ERC FUNDED PROJECTS

The bottom-up assembly of tissue from cellular building blocks constitutes a promising, yet highly challenging approach to engineer complex tissues. The challenge lies in controlling cell-cell interactions, which determine how cells organize with respect to each other, how they work together and consequently whether such a multicellular architecture will be functional. The limited spatial and temporal control over cell-cell interactions current biological and chemical approaches provide severely restricts bottom-up tissue engineering. Here, I propose a new way to control cell-cell interactions. I aim to regulate cell-cell interactions with visible light using proteins that reversibly homo- or heterodimerize under blue or red light. These photoswitchable cell-cell interactions provide sustainable, non-invasive, dynamic and reversible control over cell-cell interactions with unprecedented spatial and temporal resolution. First of all, we will focus on various light dependent protein interactions to mediate cell-cell contacts. The detailed characterization (strength, dynamics, interaction modes and orthogonality) of these new photoswitchable cell-cell interactions will provide the framework for the bottom-up construction of tissue-like structures. Secondly, we will use these photoswitchable cell-cell interactions to assemble cells into multicellular architectures with predictable and programmable organization. The dynamic and reversible nature of the photoswitchable contacts will allow us to locally alter interactions at any point in time, to rearrange and obtain asymmetric multicellular structures, which are typical of tissues. Finally, we will also explore how the photoswitchable cell-cell interactions alter cell behavior and signaling. Ultimately, this will pave the way for the bottom-up assembly of multicellular architectures, enabling us to control precisely and dynamically their organization in space and time as well as regulate how cells work together.

1 937 000 €

Start date: 2018-07-01, End date: 2023-06-30

It is a basic textbook notion that the plasma membranes of virtually all organisms display an asymmetric lipid distribution between inner and outer leaflets far removed from thermodynamic equilibrium. As a fundamental biological principle, lipid asymmetry has been linked to numerous cellular processes. However, a clear mechanistic justification for the continued existence of lipid asymmetry throughout evolution has yet to be established. We propose here that lipid asymmetry serves as a store of potential energy that is used to fuel energy-intense membrane remodelling and signalling events for instance during membrane fusion and fission. This implies that rapid, local changes of trans-membrane lipid distribution rather than a continuously maintained out-of-equilibrium situation are crucial for cellular function. Consequently, new methods for quantifying the kinetics of lipid trans-bilayer movement are required, as traditional approaches are mostly suited for analysing quasi-steady-state conditions. Addressing this need, we will develop and employ novel photochemical lipid probes and lipid biosensors to quantify localized trans-bilayer lipid movement. We will use these tools for identifying yet unknown protein components of the lipid asymmetry regulating machinery and analyse their function with regard to membrane dynamics and signalling in cell motility. Focussing on cell motility enables targeted chemical and genetic perturbations while monitoring lipid dynamics on timescales and in membrane structures that are well suited for light microscopy. Ultimately, we aim to reconstitute lipid asymmetry as a driving force for membrane remodelling in vitro. We expect that our work will break new ground in explaining one of the least understood features of the plasma membrane and pave the way for a new, dynamic membrane model. Since the plasma membrane serves as the major signalling hub, this will have impact in almost every area of the life sciences.

1 500 000 €

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

During the last decade, a huge number of earth observation (EO) satellites with optical and Synthetic Aperture Radar sensors onboard have been launched and advances in satellite systems have increased the amount, variety and spatial/spectral resolution of EO data. This has led to massive EO data archives with huge amount of remote sensing (RS) images, from which mining and retrieving useful information are challenging. In view of that, content based image retrieval (CBIR) has attracted great attention in the RS community. However, existing RS CBIR systems have limitations on: i) characterization of high-level semantic content and spectral information present in RS images, and ii) large-scale RS CBIR problems since their search mechanism is time-demanding and not scalable in operational applications. The BigEarth project aims to develop highly innovative feature extraction and content based retrieval methods and tools for RS images, which can significantly improve the state-of-the-art both in the theory and in the tools currently available. To this end, very important scientific and practical problems will be addressed by focusing on the main challenges of Big EO data on RS image characterization, indexing and search from massive archives. In particular, novel methods and tools will be developed, aiming to: 1) characterize and exploit high level semantic content and spectral information present in RS images; 2) extract features directly from the compressed RS images; 3) achieve accurate and scalable RS image indexing and retrieval; and 4) integrate feature representations of different RS image sources into a unified form of feature representation. Moreover, a benchmark archive with high amount of multi-source RS images will be constructed. From an application point of view, the developed methodologies and tools will have a significant impact on many EO data applications, such as accurate and scalable retrieval of: specific man-made structures and burned forest areas.

1 491 479 €

Start date: 2018-04-01, End date: 2023-03-31

The proposed project will significantly improve the insight in the processes that have changed a comet nucleus or asteroid since their formation. These processes typically go along with activity, the observable release of gas and/or dust. Understanding the evolutionary processes of comets and asteroids will allow us to answer the crucial question which aspects of these present-day bodies still provide essential clues to their formation in the protoplanetary disc of the early solar system. Ground-breaking progress in understanding these fundamental questions can now be made thanks to the huge and unprecedented data set returned between 2014 and 2016 by the European Space Agency’s Rosetta mission to comet 67P/Churyumov-Gerasimenko, and by recent major advances in the observational study of active asteroids facilitated by the increased availability of sky surveys and follow-on observations with world-class telescopes. The key aims of this proposal are to - Obtain a unified quantitative picture of the different erosion processes active in comets and asteroids, - Investigate how ice is stored in comets and asteroids, - Characterize the ejected dust (size distribution, optical and thermal properties) and relate it to dust around other stars, - Understand in which respects comet 67P can be considered as representative of a wider sample of comets or even asteroids. We will follow a highly multi-disciplinary approach analyzing data from many Rosetta instruments, ground- and space-based telescopes, and connect these through numerical models of the dust dynamics and thermal properties.

1 484 688 €

Start date: 2018-03-01, End date: 2023-02-28

Traditional complexity theory focuses on the dichotomy between P and NP-hard problems. Lately, it has become increasingly clear that this misses a major part of the picture. Results by the PI and others offer glimpses on a fascinating structure hiding inside NP: new computational problems that seem to lie between polynomial and NP-hard have been identified; new conditional lower bounds for problems with large polynomial running times have been found; long-held beliefs on the difficulty of problems in P have been overturned. Computational geometry plays a major role in these developments, providing some of the main questions and concepts. We propose to explore this fascinating landscape inside NP from the perspective of computational geometry, guided by three complementary questions: (A) What can we say about the complexity of search problems derived from existence theorems in discrete geometry? These problems offer a new perspective on complexity classes previously studied in algorithmic game theory (PPAD, PLS, CLS). Preliminary work indicates that they have the potential to answer long-standing open questions on these classes. (B) Can we provide meaningful conditional lower bounds on geometric problems for which we have only algorithms with large polynomial running time? Prompted by a question raised by the PI and collaborators, such lower bounds were developed for the Frechet distance. Are similar results possible for problems not related to distance measures? If so, this could dramatically extend the traditional theory based on 3SUM-hardness to a much more diverse and nuanced picture. (C) Can we find subquadratic decision trees and faster algorithms for 3SUM-hard problems? After recent results by Pettie and Gronlund on 3SUM and by the PI and collaborators on the Frechet distance, we have the potential to gain new insights on this large class of well-studied problems and to improve long-standing complexity bounds for them.

