ERC FUNDED PROJECTS

Whether and where clouds consist of liquid water, ice or both (i.e. their thermodynamic phase distribution), has major impacts on the clouds’ dynamical development, their radiative properties, their efficiency to form precipitation, and their impacts on the atmospheric environment. Cloud ice formation in the temperature range between 0 and -37°C is initiated by aerosol particles acting as heterogeneous ice nuclei and propagates through the cloud via a multitude of microphysical processes. Enormous progress has been made in recent years concerning the understanding and model parameterization of primary ice formation. In addition, high-resolution atmospheric models with complex cloud microphysics schemes can now be employed for realistic case studies of clouds. Finally, new retrieval schemes for the cloud (top) phase have recently been developed for various satellites, including passive polar orbiting and geostationary sensors, which provide a good spatial and temporal coverage and a long data record. We propose here to merge the bottom-up, forward modeling approach for the cloud phase distribution with the top-down view of satellites. C2Phase will conduct systematic closure studies for variables related to the cloud phase distribution such as the cloud ice area fraction, its distribution as function of temperature and its temporal evolution, with a focus on Europe. For this, we will (1) use clustering techniques to separate different cloud regimes in model and satellite data, (2) explore the parameters and processes which the simulated phase distribution is most sensitive to, (3) investigate whether closure is reached between state-of-the art cloud resolving models and satellite observations, and how this closure can be improved by consistent and physically justified changes in microphysical parameterizations, and (4) use our results to improve the representation of mixed-phase clouds in weather and climate models and to quantify the impacts of these improvements.

1 499 549 €

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

Cell-state switching in cancer allows cells to transition from a proliferative to an invasive and drug-resistant phenotype. This plasticity plays an important role in cancer progression and tumour heterogeneity. We have made a striking observation that cancer cells of different origin can switch to a common survival state. During this epigenomic reprogramming, cancer cells re-activate genomic enhancers from specific regulatory programs, such as wound repair and epithelial-to-mesenchymal transition. The goal of my project is to decipher the enhancer logic underlying this canalization effect towards a common survival state. We will then employ this new understanding of enhancer logic to engineer synthetic enhancers that are able to monitor and manipulate cell-state switching in real time. Furthermore, we will use enhancer models to identify cis-regulatory mutations that have an impact on cell-state switching and drug resistance. Such applications are currently hampered because there is a significant gap in our understanding of how enhancers work. To tackle this problem we will use a combination of in vivo massively parallel enhancer-reporter assays, single-cell genomics on microfluidic devices, computational modelling, and synthetic enhancer design. Using these approaches we will pursue the following aims: (1) to identify functional enhancers regulating cell-state switching by performing in vivo genetic screens in mice; (2) to elucidate the dynamic trajectories whereby cells of different cancer types switch to a common survival cell-state, at single-cell resolution; (3) to create synthetic enhancer circuits that specifically kill cancer cells undergoing cell-state switching. Our findings will have an impact on genome research, characterizing how cellular decision making is implemented by the cis-regulatory code; and on cancer research, employing enhancer logic in the context of cancer therapy.

1 999 660 €

Start date: 2017-06-01, End date: 2022-05-31

Naturally-emitted very short-lived halogens (VSLH) have a profound impact on the chemistry and composition of the atmosphere, destroying greenhouse gases and altering aerosol production, which together can change the Earth´s radiative balance. Therefore, natural halogens possess leverage to influence climate, although their contribution to climate change is not well established and most climate models have yet to consider their effects. Also, there is increasing evidence that natural halogens i) impact on the air quality of coastal cities, ii) accelerates the atmospheric deposition of mercury (a toxic heavy metal) and iii) that their natural ocean and ice emissions are controlled by biological and photochemical mechanisms that may respond to climate changes. Motivated by the above, this project aims to quantify the so far unrecognized natural halogen-climate feedbacks and the impact of these feedbacks on global atmospheric oxidizing capacity (AOC) and radiative forcing (RF) across pre-industrial, present and future climates. Answering these questions is essential to predict if these climate-mediated feedbacks can reduce or amplify future climate change. To this end we will develop a multidisciplinary research approach using laboratory and field observations and models interactively that will allow us to peel apart the detailed physical processes behind the contribution of natural halogens to global climate change. Furthermore, the work plan also involves examining past-future climate impacts of natural halogens within a holistic Earth System model, where we will develop the multidirectional halogen interactions in the land-ocean-ice-biosphere-atmosphere coupled system. This will provide a breakthrough in our understanding of the importance of these natural processes for the composition and oxidation capacity of the Earth´s atmosphere and climate, both in the presence and absence of human influence.

