interconnected topics: democratizing democracy, intercultural constitutionalism, the other economy, human rights (right to health in particular). In a sense that the European challenges are unique but, in one way or another, are being experienced in different corners of the world. The novelty resides in bringing new ideas and experiences into the European conversation, show their relevance to our current uncertainties and aspirations and thereby contribute to face them with new intellectual and political resources. The usefulness and relevance of non-European conceptions and experiences un-thinking the conventional knowledge through two epistemological devices I have developed: the ecology of knowledges and intercultural translation. By resorting to them I will show that there are alternatives but they cannot be made credible and powerful if we go on relying on the modes of theoretical and political thinking that have dominated so far. In other words, the claim put forward by and worked through this project is that in Europe we don’t need alternatives but rather an alternative thinking of alternatives.

2 423 140 €

Start date: 2011-07-01, End date: 2016-12-31

"The first decade of Algorithmic Mechanism Design (AMD) concentrated, very successfully, on the design of truthful mechanisms for the allocation of resources among agents with private preferences. Truthful mechanisms are ones that incentivize rational users to report their preferences truthfully. Truthfulness, however, for all its theoretical appeal, suffers from several inherent limitations, mainly its high communication and computation complexities. It is not surprising, therefore, that practical applications forego truthfulness and use simpler mechanisms instead. Simplicity in itself, however, is not sufficient, as any meaningful mechanism should also have some notion of fairness; otherwise agents will stop using it over time. In this project I plan to develop an innovative AMD theoretical framework that will go beyond truthfulness and focus instead on the natural themes of simplicity and fairness, in addition to computational tractability. One of my primary goals will be the design of simple and fair poly-time mechanisms that perform at near optimal levels with respect to important economic objectives such as social welfare and revenue. To this end, I will work toward providing precise definitions of simplicity and fairness and quantifying the effects of these restrictions on the performance levels that can be obtained. A major challenge in the evaluation of non-truthful mechanisms is defining a reasonable behavior model that will enable their evaluation. The success of this project could have a broad impact on Europe and beyond, as it would guide the design of natural mechanisms for markets of tens of billions of dollars in revenue, such as online advertising, or sales of wireless frequencies. The timing of this project is ideal, as the AMD field is now sufficiently mature to lead to a breakthrough and at the same time young enough to be receptive to new approaches and themes."

1 394 600 €

Start date: 2013-11-01, End date: 2018-10-31

The technology validation was successfully completed indicating a great commercial potential, and the innovative and inventive aspects of the assay platform are now covered by the filed priority European Patent Office (EPO) patent applications. Validated glycoprofiling of the proteins now uses lectins in a format, fully compatible with clinical PSA assay kits. This PoC grant focuses on 1. Pre-clinical retrospective validation of the early stage biomarker of prostate cancer (PCa) and 2. Commercialisation of the PCa diagnostics kit. Pre-clinical (60 human serum samples) is ongoing and retrospective validation study (450 human serum samples) of the assay will be performed by statistical analysis using a receiver operating characteristic (ROC) curve. The PoC describes all steps, which have been developed so far and all necessary steps, which need to be done for retrospective validation study, product development and commercialisation through our newly incorporated start-up Glycanostics Ltd. (www.glycanostics.com). We will provide PCa diagnostic test resulting in a second opinion to guide the right decision if the biopsy is needed. This will avoid the needless and unreliable biopsies and in the future rival an inaccurate PSA testing.

149 500 €

Start date: 2018-12-01, End date: 2020-05-31

What does the fossil record tell us about the evolution of colour in animals through deep time? Evidence of colour in fossils can inform on the visual signalling strategies used by ancient animals. Research to date often has a narrow focus, lacks a broad phylogenetic and temporal context, and rarely incorporates information on taphonomy. This proposal represents a bold new holistic approach to the study of fossil colour: it will couple powerful imaging- and chemical analytical techniques with a rigorous programme of fossilisation experiments simulating decay, burial, and transport, and analysis of fossils and their sedimentary context, to construct the first robust models for the evolution of colour in animals through deep time. The research will resolve the original integumentary colours of fossil higher vertebrates, and the original colours of fossil hair; the fossil record of non-melanin pigments in feathers and insects; the biological significance of monotonal patterning in fossil insects; and the evolutionary history of scales and 3D photonic crystals in insects. Critically, the research will test, for the first time, whether evidence of fossil colour can solve broader evolutionary questions, e.g. the true affinities of enigmatic Cambrian chordate-like metazoans, and feather-like integumentary filaments in dinosaurs. The proposal entails construction of a dedicated experimental maturation laboratory for simulating the impact of burial on tissues. This laboratory will form the core of the world’s first integrated ‘experimental fossilisation facility’, consolidating the PI’s team as the global hub for fossil colour research. The research team comprises the PI, three postdoctoral researchers, and three PhD students, and will form an extensive research network via collaborations with 13 researchers from Europe and beyond. The project will reach out to diverse scientists and will inspire a positive attitude to science among the general public and policymakers alike.