1 486 800 €

Start date: 2018-02-01, End date: 2023-01-31

The three-dimensional organization of chromosomes is necessary for hereditary fidelity and gene regulation. Recent studies have found that eukaryotic interphase chromosomes are spatially organized in compartments, chiefly topologically associated domains (TADs), in a hierarchical order of nested chromatin loops, coining the term “chromosome folding”. TADs are clusters of genes and regulatory elements that are confined to their genomic compartment by spatially constricting their accessible range of action. The folded structure of chromosomes through long-range loops enables mutual interactions of distant genomic loci that otherwise would not be in contact. While crosslinking-based chromosome conformation capture (3C) techniques have revealed the underlying structure of interphase chromosomes, the molecular mechanism of how chromosome-organizing proteins, such as the insulator CTCF or the structural maintenance of chromosomes (SMC) complex cohesin build the chromosomal scaffold and contribute to genomic organization, is not understood. Due to the complexity of the processes involved, biochemical information on how chromosomal proteins contribute to the establishment of TADs is scarce. I have previously demonstrated that single molecule techniques can be used to study the interactions of single cohesin complexes with DNA, chromatin and DNA-bound proteins and to resolve processes that are inaccessible in bulk biochemical experiments. In this project, I will use and expand the high-throughput single molecule technique of DNA curtains to study the molecular details of how chromosomal scaffolding proteins and genetic insulators form the basis for the three-dimensional folding of chromosomes. My experiments will build a novel experimental platform to study the dynamics of chromosomal configuration and maintenance in a reconstituted single molecule assay and will reveal the molecular details that drive the organization of chromosomes into hierarchically organized structures.

1 499 350 €

Start date: 2018-07-01, End date: 2023-06-30

The idea to freely control the atomic-scale structure of matter has intrigued scientists for many decades. The low-temperature scanning probe microscope (LT SPM) has become the instrument of choice for this task since it allows the rearrangement of atoms and molecules on a surface. There is, however, no generic SPM-based method for the manipulation of molecules beyond lateral rearrangement. The goal of this project is to develop controlled mechanical manipulation of molecules (CM3) in which a LT SPM is used to handle large organic molecules in three dimensions with optimal control over position, orientation and shape. CM3 will become a game-changing technique for research on molecular properties and molecular-scale engineering, because it combines fully deterministic manipulation with broad access to molecular degrees of freedom for the first time. In CM3 the tip is attached to a single reactive atom within a molecule. Tip displacement guides the molecule into a desired conformation while the surface provides a second (weaker) fixation. The fundamental challenge addressed by this project is the identification of precise molecular conformations at any time during manipulation. The solution is a big data approach where large batches of automatically recorded SPM manipulation data are structured using machine learning and interpreted by comparison to atomistic simulations. The key idea is a comparison of entire conformation spaces at once, which is robust, even if the theory is not fully quantitative. The obtained map of the conformation space is used to determine molecular conformations during manipulation by methods of control theory. The effectiveness of this approach will be demonstrated in experiments that unambiguously reveal the structure-conductance relation for a series of molecules and that realize the engineering paradigm of piecewise assembly on the molecular scale by constructing a direct current rotor / motor from individual components.

1 465 944 €

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

Social protection has been one of the most popular instruments for promoting human development across the globe. However, the great majority of the global population is not or only partly covered by social protection. Especially in developing countries it is often the very poorest who do not receive essential social benefits. This is highly problematic since inclusive social protection is assumed to be a key factor for national productivity, global economic growth and domestic stability. Social protection in many developing countries can be traced back to colonial times. Surprisingly, the influence of colonialism has been a blind spot for existing theories and empirical studies of comparative social policy. In this project it is argued that the colonial legacy in terms of the imperial strategy of the colonial power, the characteristics of the colonized society and the interplay between the two is crucial in explaining early and contemporary social protection. Hence, the main objective of this project is to systematically understand how colonialism has shaped the remarkable differences in social protection and its postcolonial outcomes. Given the paucity of our information and understanding of social protection in former colonies, an interactive dataset on the characteristics, origins and outcomes of social protection will be developed including comprehensive data on former British and French colonies from the beginning of the 20th century until today. The dataset will be backed by insights derived from four case studies elucidating the causal mechanisms between the colonial legacy and early and contemporary social protection. The proposed project breaks new ground by improving our understanding of why social protection in some developing countries has led to more inclusive societies while reinforcing existing inequalities in others. Such an understanding is a prerequisite in informing the contemporary struggle against poverty and social inequality.

1 486 250 €

Start date: 2018-04-01, End date: 2023-03-31

Do Legislatures Enhance Democracy in Africa? This project seeks to investigate the role of legislatures in African electoral authoritarian regimes. There are two opposing theoretical views: While several studies have found that holding elections, introducing a national assembly and a multiparty system prolongs the life of autocracies, other authors claim the exact opposite: in their view, the more successive multiparty elections take place, the more democratic a regime becomes. Answering these questions is difficult due to the opaqueness of authoritarian regimes. Moreover, most work has concentrated on only a few cases – African cases, in particular, have remained largely absent from the research agenda. This project attempts to fill these gaps by collecting data on authoritarian legislatures in seven African countries. We focus on three areas of investigation: 1) law-making; 2) interaction patterns and political dialogue between the ruling party and the opposition; and 3) representation and constituency responsiveness. The main question is whether legislatures in authoritarian countries actually have a potential to enhance democracy. We use a Mixed Methods-Design which combines qualitative and quantitative data. To answer Question 1, we use content analysis of parliamentary debates. For Question 2 and 3, we will conduct full population surveys in the national assemblies of our seven countries. We will collect biographical and opinion data, as well as data on the social interactions between government and opposition, which will be analyzed with the methods of Social Network Analysis. Furthermore, we employ process tracing to understand the causal mechanism between legislative behaviour and the level of democracy. With a strong team of partner institutions in seven African countries, this project fills a research gap by collecting extensive and systematic empirical evidence on legislative behaviour in electoral autocracies for the first time.