1 979 112 €

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

Processes on the Antarctic continental shelf and slope are crucially important for determining the rate of future sea level rise, setting the properties and volume of dense bottom water exported globally, and regulating the carbon cycle. Yet our ability to model and predict these processes over future decades remains rudimentary. This deficiency in understanding originates in a lack of observations in this inaccessible region. The COMPASS project seeks to rectify that by exploiting new technology - autonomous marine vehicles called gliders - to observe, quantify and elucidate processes on the continental shelf and slope of Antarctica that are important for climate. The COMPASS objective is to make a step-change in our quantitative understanding of: (i) the ocean front that marks the boundary between the Antarctic continental shelf and the open ocean, and its associated current system; (ii) the interaction between ocean, atmosphere and sea-ice on the Antarctic continental shelf; and (iii) the exchange of heat, salt and freshwater with the cavities beneath ice shelves. These goals will be met by a series of targeted ocean glider campaigns around Antarctica, spanning different flow regimes, including areas where warm water is able to access the continental shelf and influence ice shelves, areas where the continental shelf is cold and fresh, and areas where the continental shelf hosts cold, salty, dense water that eventually spills into the abyss. A unique circumpolar assessment of ocean properties and dynamics, including instabilities and mixing, will be undertaken. COMPASS will develop new technology to deploy a profiling glider into inaccessible environments such as Antarctic polynyas (regions of open water surrounded by sea-ice). As well as scientific breakthroughs that will feed into future climate assessments, improving projections of future sea level rise and global temperatures, COMPASS will deliver enhanced design for future ocean observing systems.

3 499 270 €

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

Via our connections we learn about new ideas, quality of products, new investment opportunities and job opportunities. We influence and are influenced by our circle of friends. Firms are interconnected in complex processes of production and distribution. A firm’s decisions in a supply chain depends on other firms’ choices in the same supply chain, as well as on firms' behaviour in competing chains. Research on networks in the last 20 years has provided a series of tolls to study a system of interconnected economic agents. This project will advance the state of the art by further developing new applications of networks to better understand modern oligopoly markets. The project is organised into two sub-projects. In sub-project 1 networks will be used to model diffusion and adoption of network goods. Different consumers' network locations will summarise different consumers' level of influence. The objectives are to understand how firms incorporate information about consumers' influence in their marketing strategies—pricing strategy and product design. It will provide a rigorous framework to evaluate how the increasing ability of firms to gather information on consumers’ influence affects outcomes of markets with network effects. In sub-project 2 networks will be used to model how inputs—e.g., intermediary goods and patents—are combined to deliver final goods. Possible applications are supply chains, communication networks and networks of patents. The objectives are to study firms' strategic behaviour, like pricing and R&D investments, in a complex process of production and distribution, and to understand the basic network metrics that are useful to describe market power. This is particularly important to provide a guide to competition authorities and alike when they evaluate mergers in complex interconnected markets.

