ERC FUNDED PROJECTS

The importance of understanding the functions of the basic building blocks of life, such as proteins, cannot be overstated (as asserted by two recent Nobel prizes in Chemistry), as this understanding unravels the mechanisms that control all organisms. The critical step towards such an understanding is to reveal the structures of these building blocks. A leading method for resolving such structures is cryo-electron microscopy (cryo-EM), in which the structure of a molecule is recovered from its images taken by an electron microscope, by using sophisticated mathematical algorithms (to which my group has made several key mathematical and algorithmic contributions). Due to hardware breakthroughs in the past three years, cryo-EM has made a giant leap forward, introducing capabilities that until recently were unimaginable, opening an opportunity to revolutionize our biological understanding. As extracting information from cryo-EM experiments completely relies on mathematical algorithms, the method’s deep mathematical challenges that have emerged must be solved as soon as possible. Only then cryo-EM could realize its nearly inconceivable potential. These challenges, for which no adequate solutions exist (or none at all), focus on integrating information from huge sets of extremely noisy images reliability and efficiently. Based on the experience of my research group in developing algorithms for cryo-EM data processing, gained during the past eight years, we will address the three key open challenges of the field – a) deriving reliable and robust reconstruction algorithms from cryo-EM data, b) developing tools to process heterogeneous cryo-EM data sets, and c) devising validation and quality measures for structures determined from cryo-EM data. The fourth goal of the project, which ties all goals together and promotes the broad interdisciplinary impact of the project, is to merge all our algorithms into a software platform for state-of-the-art processing of cryo-EM data.

1 751 250 €

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

Sugars, aminoacids or organic acids are typically solid at room temperature. Nonetheless when combined at a particular molar fraction they present a high melting point depression, becoming liquids at room temperature. These are called Natural Deep Eutectic Solvents – NADES. NADES are envisaged to play a major role on different chemical engineering processes in the future. Nonetheless, there is a significant lack of knowledge on fundamental and basic research on NADES, which is hindering their industrial applications. For this reason it is important to extend the knowledge on these systems, boosting their application development. NADES applications go beyond chemical or materials engineering and cover a wide range of fields from biocatalysis, extraction, electrochemistry, carbon dioxide capture or biomedical applications. Des.solve encompasses four major themes of research: 1 – Development of NADES and therapeutic deep eutectic solvents – THEDES; 2 – Characterization of the obtained mixtures and computer simulation of NADES/THEDES properties; 3 – Phase behaviour of binary/ternary systems NADES/THEDES + carbon dioxide and thermodynamic modelling 4 – Application development. Starting from the development of novel NADES/THEDES which, by different characterization techniques, will be deeply studied and characterized, the essential raw-materials will be produced for the subsequent research activities. The envisaged research involves modelling and molecular simulations. Des.solve will be deeply engaged in application development, particularly in extraction, biocatalysis and pharmaceutical/biomedical applications. The knowledge that will be created in this proposal is expected not only to have a major impact in the scientific community, but also in society, economy and industry.

1 877 006 €

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

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

2 461 111 €

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

Major advances were made in understanding circuits that underlie aversive emotional learning. The majority gained by using classical associative models, mainly tone/context-shock conditioning. Failure to extinguish the response or to discriminate from other safe stimuli (generalization), form two main animal models for human anxiety-disorders and post-traumatic-stress. These simple yet powerful approaches enabled cutting-edge techniques in rodents to unveil amygdala circuitry and its connectivity with the medial-prefrontal-cortex. Yet, we have less understanding of the mechanisms that underlie elaborated behavioural models of mal-adaptive behaviour, as well as less understanding of neural codes and computations in the evolutionary-expanded primate amygdala. Our lab recently embarked on exploring these venues by pioneering physiological studies of generalization and extinction protocols in primates. The goal of the current project is to develop behavioural models of complex learning and maladaptive behaviour, and then examine and shed light on the underlying computations in primate amygdala-PFC circuit. We design a novel rule-based learning task, and examine its acquisition, extinction, generalization and exploration-exploitation trade-off in dangerous environments. Specifically, the concepts of rule learning and exploration-exploitation tradeoff form novel insights and aspects of [mal-]adaptive behaviours, and will suggest new animal models of learned anxiety. We record dozens of neurons in the amygdala and prefrontal-cortex simultaneously using deep multi-contact arrays, supplemented by stimulation to address functional connectivity, and development of modelling approaches for the behaviour and neural codes. We posit that the development of more [complex] models is crucial and the next logical step in achieving translation of animal models of anxiety disorders, as well as in understanding basic mechanisms behind the rich repertoire of emotional behaviours.