1 489 925 €

Start date: 2018-08-01, End date: 2023-07-31

The mosquito-borne Plasmodium falciparum parasite is responsible for over 200 million malaria cases and nearly half a million deaths each year among African children. Dependent on Anopheles mosquito for transmission, the parasite faces a challenge during the dry season in the regions where rain seasonality limits vector availability for several months. While malaria cases are restricted to the wet season, clinically silent P. falciparum infections can persist through the dry season and are an important reservoir for transmission. Our preliminary data provides unequivocal evidence that P. falciparum modulates its transcription during the dry season, while the host immune response seems to be minimally affected, suggesting that the parasite has the ability to adapt to a vector-free environment for long periods of time. Understanding the mechanisms which allow the parasite to remain undetectable in absence of mosquito vector, and to restart transmission in the ensuing rainy season will reveal complex interactions between P. falciparum and its host. To that end I propose to: (i) Identify the Plasmodium signalling pathway(s) and metabolic profile associated with long-term maintenance of low parasitaemias during the dry season, (ii) Determine which PfEMP1 are expressed by parasites during the dry season and how effectively they are detected by the immune system, and (iii) Investigate the kinetics of P. falciparum gametocytogenesis, its ability to transmit during the dry season, and uncover sensing molecules and mechanisms of the disappearance and return of the mosquito vector Undoubtedly, results arising from the present multidisciplinary proposal will provide novel insights into the cell biology of dry season P. falciparum parasites, will increase our understanding of their interactions with their hosts and environment. Furthermore, it may benefit the international development agenda goals to design public health strategies to fight malaria.

1 500 000 €

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

The bone marrow (BM) represents the prime location in which cancer cells survive aggressive treatments. This poses a major health challenge because the mortality rate of patients with curable cancer doubles if tumor cells persist in the BM. One unresolved question is why the immune system fails to eradicate cancer cells from this microenvironment even though it represents a lymphatic organ. Surprisingly, despite the ongoing revolution in immune oncology, the regulation and potential therapeutic activation of the immune response in the BM still remains largely unexplored. In this grant application a new line of research is proposed with the overall objective of understanding the cellular and molecular mechanisms, which control anti-cancer immune responses in the BM. The originality of this proposal relates to the hypothesis that innate and adaptive immune cells are suppressed by stroma cells in the BM. Therefore, we will conduct a comprehensive phenotypic and functional profiling of immune and stroma cells in the BM of cancer patients with and without persisting tumor cells. Based on these insights we will develop novel strategies to harness the immune system to eliminate malignant cells from the BM. The ground-breaking nature of the project is that it will shed light on the unappreciated immune microenvironment in the BM. Its specific strength lies in the multidisciplinary design encompassing informative patient cohorts, state-of-the-art mouse models and cutting-edge technologies including Next-Generation-Sequencing as well as innovative drug candidates. Hereby I can build on my internationally recognized expertise in the BM microenvironment field, which has already led to the successful development of a clinical-stage drug. Novel strategies to eliminate malignant cells from the bone marrow are of utmost medical importance because they would increase the cure rate of cancer patients.

1 490 825 €

Start date: 2018-02-01, End date: 2023-01-31

In the arising era of gravitational-wave (GW) astronomy the demand for the next-generation of neutron-star (NS) merger models has never been so great. By developing the first relativistic moving-mesh simulations of NS mergers, we will be able to reliably link observables of these spectacular events to fundamental questions of physics. Our approach will allow us to maximize the information that can be obtained from different GW oscillations of the postmerger remnant. In this way we will demonstrate the scientific potential of future postmerger GW detections to unravel unknown properties of NSs and high-density matter. Based on our models we will work out the optimal GW data analysis strategy towards this goal. Employing a revolutionary numerical technique we will be able to achieve an unprecedented resolution of the merger outflow. High-resolution simulations of these ejecta are critical to uncover the detailed conditions for nucleosynthesis, specifically, for the rapid-neutron capture process (r-process). The r-process forges the heaviest elements such as gold and uranium, but its astrophysical production site still has to be clarified. Moreover, the nuclear decays in the expanding outflow power electromagnetic counterparts, which are targets of optical survey telescopes (iPTF, ZTF, BlackGEM, LSST). Our multi-disciplinary approach combines hydrodynamical models, nuclear network calculations and light-curve computations to facilitate the interpretation of future electromagnetic observations within a multi-messenger picture. Linking these observables to the underlying outflow properties is pivotal to unravel the still mysterious origin of heavy elements created by the r-process.

1 499 485 €

Start date: 2018-07-01, End date: 2023-06-30

Even the perfect cancer drug must reach its target to have an effect. The ImPRESS project main objective is to develop a novel imaging paradigm coined Restricted Perfusion Imaging (RPI) to reveal - for the first time in humans - vascular restrictions in solid cancers caused by mechanical solid stress, and use RPI to demonstrate that alleviating this force will repair the cancerous microenvironment and improve therapeutic response. Delivery of anti-cancer drugs to the tumor is critically dependent on a functional vascular bed. Developing biomarkers that can measure how mechanical forces in a solid tumor impair perfusion and promotes therapy resistance is essential for treatment of disease. The ImPRESS project is based on the following observations; (I) pre-clinical work suggests that therapies targeting the tumor microenvironment and extracellular matrix may enhance drug delivery by decompressing tumor vessels; (II) results from animal models may not be transferable because compressive forces in human tumors in vivo can be many times higher; and (III) there are no available imaging technologies for medical diagnostics of solid stress in human cancers. Using RPI, ImPRESS will conduct a comprehensive series of innovative studies in brain cancer patients to answer three key questions: (Q1) Can we image vascular restrictions in human cancers and map how the vasculature changes with tumor growth or treatment? (Q2) Can we use medical engineering to image solid stress in vivo? (Q3) Can RPI show that matrix-depleting drugs improve patient response to conventional chemo- and radiation therapy as well as new targeted therapies? The ImPRESS project holds a unique position to answer these questions by our unrivaled experience with advanced imaging of cancer patients. With successful delivery, ImPRESS will have a direct impact on patient treatment and establish an imaging paradigm that will pave the way for new scientific knowledge on how to revitalize cancer therapies.

1 499 638 €

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

Using strong gravitational lensing, I will constrain with my unique modelling technique and acquired knowledge the properties of dark matter and potentially revise the current standard paradigm for the formation of all structures which is at the core of modern cosmology and galaxy formation theories. Numerical simulations of cosmic structure formation have shown that the amount of mass in low-mass objects depends strongly on the assumed nature of dark matter. My goal is to constrain the nature of dark matter by measuring the dark matter mass function down to ~10^6 M_sol, where the predictions from different currently viable dark matter models differ by large factors. To this end, I will use the gravitational imaging technique, an advanced modelling tool that I have developed and pioneered, and state-of-the-art strong gravitational lensing data for 12 systems observed with cm- and mm-interferometers. At present, this is the only observational probe of low-mass structure in the dark matter distribution beyond the Local Universe. This will represent an important milestone in our understanding of the dark Universe and will provide a key observational test of the Cold Dark Matter model in a regime that has not been probed before. This ERC project will challenge our standard model for small-scale structure formation and will distinguish between “warm” and “cold” hypothesis for the nature of dark matter. This ERC project will have significant implications for the fields of cosmology and galaxy formation. I am in a unique position to achieve the scientific goal here proposed. I have extended experience in studying gravitational lenses and low mass dark structures. I have an unmatched gravitational lens modelling code and high quality data. With this ERC I will build upon my previous successes and create a top-class research group for studying dark matter with gravitational lensing.