829 000 €

Start date: 2017-06-01, End date: 2022-05-31

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

1 402 666 €

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

The recent IPCC report identifies mineral dust and the associated uncertainties in climate projections as key topics for future research. Dust size distribution in climate models controls the dust-radiation-cloud interactions and is a major contributor to these uncertainties. Observations show that the coarse mode of dust can be sustained during long-range transport, while current understanding fails in explaining why the lifetime of large airborne dust particles is longer than expected from gravitational settling theories. This discrepancy between observations and theory suggests that other processes counterbalance the effect of gravity along transport. D-TECT envisages filling this knowledge gap by studying the contribution of the triboelectrification (contact electrification) on particle removal processes. Our hypothesis is that triboelectric charging generates adequate electric fields to hold large dust particles up in the atmosphere. D-TECT aims to (i) parameterize the physical mechanisms responsible for dust triboelectrification; (ii) assess the impact of electrification on dust settling; (iii) quantify the climatic impacts of the process, particularly the effect on the dust size evolution during transport, on dry deposition and on CCN/IN reservoirs, and the effect of the electric field on particle orientation and on radiative transfer. The approach involves the development of a novel specialized high-power lidar system to detect and characterize aerosol particle orientation and a large-scale field experiment in the Mediterranean Basin using unprecedented ground-based remote sensing and airborne in-situ observation synergies. Considering aerosol-electricity interactions, the observations will be used to improve theoretical understanding and simulations of dust lifecycle. The project will provide new fundamental understanding, able to open new horizons for weather and climate science, including biogeochemistry, volcanic ash and extraterrestrial dust research.

1 968 000 €

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

Historically, people around the world have demanded democratic institutions. Such democratic movements propel political change and also determine economic outcomes. In this project, we ask, how do political preferences, beliefs, and second-order beliefs shape the strategic decision to participate in a movement demanding democracy? Existing scholarship is unsatisfactory because it is conducted ex post: preferences, beliefs, and behavior have converged to a new equilibrium. In contrast, we examine a democratic movement in real time, studying the ongoing democracy movement in Hong Kong. Our study is composed of four parts. In Part 1, we collect panel survey data from Hong Kong university students, a particularly politically active subpopulation. We collect data on preferences, behavior, beliefs, and second-order beliefs using incentivized and indirect elicitation to encourage truthful reporting. We analyze the associations among these variables to shed light on the drivers of participation in the democracy movement. In Part 2, we exploit experimental variation in the provision of information to study political coordination. Among participants in the panel survey, we provide information regarding the preferences and beliefs of other students. We examine whether exposure to information regarding peers causes students to update their beliefs and change their behavior. In Part 3, we extend the analysis in Part 1 to a nationally representative sample of Hong Kong citizens. To do so, we have added a module regarding political preferences, beliefs, and behavior (including incentivized questions and questions providing cover for responses to politically sensitive topics) to the HKPSSD panel survey. In Part 4, we study preferences for redistribution – plausibly a central driver for demands for political rights – among Hong Kong citizens and mainland Chinese. We examine how these preferences differ across populations, as well as their link to support for democracy.

1 494 647 €

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

Droughts cause agricultural loss, forest mortality and drinking water scarcity. Their predicted increase in recurrence and intensity poses serious threats to future global food security. Several historically unprecedented droughts have already occurred over the last decade in Europe, Australia and the USA. The cost of the ongoing Californian drought is estimated to be about US$3 billion. Still today, the knowledge of how droughts start and evolve remains limited, and so does the understanding of how climate change may affect them. Positive feedbacks from land have been suggested as critical for the occurrence of recent droughts: as rainfall deficits dry out soil and vegetation, the evaporation of land water is reduced, then the local air becomes too dry to yield rainfall, which further enhances drought conditions. Importantly, this is not just a 'local' feedback, as remote regions may rely on evaporated water transported by winds from the drought-affected region. Following this rationale, droughts self-propagate and self-intensify. However, a global capacity to observe these processes is lacking. Furthermore, climate and forecast models are immature when it comes to representing the influences of land on rainfall. Do climate models underestimate this land feedback? If so, future drought aggravation will be greater than currently expected. At the moment, this remains largely speculative, given the limited number of studies of these processes. I propose to use novel in situ and satellite records of soil moisture, evaporation and precipitation, in combination with new mechanistic models that can map water vapour trajectories and explore multi-dimensional feedbacks. DRY-2-DRY will not only advance our fundamental knowledge of the mechanisms triggering droughts, it will also provide independent evidence of the extent to which managing land cover can help 'dampen' drought events, and enable progress towards more accurate short-term and long-term drought forecasts.