1 562 000 €

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

Campylobacter jejuni is the most common foodborne contamination in Europe, affecting millions of people, and costing billions of Euros. Current procedures to treat this contamination do not offer sufficient solutions. Here I present a unique approach to eradicate the pathogen from food by utilizing a cost-effective and safe product that does not alter the taste, texture, or appearance of the food. This innovation involves a spray composed of proprietary phage-based particles, which inject antibacterial genes into C. jejuni, thus killing the pathogen. Current phage-based technologies for decontaminating food encounter a major hurdle, because large-scale phage production in the fastidious and pathogenic C. jejuni strain is highly challenging. However, a major advantage of my product is that it can be prepared in a safe and easy-to-grow Escherichia coli host rather than in C. jejuni. Another significant advantage is that the technology producing the phages enables rapid and efficient modifications to the phage-based particles. This platform thus allows easy isolation and manufacture of cocktails of phage-based particles able to target a variety of pathogenic serotypes of C. jejuni. Furthermore, the proprietary particles all have a common scaffold, thus simplifying the regulation, safety, and route of manufacture. I propose a clear commercialization activity with a highly qualified team that I recruited, from both the scientific and commercialization fields. Developing and commercializing this product will provide a proof-of-concept to demonstrate the strength of this approach and will thus pave the way for additional innovative materials based on this technology.

150 000 €

Start date: 2018-12-01, End date: 2020-05-31

Cognition improves an animal’s ability to tune its responses to environmental conditions. In group living animals, communication works to form a collective cognition that expands the group’s abilities beyond those of individuals. Despite much research, to date, there is little understanding of how collective cognition emerges within biological ensembles. A major obstacle towards such an understanding is the rarity of comprehensive multi-scale empirical data of these complex systems. We have demonstrated cooperative load transport by ants to be an ideal system to study the emergence of cognition. Similar to other complex cognitive systems, the ants employ high levels of emergence to achieve efficient problem solving over a large range of scenarios. Unique to this system, is its extreme amenability to experimental measurement and manipulation where internal conflicts map to forces, abstract decision making is reflected in direction changes, and future planning manifested in pheromone trails. This allows for an unprecedentedly detailed, multi-scale empirical description of the moment-to-moment unfolding of sophisticated cognitive processes. This proposal is aimed at materializing this potential to the full. We will examine the ants’ problem solving capabilities under a variety of environmental challenges. We will expose the underpinning rules on the different organizational scales, the flow of information between them, and their relative contributions to collective performance. This will allow for empirical comparisons between the ‘group’ and the ‘sum of its parts’ from which we will quantify the level of emergence in this system. Using the language of information, we will map the boundaries of this group’s collective cognition and relate them to the range of habitable environmental niches. Moreover, we will generalize these insights to formulate a new paradigm of emergence in biological groups opening new horizons in the study of cognitive processes in general.

2 000 000 €

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

This proposal proceeds from an anomaly. Apartheid routinely breached the separation that it names. Whereas the South African regime was deeply isolationist in international terms, new research links it to the Cold War and decolonization. Yet this trend does not consider sufficiently that the global contest over the meaning of apartheid and resistance to it occurs on the terrain of culture. My project argues that studying the global circulation of South African cultural formations in the apartheid era provides novel historiographic leverage over Western liberalism during the Cold War. It recasts apartheid as an apparatus of transnational cultural production, turning existing historiography inside out. This study seeks: • To provide the first systematic account of the deterritorialization of “apartheid”—as political signifier and as apparatus generating circuits of transnational cultural production. • To analyze these itinerant cultural formations across media and national borders, articulating new intersections. • To map the itineraries of major South African exiles, where exile is taken to be a system of interlinked circuits of affiliation and cultural production. • To revise the historiography of states other than South Africa through the lens of deterritorialized apartheid-era formations at their respective destinations. • To show how apartheid reveals contradictions within Western liberalism during the Cold War, with special reference to racial inequality. Methodologically, I introduce the model of thick convergence to analyze three periods: 1. Kliptown & Bandung: Novel possibilities, 1948-1960. 2. Sharpeville & Memphis: Drumming up resistance, 1960-1976. 3. From Soweto to Berlin: Spectacle at the barricades, 1976-1990. Each explores a cultural dominant in the form of texts, soundscapes or photographs. My work stands at the frontier of transnational research, furnishing powerful new insights into why South Africa matters on the stage of global history.