1 359 688 €

Start date: 2018-02-01, End date: 2023-01-31

The LightZymes project aims to create artificial enzymes (LightZymes) catalyzing selective light-driven conversions of small organic molecules. Enzyme catalysis has a large potential in the development of a sustainable, bio-based economy and is increasingly applied on industrial scale. Nature’s repertoire of enzymatic reactions is huge, but for many reactions developed by chemists, no natural enzyme is available. I envision expanding the chemical diversity of enzymes to photoredox catalysis. Chemists perform this type of reactions by employing photo(organo) redox catalysts (PC). However, achieving regio- and stereoselectivities is challenging, because radical intermediates generated during the reaction are difficult to control. To solve this problem, I will combine the strength of bio- and photocatalysis: organic PCs as artificial cofactors provide new reactivities, and the proteins will be evolved to render the reactions highly selective. This approach differs from artificial photosynthesis: instead converting light energy in high-energy cofactors (NADPH, ATP), light will directly enable selective synthesis reactions. Efficient directed evolution requires an easy assembly of the catalyst, preferentially inside the cell. I propose to apply genetic code engineering and to supply the PC in the form of non-canonical amino acids (ncAA). Engineered amino acyl tRNA synthetases will incorporate the PC directly during ribosomal synthesis. This will facilitate–for the first time–the assembly of hybrid catalysts in the cytoplasm without needing further modifications or purifications. This opens the door for applying high-throughput screening based on mass spectrometry and FACS to generate highly selective variants. By bridging the concepts of photoorganocatalysis and biocatalysis, LightZymes will substantially expand the chemical repertoire of naturally evolved enzymes. This paves the way to directly using light as energy source to drive biocatalytic asymmetric reactions.

1 498 749 €

Start date: 2018-02-01, End date: 2023-01-31

The importance of mixed-phase clouds (i.e. clouds in which liquid and ice may co-exist) for weather and climate has become increasingly evident in recent years. We now know that a majority of the precipitation reaching Earth’s surface originates from mixed-phase clouds, and the way cloud phase changes under global warming has emerged as a critically important climate feedback. Atmospheric aerosols may also have affected climate via mixed-phase clouds, but the magnitude and even sign of this effect is currently unknown. Satellite observations have recently revealed that cloud phase is misrepresented in global climate models (GCMs), suggesting systematic GCM biases in precipitation formation and cloud-climate feedbacks. Such biases give us reason to doubt GCM projections of the climate response to CO2 increases, or to changing atmospheric aerosol loadings. This proposal seeks to address the above issues, through a multi-angle and multi-tool approach: (i) By conducting field measurements of cloud phase at mid- and high latitudes, we seek to identify the small-scale structure of mixed-phase clouds. (ii) Large-eddy simulations will then be employed to identify the underlying physics responsible for the observed structures, and the field measurements will provide case studies for regional cloud-resolving modelling in order to test and revise state-of-the-art cloud microphysics parameterizations. (iii) GCMs, with revised microphysics parameterizations, will be confronted with cloud phase constraints available from space. (iv) Finally, the same GCMs will be used to re-evaluate the climate impact of mixed-phase clouds in terms of their contribution to climate forcings and feedbacks. Through this synergistic combination of tools for a multi-scale study of mixed-phase clouds, the proposed research has the potential to bring the field of climate science forward, from improved process-level understanding at small scales, to better climate change predictions on the global scale.

1 500 000 €

Start date: 2018-03-01, End date: 2023-02-28

Working memory is the basis of cognition. It allows behaviour to be governed by internal goals rather than by reflexive stimulus-response mappings. The neural mechanisms of memory maintenance are heavily contested. Animal electrophysiology studies suggest a pivotal role of persistent spiking activity in single neurons of the prefrontal cortex, whereas human neuroimaging points to sub-threshold synaptic activity distributed across sensory cortex. This double dissociation of storage mechanisms and storage sites could result from the comparison of different recording methods, which measure distinct neuronal signals. Alternatively, there might be a fundamental difference between humans and animals. My key objective is to formulate general principles of working memory coding at the cellular and circuit level by integrating across previously disconnected lines of research. I will address two central questions. First, where and how is the memorized information stored? I will use an innovative approach to record large-scale single-unit activity from a cognitive (prefrontal) and a sensory (auditory) region in awake neurosurgical patients and directly compare the data to recordings from mice performing the same auditory working memory task. This will allow me to determine whether the mnemonic fingerprints are species-specific or shared across humans and rodents. Second, what neural pathways support the flow of information during working memory? Using the animal model, I will disrupt cross-regional interactions in the memory network with millisecond-precise, projection-specific optogenetic tools in order to dissect the contribution of each hub to memory storage and memory access. This project provides an unprecedented one-to-one matching of behavioural tasks and recording methods with single-cell and split-second resolution in humans and rodents. It represents a major step forward in understanding the cellular and circuit basis of a critical cognitive brain function.

1 499 989 €

Start date: 2018-02-01, End date: 2023-01-31

Humans and many animals produce complex vocal sequences in order to communicate with each other. What are the neuronal mechanisms that integrate the auditory information and permit the production of a coordinated motor response during a vocal interaction? I will address this issue in the nightingale, a songbird species that is capable of duetting with rivals. During vocal interactions, nightingales have to precisely alternate between singing and listening, and I will test whether premotor centers are differentially sensitive to auditory input during these two states. In zebra finches, I have shown that the impact of a father’s song on premotor circuitry can be regulated by inhibitory interneurons during developmental song learning. Here I ask whether this same regulation of auditory input can rapidly change to support real-time vocal coordination in a duetting songbird. To measure neuronal activity during listening and singing, I will use intracellular recordings to assay the synaptic inputs and outputs of a premotor circuit. I will use a motorized intracellular microdrive that I helped to develop during my postdoc in order to enable these measurements in the freely behaving bird. A custom built vocal robot will be used to dynamically interact with birds during neural recordings. These experiments will reveal the synaptic profile of neurons during sensorimotor integration and clarify how nightingales are able to sing a temporally precise duet. The aims of my research proposal are 1) to investigate how auditory input influences the motor program, 2) how this auditory input is gated depending on behavioral demands and 3) how a song motif is generated on a neuronal population level. I will elucidate neural dynamics essential for vocal interactions, which may provide insights into brain mechanisms involved in human communication. As a result, this work would also generate new implications for our understanding of speech disorders and impairments to social function.