1 465 000 €

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

The origin of oxygenic photosynthesis is one of the most dramatic evolutionary events that the Earth has ever experienced. At some point in Earth’s first two billion years, primitive bacteria acquired the ability to harness sunlight, oxidize water, release O2, and transform CO2 to organic carbon, and all with unprecedented efficiency. Today, oxygenic photosynthesis accounts for nearly all of the biomass on the planet, and exerts significant control over the carbon cycle. Since 2 billion years ago (Ga), it has regulated the climate of our planet, ensuring liquid water at the surface and enough oxygen to support complex life. The biological and geological consequences of oxygenic photosynthesis are so great that they effectively underpin what we think of as a habitable planet. Understanding the origins of photosynthesis is a paramount scientific challenge at the heart of some of humanity’s greatest questions: how did life evolve? how did Earth become a habitable planet? EARTHBLOOM addresses these questions head-on through the first comprehensive scientific study of Earth’s first blooming photosynthetic ecosystem, preserved as Earth’s oldest carbonate platform. This relatively unknown, >450m thick deposit, comprised largely of 2.9 Ga fossil photosynthetic structures (stromatolites), is one of the most important early Earth fossil localities ever identified, and EARTHBLOOM is carefully positioned for major discovery. EARTHBLOOM will push the frontier of field data collection and sample screening using new XRF methods for carbonate analysis. EARTHBLOOM will also push the analytical frontier in the lab by applying the most sensitive metal stable isotope tracers for O2 at ultra-low levels (Mo, U, and Ce) coupled with novel isotopic “age of oxidation” constraints. By providing new constraints on atmospheric CO2, ocean pH, oxygen production, and nutrient availability, EARTHBLOOM is poised to redefine Earth’s surface environment at the dawn of photosynthetic life.

1 848 685 €

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

The early development literature documented that the growth path of most advanced economies was accompanied by a process of structural transformation. As economies develop, the share of agriculture in employment falls and workers migrate to cities to find employment in the industrial and service sectors [Clark (1940), Kuznets (1957)]. In the first industrialized countries, technical improvements in agriculture favoured the development of industry and services by releasing labour, increasing demand and raising profits to finance other activities. However, several scholars noted that the positive effects of agricultural productivity on economic development are no longer operative in open economies. In addition, there is a large theoretical literature highlighting how market failures can retard structural transformation in developing countries. In particular, financial frictions might constrain the reallocation of capital and thus retard the process of labour reallocation. In this project, we propose to contribute to our understanding of structural transformation by providing direct empirical evidence on the effects of exogenous shocks to local agricultural and manufacturing productivity on the reallocation of capital and labour across sectors, firms and space in Brazil. For this purpose, we construct the first data set that permits to jointly observe labour and credit flows across sectors and space. To exploit the spatial dimension of the capital allocation problem, we design a new empirical which exploits the geographical structure of bank branch networks. Similarly, we propose to study the spatial dimension of the labour allocation problem by exploiting differences in migration costs across regions due to transportation and social networks.

1 486 500 €

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

Epigenetic inheritance is the transmission of information, generally in the form of DNA methylation or post-translational modifications on histones that regulate the availability of underlying genetic information for transcription. RNA itself feeds back to contribute to histone modification. Sequence accessibility is both a matter of folding the chromatin fibre to alter access to recognition motifs, and the local concentration of factors needed for efficient transcriptional initiation, elongation, termination or mRNA stability. In heterochromatin we find a subset of regulatory factors in carefully balanced concentrations that are maintained in part by the segregation of active and inactive domains. Histone H3 K9 methylation is key to this compartmentation. C. elegans provides an ideal system in which to study chromatin-based gene repression. We have demonstrated that histone H3 K9 methylation is the essential signal for the sequestration of heterochromatin at the nuclear envelope in C. elegans. The recognition of H3K9me1/2/3 by an inner nuclear envelope-bound chromodomain protein, CEC-4, actively sequesters heterochromatin in embryos, and contributes redundantly in adult tissues. Epiherigans has the ambitious goal to determine definitively what targets H3K9 methylation, and identify its physiological roles. We will examine how this mark contributes to the epigenetic recognition of repeat vs non-repeat sequence, and mediates a stress-induced response to oxidative damage. We will examine the link between these and the spatial clustering of heterochromatic domains. Epiherigans will develop an integrated approach to identify in vivo the factors that distinguish repeats from non-repeats, self from non-self within genomes and will examine how H3K9me contributes to a persistent ROS or DNA damage stress response. It represents a crucial step towards understanding of how our genomes use heterochromatin to modulate, stabilize and transmit chromatin organization.