1 861 238 €

Start date: 2014-05-01, End date: 2019-04-30

Main goal. We aim to understand the puzzling coexistence of antibiotic-resistant and antibiotic-sensitive species in natural soil environments, using novel quantitative experimental techniques and mathematical analysis. The ecological insights gained will be translated into novel treatment strategies for combating antibiotic resistance. Background. Microbial soil ecosystems comprise communities of species interacting through copious secretion of antibiotics and other chemicals. Defence mechanisms, i.e. resistance to antibiotics, are ubiquitous in these wild communities. However, in sharp contrast to clinical settings, resistance does not take over the population. Our hypothesis is that the ecological setting provides natural mechanisms that keep antibiotic resistance in check. We are motivated by our recent finding that specific antibiotic combinations can generate selection against resistance and that soil microbial strains produce compounds that directly target antibiotic resistant mechanisms. Approaches. We will: (1) Isolate natural bacterial species from individual grains of soil, characterize their ability to produce and resist antibiotics and identify the spatial scale for correlations between resistance and production. (2) Systematically measure interactions between species and identify interaction patterns enriched in co-existing communities derived from the same grain of soil. (3) Introducing fluorescently-labelled resistant and sensitive strains into natural soil, we will measure the fitness cost and benefit of antibiotic resistance in situ and identify natural compounds that select against resistance. (4) Test whether such “selection-inverting” compounds can slow evolution of resistance to antibiotics in continuous culture experiments. Conclusions. These findings will provide insights into the ecological processes that keep antibiotic resistance in check, and will suggest novel antimicrobial treatment strategies.

1 900 000 €

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

In many biomedical research and clinical applications it would be tremendously useful to know the gene expression profile of each and every cell in a sample, be it a blood sample or tumor. At present, the most advanced single-cell technologies are limited to a few thousand cells by a laborious and expensive approach. We have invented a method allowing the determination of the transcriptomes of millions of cells in parallel, using array-based technique for tagging single cells. The protocol combines our previously published protocol for single cell transcriptomics – CEL-Seq – with a new membrane based system for capturing single cells and a DNA microarray for differentially tagging each cell in the membrane. If further developed into a commercial platform, our method could have tremendous impact on clinical and research transcriptomics. Our method requires no expensive equipment, low amounts of reagents and little hands-on, making it unlike any available protocol for single cell analysis. Our method also has great versatility as it can be used for analyzing up to a million cells, but can also be easily scaled down to several hundreds, promising to make it the state of the art protocol for any lab interested in single cell biology. Our method thus represents a game-changer because it completely reinvents the scale under which cells can be examined – affordably and without a need for expensive instruments – by at least three orders of magnitude. The aim of this project is to establish a user-friendly platform for our method that could be commercially available in the coming years. The developed platform will facilitate a large-scale ability to query cells; the breadth of possible research and personal medicine applications is unimaginable at present.

150 000 €

Start date: 2015-09-01, End date: 2017-02-28

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

Software synthesis aims to automate the creation of software by generating parts of software from a higher-level description. Until recently it was believed to be impossible to practically synthesize software beyond very small fragments. However, synthesis based on learning from existing large code-bases (“Big Code”) is making synthesis into a practical reality . The purpose of this PoC is to develop a platform that would lead to commercialization of our technology to improve programming productivity and code quality. We target two closely related applications: (1) Providing automatic assistance in programming tasks by learning from existing code, and (2) Providing on-line assessment of code quality as it is being developed using learned models. These applications have the potential to dramatically reduce time-to-market of new software, and improve its quality and security.

150 000 €

Start date: 2017-05-01, End date: 2018-10-31

Axon growth potential declines during development, contributing to the lack of effective regeneration in the adult central nervous system. What determines the intrinsic growth potential of neurites, and how such growth is regulated during development, disease and following injury is a fundamental question in neuroscience. Although multiple lines of evidence indicate that intrinsic growth capability is genetically encoded, its nature remains poorly defined. Neuronal remodeling of the Drosophila mushroom body offers a unique opportunity to study the mechanisms of various types of axon degeneration and growth. We have recently demonstrated that regrowth of axons following developmental pruning is not only distinct from initial outgrowth but also shares molecular similarities with regeneration following injury. In this proposal we combine state of the art tools from genomics, functional genetics and microscopy to perform a comprehensive study of the mechanisms underlying axon growth during development and following injury. First, we will combine genetic, biochemical and genomic studies to gain a mechanistic understanding of the developmental regrowth program. Next, we will perform extensive transcriptomic analyses and comparisons aimed at defining the genetic programs involved in initial axon growth, developmental regrowth, and regeneration following injury. Finally, we will harness the genetic power of Drosophila to perform a comprehensive functional analysis of genes and pathways, those previously known and new ones that we will discover, in various neurite growth paradigms. Importantly, these functional assays will be performed in the same organism, allowing us to use identical genetic mutations across our analyses. To this end, our identification of a new genetic program regulating developmental axon regrowth, together with emerging tools in genomics, places us in a unique position to gain a broad understanding of axon growth during development and following injury.