1 491 487 €

Start date: 2018-03-01, End date: 2023-02-28

How do we experience the visual world around us? The traditional view holds that the retinal input is analyzed to reconstruct an internal image that generates our perceptual experience. However, a general theory of how visual features are experienced in space and time is lacking. The fundamental claim of this grant proposal is that only motor knowledge - i.e. the way we interact with the world - establishes the underlying metric of space and time perception. In this model view, the spatial and temporal structure of perception is embedded in the processing of neural motor maps. The project moreSense has four major objectives: First, it will unravel how neural motor maps provide the metric for the experience of visual space. It will be hypothesised that there is no central neural map of space or time but a weighted contribution of all maps. Novel experimental techniques are required to uncover the motor basis of perception, which are available by recent developments in head-mounted displays and online motion tracking. Second, it will provide a general understanding of time perception being implicitly coded in movement plans to objects in space. Third, results from the first two objectives will be applied to the long-standing mystery of visual stability and continuity across movements. A bayesian model, supported by quantitative measurements, will demonstrate how information combination from the various motor maps leads naturally to stable and continuous perception. Fourth, this new theory of space and time perception will be investigated in patients suffering from a breakdown of space perception. The results will establish causal evidence that space and time perception are generated by processing in motor maps. New rehabilitation procedures will be developed to re-establish spatial perception in these patients. The experiments in this grant proposal will unravel the fundamental spatiotemporal structure of perception which organizes our sensory experience.

1 494 059 €

Start date: 2018-04-01, End date: 2023-03-31

Today, five out of ten diseases worldwide resulting in long-term disability are related to the central nervous system. Due to the immense complexity and inter-individual variability of the human mind and brain there are still no effective and side effect free treatment options for many serious neuropsychiatric disorders, such as major depression, dementia or schizophrenia. Recent advancements in sensor technology and computational capacities resulted in the development of brain/neural-machine interfaces (B/NMIs) that translate electric, magnetic or metabolic brain activity into control signals of external devices, robots or machines. Moreover, novel transcranial magnetic and electric brain stimulation (TMS/TES) systems were developed allowing for direct modulation of brain activity. However, current B/NMIs are limited by the low information extraction rate constraining fluent direct brain-machine interaction. Furthermore, as simultaneous assessment of brain oscillations during TES was regarded unfeasible due to stimulation artefacts, current TES systems can only deliver “open-loop” stimulation unrelated to the underlying dynamic brain states resulting in highly variable TES effects. Building on the applicant’s previous work that includes pioneering work on in vivo assessment of brain oscillations during TES (Soekadar et al. 2013, Nature Communications) and full restoration of daily living activities after quadriplegia using a novel B/NMI hand exoskeleton (Soekadar et al. 2016, Science Robotics), the NGBMI project will overcome these limitations by merging both techniques. After developing the first real-time B/NMI-TES system allowing for effective modulation of brain functions and fluent direct brain-machine interaction, the system will be tested in persons with impaired brain function (e.g. depression, dementia or stroke). Finally, the B/NMI-TES paradigm will be implemented in a wireless and wearable EEG-based system that can be used in everyday life environments.

1 498 125 €

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

Given the rapid emergence of anti-infective resistance, drugs with a novel mode of action are urgently needed. Because of an exhaustion of existing strategies, a low return on investment and the fact that anti-infectives are difficult to develop (e.g., crossing the peculiar cell wall of Mycobacterium tuberculosis), promising un(der)explored targets and unconventional hit-identification strategies are needed. I have selected three anti-infective targets based on their biochemical context for which few or no small-molecule inhibitors are known: 1) The antimalarial and antituberculotic drug target DXS is part of a unique biosynthetic pathway for pathogens that is absent in humans, thereby circumventing selectivity issues. Both diseases are a serious health threat with around 1.9 million deaths per year. 2) Energy-coupling factor transporters are essential vitamin importers for pathogens such as Staphylococcus aureus, the causative agent of methicillin-resistant Staphylococcus aureus (MRSA) infections. 3) The DNA polymerase sliding clamp DnaN has polymerase and DNA repair activities and is an excellent drug target for the development of antibacterial agents against Gram-negative and –positive bacteria given the low incidence of resistance development. I will address these targets, employing a unique combination of potentially synergistic hit-identification strategies that take into account protein flexibility, provide access to novel scaffolds and give me a cutting edge for the development of novel anti-infectives. This ERC proposal builds on my experience with the first two targets and provides an excellent platform for the new target DnaN. My expertise in synthetic organic and medicinal chemistry and established hit-identification strategies together with my collaborations with protein crystallographers, biochemists and pharmacologists place me in an excellent position for not only achieving the goals of this interdisciplinary proposal but also going beyond it.

1 499 367 €

Start date: 2018-02-01, End date: 2023-01-31

This project proposes a deep and thorough study of Palestinian literature as an early and on-going case of literary displacement. It aims to find new ways to account for and analyse texts, literary production and reading publics that challenge and lie outside conventional conceptions of the nation-state. The proposed methodology will take a novel approach in merging textual analysis with reception theory and reading practices. The project is ambitious in seeking to be the first instance to explore its application on the scale of an entire ‘literature-of-a-nation’. By doing so, the project aims to introduce methodological innovations that can expand horizons beyond textual and national analyses towards interdisciplinary models that contend with the multi-faceted and unconventional dimensions of the Palestinian case, and generate a richer and more nuanced history of its literature. The proposed project will explore, for the first time under one analytic roof, all the geographic fragments of Palestinian literature together, traditionally studied separately, or limited to certain authors or time periods. The project’s novelty also lies in broadening the horizons of literary analysis towards an interdisciplinary and transmedial approach that embeds literary production into a wider cultural web of intersecting media and genres. A creative approach will be developed to overcome the hurdles of working, in the Palestinian case, with few scholarly precedents, and scattered, lost or damaged primary and secondary sources. The project’s four work packages will trace connections and disconnections and transformations of publics and reading practices across dispersed Palestinian literary communities of writers and readers over time. The focus will be on identifying, tracing and elaborating key and/or turning point moments across the various localities of the Palestinian literary sphere. An online platform will visual, digitalize and make accessible the project’s outputs.

1 493 439 €

Start date: 2018-04-01, End date: 2023-03-31

Numerical tasks - integration, linear algebra, optimization, the solution of differential equations - form the computational basis of machine intelligence. Currently, human designers pick methods for these tasks from toolboxes. The generic algorithms assembled in such collections tend to be inefficient on any specific task, and can be unsafe when used incorrectly on problems they were not designed for. Research in numerical methods thus carries carries the potential for groundbreaking advancements in the performance and quality of AI. Project PANAMA will develop a framework within which numerical methods can be constructed in an increasingly automated fashion; and within which numerical methods can assess their own suitability, and adapt both model and computations to the task, at runtime. The key tenet is that numerical methods, since they perform tractable computations to estimate a latent quantity, can themselves be interpreted explicitly as active inference agents; thus concepts from machine learning can be translated to the numerical domain. Groundwork for this paradigm - probabilistic numerics - has recently been developed into a rigorous mathematical framework by the PI and others. The proposed research will simultaneously deliver new general theory for the computations of learning machines, and concrete new algorithms for core areas of machine learning. In doing so, Project PANAMA will improve the efficiency and safety of artificial intelligence, addressing scientific, technological and societal challenges affecting Europeans today.