2 500 000 €

Start date: 2017-06-01, End date: 2022-05-31

One of the ultimate goals of economics is to inform a policy that improves welfare. Despite that the vast amount of empirical works in economics aims to achieve this goal, the current state of the art in econometrics is silent about concrete recommendation for how to estimate the welfare maximizing policy. This project addresses statistically optimal and practically useful ways to learn the welfare-maximizing policy from data by developing novel econometric frameworks, sampling design, and estimation approaches that can be applied to a wide range of policy design problems in reality. Development of econometric methods for optimal empirical policy design proceeds by answering the following open questions. First, given a sampling process, how do we define optimal estimation for the welfare-maximizing policy? Second, what estimation method achieves this statistical optimality? Third, how do we solve policy decision problem when the sampling process only set-identifies the social welfare criterion? Fourth, how can we integrate the sampling step and estimation step to develop a package of optimal sampling and optimal estimation procedures? I divide the project into the following four parts. Each part is motivated by important empirical applications and has methodological challenges related to these four questions. 1) Estimation of treatment assignment policy 2) Estimation of optimal policy in other public policy applications 3) Policy design with set-identified social welfare 4) Sampling design for empirical policy design

1 291 064 €

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

Despite the dramatic impact of earthquakes, the physics of their onset and the short-term behavior of fault are still poorly understood. Using existing high quality seismic observations, we propose to develop a novel functional imaging of the brittle crust to clarify not only structural properties but also the dynamics of faults. We will analyze spatio-temporal changes of elastic properties around fault zones to highlight the interplay between changes in the host rocks and fault slip. Imaging the damage structure around faults and its evolution requires new seismological methods. With novel methods to image the highly heterogeneous fault regions, we will provide multi-scale descriptions of fault zones, including their laterally variable thicknesses and depth dependence. In parallel we will image temporal changes of seismic velocities and scattering strength. External natural forcing terms (e.g. tides, seasonal hydrologic loadings) will be modeled to isolate the signals of tectonic origin. This will also allow us to monitor the evolving seismic susceptibility, i.e. a measure of the proximity to a critical state of failure. Improved earthquake detection techniques using ‘deep machine learning’ methods will facilitate tracking the evolution of rock damage. The imaging and monitoring will provide time-lapse images of elastic moduli, susceptibility and seismicity. The observed short-time changes of the materials will be included in slip initiation models coupling the weakening of both the friction and the damaged host rocks. Laboratory experiments will shed light on the transition of behavior from granular (shallow fault core) to cohesive (distant host rock) materials. Our initial data cover two well-studied fault regions of high earthquake probability (Southern California and the Marmara region, Turkey) and an area of induced seismicity (Groningen). The derived results and new versatile imaging and monitoring techniques can have fundamental social and economic impacts.

2 434 743 €

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

There is mounting evidence that firms are becoming more fragmented; production is less often made “in-house”. Firms buy inputs from abroad. Tasks are often split in parts. Some are offshored, others are subcontracted. Hence, firms buy services from other, local or international, firms. But they also supply inputs to other firms. Technical change, the internet, and globalization, all facilitate this transformation. In order to better understand how firms thrive in the new global environment, the proposed research aims to construct a networks view of the firm. Fragmentation offers new opportunities: firms may specialize in what they make best, hence creating a business network of customers and suppliers. Networks are also useful to secure provision of fragmented tasks. The firms’ suppliers of goods and services – accountants, logisticians, consultants… -- may well be related to the firm through its workers’ social networks: family ties, boardroom relations… These social networks should be useful when times are tough -- board members could help find financing in banks where their schoolmates have a job – or when times are unusually good -- employees could help in spotting the right hires among their former co-workers. The proposed research will focus on how firms social and business networks help firms to be resilient in the face of shocks. Resilience will be measured using the firms’ and workers’ outcomes – value-added, wages, employment, or occupations. The research will have a theoretical component using general equilibrium models with heterogeneous firms, an empirical component with unique data sources from at least two countries (France, Sweden), and an “econometric theory” component which will seek to develop techniques for the study of many-to-one matches in the presence of networks. The research will speak to the labor economics community but also to the international trade community, the management community, as well as the econometrics community.