2 000 000 €

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

Bacteria in nature exhibit remarkable capacity to sense their surroundings and rapidly adapt to diverse conditions by gaining new beneficial traits. This extraordinary feature facilitates their survival when facing extreme environments. Utilizing Bacillus subtilis as our primary model organism, we propose to study two facets of this vital bacterial attribute: communication via extracellular nanotubes, and persistence as resilient spores while maintaining the potential to revive. Exploring these fascinating aspects of bacterial physiology is likely to change our view as to how bacteria sense, respond, endure and communicate with their extracellular environment. We have recently discovered a previously uncharacterized mode of bacterial communication, mediated by tubular extensions (nanotubes) that bridge neighboring cells, providing a route for exchange of intracellular molecules. Nanotube-mediated molecular sharing may represent a key form of bacterial communication in nature, allowing for the emergence of new phenotypes and increasing survival in fluctuating environments. Here we propose to develop strategies for observing nanotube formation and molecular exchange in living bacterial cells, and to characterize the molecular composition of nanotubes. We will explore the premise that nanotubes serve as a strategy to expand the cell surface, and will determine whether nanotubes provide a conduit for phage infection and spreading. Furthermore, the formation and functionality of interspecies nanotubes will be explored. An additional mode employed by bacteria to achieve extreme robustness is the ability to reside as long lasting spores. Previously held views considered the spore to be dormant and metabolically inert. However, we have recently shown that at least one week following spore formation, during an adaptive period, the spore senses and responds to environmental cues and undergoes corresponding molecular changes, influencing subsequent emergence from quiescence.

1 497 800 €

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

The enormous versatility of bacteria enables the formation of multi-species communities that colonize nearly every niche on earth, making them the dominant life form and a major component of the biomass. Exchange of molecular information among neighboring bacteria in such communities, as well as between bacteria and proximal eukaryotic cells, is key for bacterial success. Yet, the principles controlling these multicellular interactions are poorly defined. Here we describe the identification of a bacterial protein complex, herein termed CORE, whose function is to traffic cytoplasmic molecules among different bacterial species, and between pathogenic bacteria and their human host cells. The CORE is composed of five membrane proteins, highly conserved across the entire bacterial kingdom, providing a ubiquitous platform that facilitates both intra- and inter-kingdom crosstalk. Our preliminary data support the idea that the CORE acts as a shared module for the assembly of larger apparatuses, executing this universal molecular flow among organisms. We propose to elucidate components, structure and biogenesis of the CORE machinery, operating during bacteria-bacteria and pathogen-host interactions. We further aim to provide an unbiased-global view of the extent and identity of cytoplasmic molecules traded via CORE including metabolites, proteins and RNA, and to reveal the criteria determining the specificity of the transported cargo. Furthermore, we intend to decipher the impact of CORE-mediated molecular exchange on bacterial physiology and virulence, and devise anti-CORE compounds to combat pathogenic bacteria. This study is expected to transform the way we currently view bacterial communities and host-pathogen interactions. We anticipate these findings to lead to the development of creative strategies to modulate, predict and even design bacterial communities, and lay the foundation for new and innovative approaches to fight bacterial diseases.

6 930 796 €

Start date: 2019-04-01, End date: 2025-03-31

Cancer is the leading cause of death in the Western world and the second cause of death worldwide. Despite advances in medical research, 30% of cancer patients are prescribed a medication the tumor does not respond to, or, alternatively, drugs that induce adverse side effects patients' cannot tolerate. Nanotechnologies are becoming impactful therapeutic tools, granting tissue-targeting and cellular precision that cannot be attained using systems of larger scale. In this proposal, I plan to expand far beyond the state-of-the-art and develop a conceptually new approach in which diagnostic nanoparticles are designed to retrieve drug-sensitivity information from malignant tissue inside the body. The ultimate goal of this program is to be able to predict, ahead of time, which treatment will be best for each cancer patient – an emerging field called personalized medicine. This interdisciplinary research program will expand our understandings and capabilities in nanotechnology, cancer biology and medicine. To achieve this goal, I will engineer novel nanotechnologies that autonomously maneuver, target and diagnose the various cells that compose the tumor microenvironment and its disseminated metastasis. Each nanometric system will contain a miniscule amount of a biologically-active agent, and will serve as a nano lab for testing the activity of the agents inside the tumor cells. To distinguish between system to system, and to grant single-cell sensitivity in vivo, nanoparticles will be barcoded with unique DNA fragments. We will enable nanoparticle' deep tissue penetration into primary tumors and metastatic microenvironments using enzyme-loaded particles, and study how different agents, including small-molecule drugs, proteins and RNA, interact with the malignant and stromal cells that compose the cancerous microenvironments. Finally, we will demonstrate the ability of barcoded nanoparticles to predict adverse, life-threatening, side effects, in a personalized manner.