1 450 000 €

Start date: 2018-03-01, End date: 2023-02-28

As neuroscientific findings on brain functions accumulate, it is increasingly important to derive a set of overarching general principles about how the human brain works. For this, the predictive coding framework emerges as a promising route, with the notion that the brain operates as a prediction machine; internal models in the brain predict future states against which incoming information of new experience is compared. This new conceptual framework leads to two essential empirical questions that PIVOTAL will tackle: (1) What is the nature of the internal models on which predictions are generated and how do our actual experiences shape them? (2) How do prediction processes play out in human brains that are inherently diverse due to changes such as those caused by maturation and senescence. Addressing these issues is important for advancing our basic understanding of the neurocognitive architectures that enable the brain to perform adaptively in our environment, with predictive processing as a fundamental operation. PIVOTAL will integrate three separate strands of cognitive neuroscience research on predictive coding, memory systems, and lifespan development. By using functional magnetic resonance imaging (fMRI) in experimental research designs, we aim to unravel the cognitive and neural mechanisms that underlie predictive processing based on individuals’ memory of prior experience (episodic memory) and well-learned knowledge about the world (semantic memory). These mechanisms will be systematically examined in samples of children, younger adults, and older adults, who differ from each other in important ways due to divergence in developmental orientation (progression vs. conservation) and neurocognitive landscape (structural and functional integrity of memory neural circuits). By explicating a more dynamic version of the predictive brain principle, we can start addressing issues related to the emergence of disorders at particular time windows in life.

1 416 934 €

Start date: 2018-02-01, End date: 2023-01-31

Pain is a burden for millions of people in terms of suffering, as well as for society in terms of costs. While it is well established that the perception of pain is not necessarily related to the amount of sensory input, a mechanistic framework for this is still lacking at the neurobiological level, although it would be of utmost importance for inspiring new therapeutic approaches. In PredictingPain, I will provide such a framework by applying recent insights from computational neuroscience in the form of ‘predictive coding’ to pain. Predictive coding models assume that perception is an active process in which the brain is not just passively responding to sensory inputs, but is instead constantly generating predictions about its sensory inputs. I will employ three complementary work packages (WP) – all of which use cutting-edge neuroimaging methods in human volunteers – to answer the important question of whether predictive coding can serve as a fundamental mechanism underlying the perception of pain. In WP1, I will elucidate whether the neural architecture of the nociceptive system is capable of implementing a predictive coding scheme. With WP2, I will unravel how the subjective experience of pain is constructed from a rich array of predictive signals. Finally, in WP3 I will employ an experimental model of chronic pain to test how predictions of pain relief exert their beneficial effects when pain is ongoing. A large part of the research in PredictingPain will focus on the human spinal cord, in order to capture predictive signals at this earliest level of central nervous system pain processing, since they will exert a profound effect on processing at higher levels and the resulting pain perception. Together, the outcomes from PredictingPain will provide a novel and mechanistic understanding of pain perception that will provide impetus for the development of new therapeutic approaches in order to reduce the suffering and financial burden that pain imposes.

1 499 922 €

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

Overtreatment in prostate cancer (PCa) is a burden for health care economy and for quality of life. Correct diagnosis of early stage PCa is challenging given the limitations of the currently available clinical tools and the biological understanding of PCa. In this inter-disciplinary project, I propose an innovative approach enabling several cutting-edge ‘omics’ technologies (spatial metabolomics, genomics, transcriptomics) as well as histopathology to be performed on the same tissue sample. My goal is to reveal the molecular mechanisms of novel, but also promising metabolite biomarkers (citrate, polyamines, succinate and zinc) and their connection to recurrence, tissue heterogeneity and immune responses in complex human tissues. Such markers can personalize PCa diagnosis, open up new treatment strategies and fundamentally change the view of how to analyze tissue samples in the future. Furthermore, I want to demonstrate that citrate and polyamines are reliable prognostic markers that can be analyzed both in tissue and in patients in vivo by MR spectroscopic imaging. This work is made possible by the availability of high-quality fresh frozen tissue biobanks of prostatectomy biopsies with 5-10 years of follow-up data (N=1000)/slices (N=1000) and targeted in vivo snap-shot biopsies from clinical MR guided procedures (N=100). Among other techniques, I will implement high speed MALDI imaging (RapifleX MALDI TissueTyper) to the multi-omics protocol to study the spatial distribution and provide high resolution metabolic maps for each cell type, and which can be matched to both histopathology and MR Imaging. Multi-disciplinary platforms on large cohorts are needed to explore the clinical potential of the suggested molecular mechanisms. I expect that this ambitious proposal will address the diagnostic challenges of PCa and will further inspire the clinic and scientific community to follow the multi-omics approach within diagnosis and cancer research.

1 500 000 €

Start date: 2018-02-01, End date: 2023-01-31

The primary objective of this project is to explore the properties of a new state of matter, the Quark-Gluon Plasma (QGP), at the highest energies to date. The QGP consists of asymptotically free quarks and gluons and the evidence for its discovery was announced in experiments analyzing collisions of heavy ions. Previous experiments at lower energies have caused a dramatic change of paradigm in our understanding - measurements at Relativistic Heavy Ion Collider showed that the QGP behaves like a strongly coupled liquid, instead of the weakly interacting gas expected by theorists. The focus of this project is the measurement of the anisotropic flow, which has proven to be the most informative probe for studying the properties of nuclear matter produced in heavy-ion collisions. The analysis methods to be utilized are multiparticle correlation techniques developed by the PI. Currently mainly the first moments (averages) of multiparticle correlations are used. Within the scope of the theoretical subproject we aim to derive analytic expressions for higher order moments of multiparticle correlations by continuing a pioneering work recently initiated by the PI. The here proposed project aims also the measurement of new flow observables, so-called Symmetric Cumulants, recently introduced in the field by PI. The recent restart of Large Hadron Collider at top energy, a record breaking 5.02 TeV center of mass energy, offers a truly unique and a timely opportunity for this project. The main dataset will comprise the heavy-ion collisions collected with ALICE detector at the Large Hadron Collider. Collisions of smaller systems will be scrutinized as well in order to determine the onset of QGP formation. This project offers a unique opportunity to pin down quantitatively the properties of the QGP, beyond the rather qualitative analyses that are currently carried out in the field. It also will impact the fields of high energy physics, nuclear physics, cosmology and hydrodynamics.