1 753 288 €

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

Atmospheric aerosol particles impact Earth’s climate, by directly scattering sunlight and indirectly by affecting cloud properties. The largest uncertainties in climate change projections are associated with the atmospheric aerosol system that has been altered by anthropogenic activities. A major source of that uncertainty involves the formation of secondary particles and cloud condensation nuclei from natural and anthropogenic emissions of volatile compounds. This research challenge persists despite significant efforts within recent decades. I will build a research group that aims to resolve the atmospheric oxidation processes that convert volatile trace gases to particle precursor vapours, clusters and new aerosol particles. We will create novel measurement techniques and utilize the tremendous potential of mass spectrometry for detection of i) particle precursor vapours ii) oxidants, both conventional but also recently discovered stabilized Criegee intermediates, and, most importantly, iii) newly formed clusters. These methods and instrumentation will be applied for resolving the initial steps of new particle formation on molecular level from oxidation to clusters and stable aerosol particles. To reach these goals, targeted laboratory and field experiments together with long term field measurements will be performed employing the state-of-the-art instrumentation developed. Principal outcomes of this project include i) new experimental methods and techniques vital for atmospheric research and a deep understanding of ii) oxidation pathways producing aerosol particle precursors, iii) the initial molecular steps of new particle formation and iv) mechanisms of growth of freshly formed clusters toward larger sizes, particularly in the crucial size range of a few nanometers. The conceptual understanding obtained during this project will open multiple new research horizons from oxidation chemistry to Earth system modeling.

1 953 790 €

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

Recent breakthroughs in the field of genome editing provide a genuine opportunity to establish innovative approaches to repair DNA mutations to replace, engineer or regenerate malfunctioning cells in vitro or in vivo. However, most of the recently developed technologies introduce double-strand DNA breaks at a target locus as the first step to gene correction. These breaks are subsequently repaired by one of the cell intrinsic DNA repair pathways, typically inducing an abundance of insertions and deletions (indels). Ideally, for many applications genome editing should, however, be efficient and specific, without the introduction of indels. Site-specific recombinases (SSRs) allow precise genome editing without triggering endogenous DNA repair pathways and possess the unique ability to fulfill both cleavage and immediate resealing of the processed DNA in vivo. However, customizing the DNA binding specificity of SSRs is not straightforward. With this project, we propose to solve this shortcoming. We have already demonstrated that by applying substrate-linked directed evolution, SSRs can be generated that specifically recognize therapeutic targets. The objective of this project is the development of a universal genome editing platform that allows flexible, efficient and safe gene corrections in cells of any origin without triggering cell intrinsic DNA repair. GenSurge aims to: i) sequence an unprecedented, comprehensive compendium of evolved SSRs to understand the directed molecular evolution process at nucleotide resolution; ii) integrate the knowledge obtained in i) to develop a unique SSR-based approach to correct genomic inversions; iii) develop a universal SSR-based strategy that allows flawless, precise and safe genome editing to correct any gene defect in human, animal or plant cells. The successful implementation of this project will deliver a comprehensive, safe and efficient platform from which genome surgery-based cure strategies can be initiated.

2 380 425 €

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

Advancing age is the major risk factor for disability and illness, including cardiovascular, metabolic and neu-rodegenerative disease and cancer. The increasing incidence of older people in European countries is posing major medical, social and economic challenges, and there is an urgent need to find ways of compressing late-life morbidity. Ageing has proved malleable to genetic and pharmacological interventions in laboratory animals, and at least some of the mechanisms are conserved over large evolutionary distances. Reduced activity of the nutrient-sensing insulin/insulin-like growth factor/TOR signalling network can increase health and combat ageing-related disease in laboratory animals, with increasing evidence of its importance in human ageing. There is thus a prospect for pharmacological intervention to prevent more than one ageing-related condition, rather than tackling diseases one by one and as they arise. The aim of this research programme is to evaluate the potential for pharmacological prevention of ageing-related decline in humans with a polypill targeting the nutrient-sensing network. We find that three licensed drugs, lithium, rapamycin and trametinib, act independently, at different nodes in the network, to increase lifespan in the fruitfly Drosophila, implying that the network controls more than one underlying mechanism of ageing, and that a polypill of these drugs could be particularly effective. We shall test this idea in mice, and assess the underlying mechanisms in Drosophila and mice. We have found that suppression of the Ras signalling branch of the network, which has a well known role in human cancer, can extend lifespan in both the fruitfly Drosophila and mice, and we shall assess its role in humans. Interventions that ameliorate ageing often have sex-specific effects, and we shall investigate the mechanisms leading to these for the nutrient-sensing network. The outputs of the work will inform future clinical trails in humans.