1 499 250 €

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

Next generation sequencing (NGS) is revolutionizing all fields of biological research but it fails to extract the full range of information associated with genetic material and is lacking in its ability to resolve variations between genomes. The high degree of genome variation exhibited both on the population level as well as between genetically “identical” cells (even in the same organ) makes genetic and epigenetic analysis on the single cell and single genome level a necessity. Chromosomes may be conceptually represented as a linear one-dimensional barcode. However, in contrast to a traditional binary barcode approach that considers only two possible bits of information (1 & 0), I will use colour and molecular structure to expand the variety of information represented in the barcode. Like colourful beads threaded on a string, where each bead represents a distinct type of observable, I will label each type of genomic information with a different chemical moiety thus expanding the repertoire of information that can be simultaneously measured. A major effort in this proposal is invested in the development of unique chemistries to enable this labelling. I specifically address three types of genomic variation: Variations in genomic layout (including DNA repeats, structural and copy number variations), variations in the patterns of chemical DNA modifications (such as methylation of cytosine bases) and variations in the chromatin composition (including nucleosome and transcription factor distributions). I will use physical extension of long DNA molecules on surfaces and in nanofluidic channels to reveal this information visually in the form of a linear, fluorescent “barcode” that is read-out by advanced imaging techniques. Similarly, DNA molecules will be threaded through a nanopore where the sequential position of “bulky” molecular groups attached to the DNA may be inferred from temporal modulation of an ionic current measured across the pore.

1 627 600 €

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

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

1 445 000 €

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

We propose to establish a research group that will unveil the combinatorial nature of the second uncountable cardinal. This includes its Ramsey-theoretic, order-theoretic, graph-theoretic and topological features. Among others, we will be directly addressing fundamental problems due to Erdos, Rado, Galvin, and Shelah. While some of these problems are old and well-known, an unexpected series of breakthroughs from the last three years suggest that now is a promising point in time to carry out such a project. Indeed, through a short period, four previously unattainable problems concerning the second uncountable cardinal were successfully tackled: Aspero on a club-guessing problem of Shelah, Krueger on the club-isomorphism problem for Aronszajn trees, Neeman on the isomorphism problem for dense sets of reals, and the PI on the Souslin problem. Each of these results was obtained through the development of a completely new technical framework, and these frameworks could now pave the way for the solution of some major open questions. A goal of the highest risk in this project is the discovery of a consistent (possibly, parameterized) forcing axiom that will (preferably, simultaneously) provide structure theorems for stationary sets, linearly ordered sets, trees, graphs, and partition relations, as well as the refutation of various forms of club-guessing principles, all at the level of the second uncountable cardinal. In comparison, at the level of the first uncountable cardinal, a forcing axiom due to Foreman, Magidor and Shelah achieves exactly that. To approach our goals, the proposed project is divided into four core areas: Uncountable trees, Ramsey theory on ordinals, Club-guessing principles, and Forcing Axioms. There is a rich bilateral interaction between any pair of the four different cores, but the proposed division will allow an efficient allocation of manpower, and will increase the chances of parallel success.

1 362 500 €

Start date: 2018-10-01, End date: 2023-09-30

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

The dielectric properties of biological tissues are of fundamental importance to the understanding of the interaction of electromagnetic fields with the human body. These properties are used to determine the safety of electronic devices, and in the design, development and refinement of electromagnetic medical imaging and therapeutic devices. Many historical studies have aimed to establish the dielectric properties of a broad range of tissues. A growing number of recent studies have sought to more accurately estimate these dielectric properties by standardising measurement procedures, and in some cases, measuring the dielectric properties in-vivo. However, these studies have often produced results in direct conflict with historical studies, casting doubt on the accuracy of the currently utilised dielectric properties. At best, this uncertainty could significantly delay the development of electromagnetic imaging or therapeutic medical devices. At worst, the health dangers of electromagnetic radiation could be under-estimated. The applicant will embark upon frontier research to develop improved methods and standards for the measurement of the dielectric properties of biological tissue. The research programme will accelerate the design and development of electromagnetic imaging and therapeutic devices, at a time when the technology is gaining significant momentum. The primary objective of the research is to develop a deep understanding of the fundamental factors which contribute to errors in dielectric property measurement. These factors will include in-vivo/ex-vivo measurements and dielectric measurement method used, amongst many others. Secondly, a new open-access repository of dielectric measurements will be created based on a greatly enhanced understanding of the mechanisms underlying dielectric property measurement. Finally, new electromagnetic-based imaging and therapeutic medical devices will be investigated, based on the solid foundation of dielectric data.