1 366 875 €

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

The Standard Model of particle physics (SM), while largely successful, fails to accurately describe the state of the Universe, e.g. with respect to the evident matter/antimatter asymmetry. Various theories seek to conciliate the SM with observations by extending it, and most of these extensions introduce a massive violation of the combined charge invariance and parity (CP) symmetry. The CP violation would reflect in a sizeable permanent electric dipole moment (EDM) of fundamental particles, large enough to be detected by realistic future experiments. A few pioneering experiments already set out to measure the EDM of neutrons, electrons, or atoms. The most stringent upper limit to any EDM is currently obtained by an experiment based on room-temperature gases of mercury. I propose to take this approach to the quantum world by employing ultracold or even quantum-degenerate mercury samples. To this end, we will construct a dedicated quantum gas experiment. We will develop advanced cooling methods, obtain the world’s first Bose-Einstein condensate and degenerate Fermi gas of mercury, and introduce vacuum ultraviolet (VUV) lasers to the field. These ground-breaking innovations will increase the coherence time of the sample, enable a higher detection efficiency, and exploit coherent effects, thereby increasing the sensitivity tremendously. Our measurements of the Hg-199 atomic EDM will complement cold-molecule measurements of the electron's EDM. Technologies developed here can readily be utilized to improve the performance of Hg lattice clocks and will inspire quantum simulations of unique many-body systems. The principal investigator of this project is highly respected for his pioneering work on degenerate quantum gases of strontium. His current work on a nuclear optical clock introduced him to VUV optics and strengthened his footing in the community. Bringing together his expertise in these two fields – quantum gases and VUV optics – will lead the project to success.

1 939 263 €

Start date: 2018-04-01, End date: 2023-03-31

Arbuscular mycorrhiza (AM) is an ancient plant-fungus symbiosis that is wide-spread in the plant kingdom. AM improves plant nutrition, stress resistance and general plant performance and thus represents a promising addition to sustainable agricultural practices. Mineral nutrients are released from the fungus to the plant at highly branched hyphal structures, the arbuscules, which form inside root cortex cells. Like the cells of other multicellular eukaryotes, plant cells show a remarkable developmental plasticity. Single cell re-differentiation is a fascinating process during arbuscule development, which can be conceptually separated into distinct stages controlled by the plant cell which precisely guide the step-wise formation of different parts of the arbuscule. It involves cell autonomous transcriptional reprogramming and subcellular remodelling, leading to repositioning of subcellular structures, cell polarization and multiplication of organelles. It is currently unknown how cell-autonomous reprogramming during arbuscule development is regulated. RECEIVE utilizes an integrated strategy combining transcriptional profiling, transcription factor identification, interaction network analysis with reverse genetics and cell biological techniques to understand the coordinated step-wise progression of arbuscule development. RECEIVE builds on the hypothesis that each stage of arbuscule development is accompanied by a stage-specific wave of gene expression and that transcriptional regulation is a key determinant of the developmental progress from stage to stage. The characterisation of these waves and the identification of the underlying transcriptional regulatory nodes is the focus of this project. RECEIVE aims to bridge a major knowledge gap about the molecular basis of one of the most important symbioses on earth.

1 499 625 €

Start date: 2018-02-01, End date: 2023-01-31

Temporary employment has become widespread in industrialized nations and many concerns have been raised about this development. Against this background, we will provide new insights into the multi-faceted socio-economic consequences of temporary work. Theoretically, this project is innovative by developing a multilevel dynamic model that combines ideas from sociology, economics, psychology, and social policy. Specifically, we will gain a novel, comprehensive understanding of how temporary jobs affect the employment and work career, risks of income poverty and material deprivation, and subjective well-being. This project aims at estimating causal effects of temporary work using panel data and applying state-of-the-art methods of modern causal analysis. Complementing the dominant “upward” comparison of temporary jobs to permanent ones with a “downward” comparison of temporary jobs to unemployment has the potential for producing ground-breaking results on the integrative potential of temporary work for the unemployed. Furthermore, new evidence on the heterogeneity in the effects of temporary employment at the micro-level will be gained by conducting detailed subgroup analyses. Moreover, this project will advance research by elaborating the socio-economic consequences of temporary employment in a dynamic process and life course perspective. The selection, treatment, and outcome dynamics are investigated by following temporary workers and their household living arrangements over time. While previous studies have only focused on individual workers, the important household perspective and its moderating role will be elaborated, too. Analysing Western and Eastern European countries as well as the liberal welfare states Canada, the United States, South Korea, Japan and Australia and applying innovative multilevel panel data methods will result in significant new insights and represent frontier research on the moderating role of the structural and institutional macro context.

1 393 561 €

Start date: 2018-04-01, End date: 2023-03-31

For the past 50 years, our use of ice core records as climate archives has relied on the fundamental assumption that the isotopic composition of precipitation deposited on the ice sheet surface determines the ice core water isotopic composition. Since the isotopic composition in precipitation is assumed to be governed by the state of the climate this has made ice core isotope records one of the most important proxies for reconstructing the past climate. New simultaneous measurements of snow and water vapor isotopes have shown that the surface snow exchanges with the atmospheric water vapor isotope signal, altering the deposited precipitation isotope signal. This severely questions the standard paradigm for interpreting the ice core proxy record and gives rise to the hypothesis that the isotope record from an ice core is determined by a combination of the atmospheric water vapor isotope signal and the precipitation isotope signal. The SNOWISO project will verify this new hypothesis by combining laboratory and field experiments with in-situ observations of snow and water vapor isotopes in Greenland and Antarctica. This will enable me to quantify and parameterize the snow-air isotope exchange and post-depositional processes. I will implement these results into an isotope-enabled Regional Climate Model with a snowpack module and benchmarked against in-situ observations. Using the coupled snow-atmosphere isotope model I will establish the isotopic shift due to post-depositional processes under different climate conditions. This will facilitate the use of the full suite of water isotopes to infer past changes in the climate system, specifically changes in ocean sea surface temperature and relative humidity. By establishing how the water isotope signal is recorded in the snow, the SNOWISO project will build the foundation for future integration of isotope-enabled General Circulation Models with ice core records; this opens a new frontier in climate reconstruction.