2 500 000 €

Start date: 2017-12-01, End date: 2022-11-30

Researchers and policymakers alike have highlighted the potential efficiency gains of a global production structure. However, such linkages also raise the possibility of risks. This proposal tackles both empirical and theoretical challenges in incorporating the microeconomic structure of trade and international production networks in the study of the propagation of shocks internationally, and their impact on macroeconomic interdependence. Using newly constructed micro-level datasets, I provide quantitative analysis of the importance of the linkages in multicountry general equilibrium models of trade. First, using firm export and imported-input linkages, I provide a novel model-based estimation strategy to identify the role of country and firm-level shocks, and the implications of these estimates for the transmission of shocks across borders. By using structural trade models to estimate shocks at the firm level and studying the implications for the transmission of shocks across borders, I help bridge the micro-macro nexus in international economics. Second, I take an even more granular focus by studying the role of firm-to-firm production linkages in transmitting shocks across countries. To do so, I exploit a novel matching procedure between a country’s administrative dataset and cross-country firm-level data. I further build on these data by adding in domestic bank-firm relationships. This strategy allows for the study of how financial shocks are exported abroad via firms’ trade and multinational linkages. Third, I incorporate the insights from the empirical work into a full-scale multicountry general equilibrium model of trade, which allows for firm-level heterogeneity and microeconomic and macroeconomics shocks. I use the model for a quantitative study of the cross-country transmission of the different shocks via trade. This allows me to perform counterfactuals and examine the impact of policies, such as how opening to trade impacts macroeconomic interdependence.

1 381 250 €

Start date: 2017-05-01, End date: 2022-04-30

The surface of every living cell is covered with a dense matrix of glycans. Its particular composition and structure codes important messages in cell-cell communication, influencing development, differentiation, and immunological processes. The matrix is formed by highly complex biopolymers whose compositions vary from cell to cell, even between genetically identical cells. This gives rise to population noise in cell-cell communication. A second level of noise stems from glycans present on the same cell that disturb the decoding of the message by glycans binding receptors through competitive binding. Glycan-based communication is characterized by a high redundancy of both glycans and their receptors. Thus, noise and redundancy emerge as key properties of glycan-based cell-cell communication, but their extent and function are poorly understood. By adapting a transmitter-receiver model from communication sciences and combining it with state-of-the-art experimental techniques from biophysics and cell biology, we will address two fundamental questions: What is the role of the redundancy in glycan-based communication? How much ‚noise’ can it tolerate, before the message is lost? To do so, we first establish a simplified model system for glycan-based communication. Biophysical rate constants are determined for lectin-glycan interactions and expanded to glycosylated microparticles that trigger a biological response in lectin expressing receiver cells. Next, single cell glycomes are reconstructed from ultra-high dimensional flow cytometry data using lectin mixtures enabled by recent advancements in instrumentation and glycobioinformatics software. Glycomes accessible on single cell level allow replacing the microparticles with transmitter cells and employ a cell-cell interaction model. Our transmitter-receiver model is used to quantify the noise and reveals how redundancy provides robustness of messaging by cell surface glycans in cellular communication.