1 499 329 €

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

Identifying risk factors for diseases that can be prevented or delayed by early intervention is of major importance, and numerous genetic, lifestyle, anthropometric and clinical risk factors were found for many different diseases. Another source of potentially pertinent disease risk factors is the human microbiome - the collective genome of trillions of bacteria, viruses, fungi, and parasites that reside in the human gut. However, very few microbiome disease markers were found to date. Here, we aim to develop risk prediction tools based on the human microbiome that predict the likelihood of an individual to develop a particular condition or disease within 5-10 years. We will use a cohort of >2200 individuals that my group previously assembled, for whom we have clinical profiles, gut microbiome data, and banked blood and stool samples. We will invite people 5-10 years after their initial recruitment time, profile disease status and blood markers, and develop algorithms for predicting 5-10 year onset of Type 2 diabetes, cardiovascular disease, and obesity, using microbiome data from recruitment time. To increase the likelihood of finding microbiome markers predictive of disease onset, we will develop novel experimental and computational methods for in-depth characterization of microbial gene function, the metabolites produced by the microbiome, the underexplored fungal microbiome members, and the interactions between the gut microbiota and the host adaptive immune system. We will then apply these methods to >2200 banked samples from cohort recruitment time and use the resulting data in devising our microbiome-based risk prediction tools. In themselves, these novel assays and their application to >2200 samples should greatly advance the microbiome field. If successful, our proposal will identify new disease risk factors and risk prediction tools based on the microbiome, paving the way towards using the microbiome in early disease detection and prevention.

2 500 000 €

Start date: 2019-03-01, End date: 2024-02-29

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

2 125 980 €

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

Cell motility is a fascinating dynamic process crucial for a wide variety of biological phenomena including defense against injury or infection, embryogenesis and cancer metastasis. A spatially extended, self-organized, mechanochemical machine consisting of numerous actin polymers, accessory proteins and molecular motors drives this process. This impressive assembly self-organizes over several orders of magnitude in both the temporal and spatial domains bridging from the fast dynamics of individual molecular-sized building blocks to the persistent motion of whole cells over minutes and hours. The molecular players involved in the process and the basic biochemical mechanisms are largely known. However, the principles governing the assembly of the motility apparatus, which involve an intricate interplay between biophysical processes and biochemical reactions, are still poorly understood. The proposed research is focused on investigating the biophysical aspects of the self-organization processes underlying cell motility and trying to adapt these processes to instill motility in artificial cells. Important biophysical characteristics of moving cells such as the intracellular fluid flow and membrane tension will be measured and their effect on the motility process will be examined, using fish epithelial keratocytes as a model system. The dynamics of the system will be further investigated by quantitatively analyzing the morphological and kinematic variation displayed by a population of cells and by an individual cell through time. Such measurements will feed into and direct the development of quantitative theoretical models. In parallel, I will work toward the development of a synthetic physical model system for cell motility by encapsulating the actin machinery in a cell-sized compartment. This synthetic system will allow cell motility to be studied in a simplified and controlled environment, detached from the complexity of the living cell.

900 000 €

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

Resolution of singularities is one of classical, central and difficult areas of algebraic geometry, with a centennial history of intensive research and contributions of such great names as Zariski, Hironaka and Abhyankar. Nowadays, desingularization of schemes of characteristic zero is very well understood, while semistable reduction of morphisms and desingularization in positive characteristic are still waiting for major breakthroughs. In addition to the classical techniques with their triumph in characteristic zero, modern resolution of singularities includes de Jong's method of alterations, toroidal methods, formal analytic and non-archimedean methods, etc. The aim of the proposed research is to study nearly all directions in resolution of singularities and semistable reduction, as well as the wild ramification phenomena, which are probably the main obstacle to transfer methods from characteristic zero to positive characteristic. The methods of algebraic and non-archimedean geometries are intertwined in the proposal, though algebraic geometry is somewhat dominating, especially due to the new stack-theoretic techniques. It seems very probable that increasing the symbiosis between birational and non-archimedean geometries will be one of by-products of this research.