2 000 000 €

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

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

1 867 181 €

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

Cancer is a growing medical problem which genetic and environmental basis is not clearly understood. Massive efforts over the last decade have identified differences in cancer gene expression that cannot be explained by coding sequences or promoter variations, whereas the effect of transcriptional enhancers remains unclear due to the lack of an effective way to link enhancers with their controlled genes. Recently, we discovered a class of inter-tumor, inter-patient DNA methylation variations in putative enhancers that predict changes in gene expression levels with much greater power than promoter or sequence analyses. The overall goal of this proposal is to determine if changes in enhancer methylation form part of the genomic basis of cancer. Our aim is to elucidate methylation-influenced disease regulatory circuits that affect cancer driver and risk genes and may ultimately serve as markers for disease progression and drug response. Utilizing a new genomic methodology, which allows systematic prediction and verification of gene-enhancer pairing, I will test the above hypothesis in two disease models: breast cancer and glioblastoma. I will methodologically assess numerous potential enhancers across the disease genomes and explore the effects of genetic and epigenetic mutations and variations at these sites. Informative sites will then be evaluated as markers of gene expression level in tumor biopsies. Ultimately, I will apply novel tools to manipulate selected enhancers genetically and epigenetically, thus investigating the causal relationships between enhancer methylation and gene expression, and assessing the potential for tuning gene expression levels by enhancer methylation modification. This study may transform our understanding of the mechanisms underlying disease predisposition, determine the regulatory circuits of key disease genes, lead to improved diagnosis and predictive abilities, and may pave the way for precision epigenetic therapy.

2 000 000 €

Start date: 2017-04-01, End date: 2022-03-31

Quark-Gluon Plasma (QGP) is a primordial state of matter, which consists of interacting free quarks and gluons. QGP likely existed immediately after the Big-Bang, and this extreme form of matter is today created in Little Bangs, which are ultra-relativistic collisions of heavy nuclei at the LHC and RHIC experiments. Based on the deconfinement ideas, a gas-like behaviour of QGP was anticipated. Unexpectedly, predictions of relativistic hydrodynamics - applicable to low momentum hadron data - indicated that QGP behaves as nearly perfect fluid, thus bringing exciting connections between the hottest (QGP) and the coldest (perfect Fermi gas) matter on Earth. However, predictions of hydrodynamical simulations are often weakly sensitive to changes of the bulk QGP parameters. In particular, even a large increase of viscosity not far from the phase transition does not notably change the low momentum predictions; in addition, the origin of the surprisingly low viscosity remains unclear. To understand the QGP properties, and to challenge the perfect fluid paradigm, we will develop a novel precision tomographic tool based on: i) state of the art, no free parameters, energy loss model of high momentum parton interactions with evolving QGP, ii) simulations of QGP evolution, in which the medium parameters will be systematically varied, and the resulting temperature profiles used as inputs for the energy loss model. In a substantially novel approach, this will allow using the data of rare high momentum particles to constrain the properties of the bulk medium. We will use this tool to: i) test our “soft-to-hard” medium hypothesis, i.e. if the bulk behaves as a nearly perfect fluid near critical temperature Tc, and as a weakly coupled system at higher temperatures, ii) map “soft-to-hard” boundary for QGP, iii) understand the origin of the low viscosity near Tc, and iv) test if QGP is formed in small (p+p or p(d)+A) systems.

1 356 000 €

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

Understanding and quantifying the impacts of climate change at the regional and hemispheric scales are particularly difficult with respect to changes in rainfall and temperature patterns that lead to extended droughts and flooding events. Isotopic records in speleothems are increasingly used to determine climate variability on land and for data-model comparisons. However, transferring speleothem records into quantitative climate parameters suffers from a major limitation: speleothem formation processes result in geochemical disequilibrium and there is currently no way to correct for it in paleoclimate data. SPADE will shift the treatment of paleoclimate archives from regarding them as recorders of slow geological processes to consideration of geological material as recording much faster chemical reactions. As such, they cannot be assumed to form at equilibrium. SPADE will create a new framework, based on one classic and two novel isotopic tracers in carbonates (δ18O-Δ17O-Δ47) to quantify disequilibrium in cave records and overcome this underlying limitation. SPADE’s unique approach is based first on laboratory experiments that isolate chemical processes of speleothem formation, to test their respective effects on isotopic disequilibrium. Then speleothem analog experiments and modern cave material are combined to create speleothem specific calibrations for these isotopic proxies. These SPADE results will then be applied to classic paleoclimate records of dryland hydrology, such as Soreq Cave (Israel) and Devils Hole (Nevada). SPADE will address long standing climatic hypotheses regarding the interplay between temperature, amount of rainfall, surface evaporation, moisture sources, and regional climate connections in these drought vulnerable regions, and will make these records much more useful. A detailed understanding of disequilibrium will enable the use of these innovative geochemical tools in speleothems and more broadly, in other paleoclimate carbonate archives.

2 000 000 €

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

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

2 220 000 €

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