1 499 813 €

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

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

2 000 000 €

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

A critical question in Earth system science is what was the impact of prehistoric people on the biosphere and climate? There is much information about human impact through clearance, agriculture, erosion, and modifying water and nutrient budgets. Humans have greatly changed the Earth in the last 8000 years, but did humans modify the major ecological processes (e.g. assembly rules) that shape community assembly and dynamics? Did inter-relationships between processes change in response to human impact? Lyons et al. & Dietl (2016 Nature) suggest that human activities in the last 6000 years had such impacts. Dietl proposes that using past ‘natural experiments’ to predict future changes is “flawed” and “out is the use of uniformitarianism”. As using natural experiments is a common strategy and uniformitarianism is the major working concept in Earth sciences, it is imperative to test whether prehistoric human activity changed major ecological processes determining community development. To test this hypothesis, patterns in pollen-stratigraphical data for the past 11,500 years from over 2000 sites across the globe will be explored consistently using numerical techniques to discern changes in 25 ecosystem properties (richness, evenness, and diversity; turnover; rates of change; taxon co-occurrences, etc.). Patterns in these properties will be compared statistically at sites within biomes, between biomes, within continents, and between continents to test the hypotheses that prehistoric human activities changed the basic ecological processes of community assembly and that their inter-relationships changed through time. These areas provide major contrasts in human prehistory and biomes. HOPE is interdisciplinary: pollen analysis, databases, multivariate analysis, ecology, new statistical methods, numerical simulations, statistical modelling. HOPE’s impact goes beyond human effects on the biosphere and extends to the very core of Earth science’s basic conceptual framework.

2 278 884 €

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

IASI - Flux and temperature July 2016 was Earth's warmest month on record. The first six months of 2016 were also the warmest six-month period since modern meteorology observations began. This, along with the recent so-called “hiatus” in the warming trend, and the Paris climate agreement, all attracted scientific and public attention as to how reliable the historical temperature record is, and to the level of confidence in future model climate projections. Although the role of satellites in observing the variability and change of the Earth system has increased in recent decades, remotely-sensed observations are still underexploited to accurately assess climate change fingerprints. The IASI - Flux and Temperature (IASI-FT) project aims at providing new benchmarks for top-of-atmosphere radiative flux and temperature observations using the calibrated radiances measured twice a day at any location by the IASI instrument on the suite of MetOp satellites. The main challenge is to achieve the stringent accuracy and stability necessary for climate studies, particularly for climate trends. Building upon the expertise accumulated by my group during the last 10 years, I propose the development of innovative algorithms and statistical tools to generate climate data records at the global scale, of (1) spectrally resolved outgoing radiances, (2) land and sea skin surface temperatures, and (3) temperatures at selected altitudes. Time series of these quantities will be compared with in situ and other satellite observations if available, atmospheric reanalyses, and climate model simulations. The observed trends will be analyzed at seasonal and regional scales in order to disentangle natural (weather/dynamical) variability and human-induced climate forcings. This project, while clearly research-oriented, will lead towards an operational integrated observational strategy for the Earth climate system, given that the IASI program started in 2006 and will last until 2040 at least.

2 200 000 €

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

From populations of unicellular organisms to complex tissues, cell-to-cell variability in phenotypic traits seems to be universal. To study this heterogeneity and its biological consequences, researchers have used advanced microscopy-based approaches that provide exquisite spatial and temporal resolution, but these methods are typically limited to measuring a few properties in parallel. On the other hand, next generation sequencing technologies allow for massively parallel genome-wide approaches but have, until recently, relied on studying population averages obtained from pooling thousands to millions of cells, precluding genome-wide analysis of cell-to-cell variability. Very excitingly, in the last few years there has been a revolution in single-cell sequencing technologies allowing genome-wide quantification of mRNA and genomic DNA in thousands of individual cells leading to the convergence of genomics and single-cell biology. However, during this convergence the spatial and temporal information, easily accessed by microscopy-based approaches, is often lost in a single-cell sequencing experiment. The overarching goal of this proposal is to develop single-cell sequencing technology that retains important aspects of the spatial-temporal information. In particular I will focus on integrating single-cell transcriptome and epigenome measurements with the physical cell-to-cell interaction network (spatial information) and lineage information (temporal information). These tools will be utilized to (i) explore the division symmetry of intestinal stem cells in vivo; (ii) to reconstruct the cell lineage history during zebrafish regeneration; and (iii) to determine lineage relations and the physical cell-to-cell interaction network of progenitor cells in the murine bone marrow.

2 500 000 €

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