1 365 600 €

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

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

The global performing arts community is requiring innovative systems to: a) document, transmit and preserve the knowledge contained in choreographic-dramaturgic practices; b) assist artists with tools to facilitate their compositional processes, preferably on a collaborative basis. The existing digital archives of performing arts mostly function as conventional e-libraries, not allowing higher degrees of interactivity or active user intervention. They rarely contemplate accessible video annotation tools or provide relational querying functionalities based on artist-driven conceptual principles or idiosyncratic ontologies. This proposal endeavours to fill that gap and create a new paradigm for the documentation of performance composition. It aims at the analysis of artists’ unique conceptual structures, by combining the empirical insights of contemporary creators with research theories from Multimodal Communication and Digital Media studies. The challenge is to design a model for a web-based collaborative platform enabling both a robust representation of performance composition methods and novel visualization technologies to support it. This can be done by analysing recurring body movement patterns and by fostering online contributions of users (a.o. performers and researchers) to the multimodal annotations stored in the platform. To accomplish this goal, two subjacent components must be developed: 1. the production of a video annotation-tool to allow artists in rehearsal periods to take notes over video in real-time and share them via the collaborative platform; 2. the linguistic analysis of a corpus of invited artists’ multimodal materials as source for the extraction of indicative conceptual structures, which will guide the architectural logics and interface design of the collaborative platform software.The outputs of these two components will generate critical case-studies to help understanding the human mind when engaged in cultural production processes.

1 378 200 €

Start date: 2014-05-01, End date: 2019-04-30

This program’s goal is to develop a scaffold using a new biomaterial source that is functionalised with on-demand delivery of genes for coordinated healing of diabetic foot ulcers (DFUs). DFUs are chronic wounds that are often recalcitrant to treatment, which devastatingly results in lower leg amputation. This project builds on the PI’s experience growing matrix from induced-pluripotent stem cell derived (iPS)-fibroblasts and in developing on-demand drug delivery technologies. The aim of this project is to first develop a SiPS: a scaffold from iPS-fibroblast grown matrix, which has never been tested as a source material for scaffolds. iPS-fibroblasts grow a more pro-repair and angiogenic matrix than (non-iPS) adult fibroblasts. The SiPS structure will be bilayered to mimic native skin: dermis made mostly by fibroblasts and epidermis made by keratinocytes. The dermal layer will consist of a porous scaffold with optimised pore size and mechanical properties and the epidermal layer will be film-like, optimised for keratinisation. Second, the SiPS will be functionalised with delivery of plasmid-DNA (platelet derived growth factor gene, pPDGF) to direct angiogenesis on-demand. As DFUs undergo uncoordinated healing, timed pPDGF delivery will guide them through angiogenesis and healing. To achieve this, alginate microparticles, designed to respond to ultrasound by releasing pPDGF, will be interspersed throughout the SiPS. This BONDS will be tested in an in vivo pre-clinical DFU model to confirm its ability to heal wounds by providing cells with the appropriate biomimetic scaffold environment and timed directions for healing. With >100 million current diabetics expected to get a DFU, the BONDS would have a powerful clinical impact. This research program combines a disruptive technology, the SiPS, with a new platform for on-demand delivery of pDNA to heal DFUs. The PI will build his lab around these innovative platforms, adapting them for treatment of diverse complex wounds.

1 372 135 €

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

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

1 500 000 €

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

Non-invasive Brain Machine Interfaces (BMI) bring great promise for neuro-rehabilitation and neuro-prosthesis, as well as for brain control of everyday devices and performance of simple tasks. Over the last 15 years the interest in BMIs has grown substantially, and a variety of interfaces have been developed. The field has been growing dramatically, and market studies reveal an estimated market size of $1.46 billion by 2020. However, non-invasive BMIs have failed to reach the impressive control seen by BMIs implanted in the brain. To date, they require considerable training to reach a moderate level of control, they are susceptible to noise and interference, do not generalize between people and devices, and performance does not show long-term consolidation. Results from our ERC-funded work uncovered a new paradigm that dramatically improves these issues. We propose to develop a prototype for a novel, standalone, non-invasive, noise-resistant BMI, based on an unexplored BMI learning paradigm. In this POC we will 1) refine the brain signal interface (decoder) to be automatically customizable to each individual and produces faster training, 2) implement our BMI technology into a portable hardware-based system, and 3) develop a virtual reality/gaming training platform that will increase learning, performance and consolidation of BMI control. In addition to these technical aims, we propose to explore commercial opportunities and societal benefits, in particular in the health sector. We will conduct market analysis and develop a business case for this product, while expanding industry contacts for production and commercialization. The work proposed in this PoC grant will permit, for the first time to our knowledge, the development of a portable, stand-alone, noise-resistant, and easy to learn BMI, applicable across a wide set of devices, which will bring a significant social impact in health, entertainment and other applications.