1 497 260 €

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

The main question to be addressed by SPOCk’S MS is how protein complex conformation adapts to local changes, such as processing of polyproteins, protein phosphorylation or conversion of substrates. While labelling strategies combined with mass spectrometry (MS), such as hydrogen deuterium exchange and hydroxyl footprinting, are very versatile in studying protein structure, these techniques are employed on bulk samples averaging over all species present. SPOCk’S MS will remedy these by studying the footprinting and therefore exposed surface area on conformation and mass selected species. Labelling still happens in solution avoiding gas phase associated artefacts. The labelling positions are then read out using newly developed top-down MS technology. Ultra-violet and free-electron lasers will be employed to fragment the protein complexes in the gas phase. In order to achieve the highest possible sequence and thus structural coverage, lasers will be complemented by additional dissociation and separation stages to allow MS^N. SPOCk’S MS will allow sampling conformational space of proteins and protein complexes and especially report about the transient nature of protein interfaces. Constraints derived in MS will be fed into a dedicated software pipeline to derive atomistic models. SPOCk’S MS will be used to study intracellular viral protein complexes, especially coronaviral replication/transcription complexes, which are highly flexible and often resist crystallisation and are barely accessible by conventional structural biology techniques. Objectives: - Integrate labelling with complex species selective native MS for time-resolved structural studies - Combine fragmentation techniques to maximise information content from MS - Develop software suite to analyse data and model protein complex structures based on MS constraints - Apply SPOCk’S MS to protein complexes of human pathogenic viruses

1 999 000 €

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

Since its discovery more than a decade ago, the most studied network in the human brain remains a paradox. The default mode network (DMN) is most active during the resting state and deactivates once subjects engage in goal directed behavior. Although reported in hundreds of studies using functional magnetic resonance imaging (fMRI), the function of the DMN is still unknown. I hypothesize that memories are consolidated in the DMN during resting state, a process that is interrupted once we engage in cognitive processing. This hypothesis is based on two complementary and recent findings. First, brain regions involved in encoding of novel or retrieval of consolidated memories strongly resemble regions of the DMN. Second, the DMN consumes most glucose during resting state as revealed by positron emission tomography (PET). Importantly, energy in the brain is mainly dedicated to neuronal signaling and synaptic plasticity related to memory consolidation. To test my hypothesis, I will use hybrid PET/MR imaging to simultaneously study fMRI activity and energy metabolism of the DMN during episodic memory processing. Integrating this novel imaging approach with my recently developed brain connectivity methods, I will (i) identify the metabolic baseline of fMRI-deactivations in the DMN, (ii) track the metabolic demand and directional connectivity in the DMN during memory consolidation, and (iii) evaluate non-invasive brain stimulation as a therapeutic option to modulate memory consolidation. The DMN is massively disturbed in psychiatric disorders such as Alzheimer’s disease, anxiety and affective disorders. SUGARCODING aims at uncovering memory consolidation as a universal function of the DMN that seems to critically orchestrate the human mind and its pathological deviations. ...

1 499 404 €

Start date: 2018-07-01, End date: 2023-06-30

Most anatomical compartments, including mucosal barrier surfaces, solid organs and vascular spaces host different types of tissue-resident lymphocytes providing local networks for immune surveillance and front-line defense to microbial invasion. In addition to immediate effector functions, tissue-resident lymphocytes orchestrate and regulate inflammatory responses, and contribute to tissue homeostasis, repair and barrier function. Understanding the generation and function of tissue-resident lymphocytes is therefore expected to reveal targets for improving vaccination and immunotherapy. Barrier tissues of free-living mice and men, but not those of laboratory mice kept under specific pathogen free conditions, are continuously exposed to an array of antigenically complex pathogens, microbial symbionts and environmental factors, which dramatically alter the abundance, composition and basal activation state of local pools of tissue-resident cells. Therefore, we propose to study the development, functions and cellular interactions of tissue-resident lymphocytes in experimental models that mirror “real-life” contexts. First, we will investigate how polyclonal pools of tissue-resident memory CD8+ T cells (TRMs) are established during infection with antigenically complex pathogens. Second, we will restore physiologic exposure to specific pathogens and induce alterations of local microbiota in SPF mice, in order to investigate the induction, function and local interactions of tissue-resident lymphocytes in physiologic tissue environments. In addition, we will explore targeted microbial exposure as a „vaccination“ strategy to induce „non-canonical“ tissue-resident cells in the lung in order to improve protection against infections with multi-resistant bacteria representing major clinical problems in hospitalized patients. In summary, we will investigate fundamental mechanisms of tissue immunity and vaccination in contexts relevant for human physiology and disease.

1 498 750 €

Start date: 2018-03-01, End date: 2023-02-28

Pathological communication between different brain regions has been implicated in various neurological disorders. However, the computational tools for assessing such communication from neuroimaging data are not sufficiently developed. The goal of TrueBrainConnect is to establish brain connectivity analysis using non-invasive electrophysiology as a practical and reliable neuroscience tool. To achieve this, we will develop novel signal processing and machine learning techniques that address shortcomings in state-of-the-art reconstruction and localization of neural activity from sensor data, the estimation of genuine neural interactions, the prediction of external (e.g., clinical) variables from estimated neural interactions, and the interpretation of the resulting models. These techniques will be thoroughly validated and then made publicly available. We will use the TrueBrainConnect methodology to characterize the neural bases underlying dementia and Parkinson's disease (PD), two of the most pressing neurological health challenges of our time. In collaboration with clinical experts, we will address practically relevant issues such as how to determine the onset of 'freezing' episodes in PD patients, and how to detect different variants and precursors of dementia. The outcome of TrueBrainConnect will be a versatile methodology allowing researchers, for the first time, to reliably estimate and anatomically localize important types of interactions between different brain structures in humans within known confidence bounds. The proposed clinical applications will improve our understanding of the studied diseases and will lay the foundation for the development of novel diagnostic markers for these diseases.

1 499 875 €

Start date: 2019-01-01, End date: 2023-12-31

UNIVERSAL HEALTH is an anthropological study that follows how a new global policy, Universal Health Coverage (UHC), travels and is engaged by policy-makers, bureaucrats and citizens in three African countries. Defined by the WHO as ensuring that all people can use the health services they need without financial hardship, UHC is a powerful concept that approaches public health as a matter of justice and obligation and is included in the Sustainable Development Goals. UHC is particularly important in Africa, where structural-adjustment policies undermined state capacity, promoted privatization and pushed the burden of payment onto the poor. Recent global health initiatives have done little to address the neglect of national health-care systems and citizens’ lack of trust in them. In these contexts UHC is interesting because it reinserts questions of state responsibility and the public good into health-care. Historically however, African states have only partially pursued the public good, while in practice UHC is surrounding by conflicting interests. UHC is thus not a universal model but a contested field, making it an intriguing site for anthropological research. With a focus on actors and institutions at global, national and local levels in each country, the project will explore how moves towards UHC engage relations between states and citizens and universal concepts such as the public good; how UHC intersects with formal systems of social protection; and how it influences informal social networks that support health, thus situating UHC in national histories and social practices. Tracking the frictions surrounding UHC at the levels of policy-making, implementation, among beneficiaries, and in public debate, the project will use ethnographic methodology in innovative ways through fieldwork that is multi-sited and multi-level. The project’s focus on a global policy and the public good opens new research directions and will produce knowledge of relevance beyond Africa.

1 484 797 €

Start date: 2018-09-01, End date: 2023-08-31