149 625 €

Start date: 2016-09-01, End date: 2018-02-28

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

A great deal is known about the neural basis of associative fear learning. However, many animal species are able to use social cues to recognize threats, a defence mechanism that may be less costly than learning from self-experience. We have previously shown that rats perceive the cessation of movement-evoked sound as a signal of danger and its resumption as a signal of safety. To study transmission of fear between rats we assessed the behavior of an observer while witnessing a demonstrator rat display fear responses. With this paradigm we will take advantage of the accumulated knowledge on learned fear to investigate the neural mechanisms by which the social environment regulates defense behaviors. We will unravel the neural circuits involved in detecting the transition from movement-evoked sound to silence. Moreover, since observer rats previously exposed to shock display observational freezing, but naive observer rats do not, we will determine the mechanism by which prior experience contribute to observational freezing. To this end, we will focus on the amygdala, crucial for fear learning and expression, and its auditory inputs, combining immunohistochemistry, pharmacology and optogenetics. Finally, as the detection of and responses to threat are often inherently social, we will study these behaviors in the context of large groups of individuals. To circumvent the serious limitations in using large populations of rats, we will resort to a different model system. The fruit fly is the ideal model system, as it is both amenable to the search for the neural mechanism of behavior, while at the same time allowing the study of the behavior of large groups of individuals. We will develop behavioral tasks, where conditioned demonstrator flies signal danger to other naïve ones. These experiments unravel how the brain uses defense behaviors as signals of danger and how it contributes to defense mechanisms at the population level.

1 412 376 €

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

Modern cryptography has deeply rooted connections with computational complexity theory and other areas of computer science. This proposal suggests to explore several {\em new connections} between questions in cryptography and questions from other domains, including computational complexity, coding theory, and even the natural sciences. The project is expected to broaden the impact of ideas from cryptography on other domains, and on the other hand to benefit cryptography by applying tools from other domains towards better solutions for central problems in cryptography.

1 459 703 €

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

Recent advances have shown that therapeutic manipulations of key cell-cell interactions can have dramatic clinical outcomes. Most notable are several early successes in cancer immunotherapy that target the tumor-T cell interface. However, these successes were only partial. This is likely because the few known interactions are just a few pieces of a much larger puzzle, involving additional signaling molecules and cell types. Dendritic cells (DCs), play critical roles in the induction/suppression of T cells. At early cancer stages, DCs capture tumor antigens and present them to T cells. However, in advanced cancers, the tumor microenvironment (TME) disrupts the crosstalk between DCs and T cells. We will take a multi-step approach to explore how the TME imposes a suppressive effect on DCs and how to reverse this hazardous effect. First, we will use single cell RNA-seq to search for genes in aggressive human and mouse ovarian tumors that are highly expressed in advanced tumors compared to early tumors and that encode molecules that suppress DC activity. Second, we will design a set of CRISPR screens to find genes that are expressed in DCs and regulate the transfer of the suppressive signals. The screens will be performed in the presence of suppressive molecules to mimic the TME and are expected to uncover many key genes in DCs biology. We will develop a new strategy to find synergistic combinations of genes to target (named Perturb-comb), thereby reversing the effect of local tumor immunosuppressive signals. Lastly, we will examine the effect of modified DCs on T cell activation and proliferation in-vivo, and on tumor growth. We expect to find: (1) Signaling molecules in the TME that affect the immune system. (2) New cytokines and cell surface receptors that are expressed in DCs and signal to T cells. (3) New key regulators in DC biology and their mechanisms. (4) Combinations of genes to target in DCs that reverse the TME’s hazardous effects.

1 500 000 €

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

We have recently shown that application of EGFR targeted synthetic dsRNA: Poly Iosine/Poly Cytosine (pIC) is highly efficient and selective against deadly cancers overexpressing EGFR, like glioblastoma (U87MGwtEGFR), breast cancer (MDA-MB-468) and adenocarcinoma (A431). Double-stranded RNA, frequently expressed in cells infected with viruses, activates a number of pro-apoptotic processes simultaneously. These dsRNA-induced mechanisms efficiently kill infected cells and induce expression of anti-proliferative cytokines from the interferon (IFN) family, thereby preventing spread of the virus. pIC delivered with Melittin-polyethylenimine-polyethyleneglycol-EGF (MPPE) eliminated orthotropic and subcutaneous tumors of the above cancers. Heterogeneous glioblastoma models where only half of the cells overexpress wtEGFR are also eliminated by local application, most likely due to a bystander antiproliferative effects, at least partially mediated by interferons (Shir et al., 2006). Systemic application of EGFR targeted pIC is also highly effective against breast and adenocarcinoma disseminated cancer models resembling metastatic cancers (Shir et al., 2011). During the last two years we have improved the vectors homing to EGFR to entities that can now be translated into clinical agents (Shaffert, 2011; Shir 2011, Abourbeh 2012). The impressive results with these more simplified vectors, make this project ready for clinical development, which requires fund raising from a Company/Venture capitalist. Commercialization of the therapy will be detailed in the proposal.

150 000 €

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