ERC FUNDED PROJECTS

We propose to develop truly two-dimensional continuous materials and two-dimensional monolayer films composed of individual nanocrystals by the comparatively fast, inexpensive, and scalable colloidal synthesis method. The materials’ properties will be studied in detail, especially regarding their (photo-) electrical transport. This will allow developing new types of device structures, such as Coulomb blockade and field enhancement based transistors. Recently, we demonstrated the possibility to synthesize in a controlled manner truly two-dimensional colloidal nanostructures. We will investigate their formation mechanism, synthesize further materials as “nanosheets”, develop methodologies to tune their geometrical properties, and study their (photo-) electrical properties. Furthermore, we will use the Langmuir-Blodgett method to deposit highly ordered monolayers of monodisperse nanoparticles. Such structures show interesting transport properties governed by Coulomb blockade effects known from individual nanoparticles. This leads to semiconductor-like behavior in metal nanoparticle films. The understanding of the electric transport in such “multi-tunnel devices” is still very limited. Thus, we will investigate this concept in detail and take it to its limits. Beside improvement of quality and exchange of material we will tune the nanoparticles’ size and shape in order to gain a deeper understanding of the electrical properties of supercrystallographic assemblies. Furthermore, we will develop device concepts for diode and transistor structures which take into account the novel properties of the low-dimensional assemblies. Nanosheets and monolayers of nanoparticles truly follow the principle of building devices by the bottom-up approach and allow electric transport measurements in a 2D regime. Highly ordered nanomaterial systems possess easy and reliably to manipulate electronic properties what make them interesting for future (inexpensive) electronic devices.

1 497 200 €

Start date: 2013-02-01, End date: 2019-01-31

Membranes are key materials in our life. Nature offers high performance membranes relying on a parallel local regulation of nanopore structure, functional placement, membrane composition and architecture. Existing technological membranes are key materials in separation, recycling, sensing, energy conversion, being essential components for a sustainable future. But their performance is far away from their natural counterparts. One reason for this performance gap is the lack of 3D nanolocal control in membrane design. This applies to each individual nanopore but as well to the membrane architecture. This proposal aims to implement 3D printing (additive manufacturing, top down) and complex near-field and total internal reflection (TIR) high resolution microscopy induced polymer writing (bottom up) to nanolocally control in hierarchical nanoporous membranes spatially and independent of each other: porosity, pore functionalization, membrane architecture, composition. This disruptive technology platform will make accessible to date unachieved, highly accurate asymmetric nanopores and multifunctional, hierarchical membrane architecture/ composition and thus highly selective, directed, transport with tuneable rates. 3D-FNPWriting will demonstrate this for the increasing class of metal nanoparticle/ salt pollutants aiming for tuneable, selective, directed transport based monitoring and recycling instead of size-based filtration, accumulation into sewerage and distribution into nature. Specifically, the potential of this disruptive technology with respect to transport design will be demonstrated for a) a 3D-printed in-situ functionalized nanoporous fiber architecture and b) a printed, nanolocally near-field and TIR-microscopy polymer functionalized membrane representing a thin separation layer. This will open systematic understanding of nanolocal functional control on transport and new perspectives in water/ energy management for future smart industry/ homes.

1 499 844 €

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

Antigenic variation is a widely employed strategy to evade the host immune response. It has similar functional requirements even in evolutionarily divergent pathogens. These include the mutually exclusive expression of antigens and the periodic, nonrandom switching in the expression of different antigens during the course of an infection. Despite decades of research the mechanisms of antigenic variation are not fully understood in any organism. The recent development of high-throughput sequencing-based assays to probe the 3D genome architecture (Hi-C) has revealed the importance of the spatial organization of DNA inside the nucleus. 3D genome architecture plays a critical role in the regulation of mutually exclusive gene expression and the frequency of translocation between different genomic loci in many eukaryotes. Thus, genome architecture may also be a key regulator of antigenic variation, yet the causal links between genome architecture and the expression of antigens have not been studied systematically. In addition, the development of CRISPR-Cas9-based approaches to perform nucleotide-specific genome editing has opened unprecedented opportunities to study the influence of DNA sequence elements on the spatial organization of DNA and how this impacts antigen expression. I have adapted both Hi-C and CRISPR-Cas9 technology to the protozoan parasite Trypanosoma brucei, one of the most important model organisms to study antigenic variation. These techniques will enable me to bridge the field of antigenic variation research with that of genome architecture. I will perform the first systematic analysis of the role of genome architecture in the mutually exclusive and hierarchical expression of antigens in any pathogen. The experiments outlined in this proposal will provide new insight, facilitating a new view of antigenic variation and may eventually help medical intervention in T. brucei and in other pathogens relying on antigenic variation for their survival.

1 498 175 €

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

Understanding the many-body physics of strongly correlated systems has always been a major challenge for theoretical and experimental physics. The recent advances in the field of ultracold quantum gases have opened a completely new way to study such strongly correlated systems. It is now feasible to use ultracold gases as quantum simulators for such diverse systems such as the Hubbard model or the BCS-BEC crossover. The objective of this project is to study a three-component Fermi gas in an optical lattice, a system with rich many-body physics. With our experiments we aim to contribute to the understanding of exotic phases which are discussed in the context of QCD and condensed matter physics.

1 469 040 €

Start date: 2011-08-01, End date: 2016-07-31

Antibiotics have contributed to a tremendous increase in human well-being, saving many millions of lives. However, antibiotics become obsolete the more they are used as selection pressure promotes the development of resistant bacteria. The World Health Organization has proclaimed antibiotic resistance as a major global threat to public health. Today, 700,000 deaths per year are due to untreatable infections. To win the battle against antibiotic resistance, new policies affecting the supply and demand of existing and new drugs must be designed. I propose new research to identify and evaluate feasible and effective demand-side policy interventions targeting the relevant decision makers: physicians and patients. ABRSEIST will make use of a broad econometric toolset to identify mechanisms linking antibiotic resistance and consumption exploiting a unique combination of physician-patient-level antibiotic resistance, treatment, and socio-economic data. Using machine learning methods adapted for causal inference, theory-driven structural econometric analysis, and randomization in the field it will provide rigorous evidence on effective intervention designs. This research will improve our understanding of how prescribing, resistance, and the effect of antibiotic use on resistance, are distributed in the general population which has important implications for the design of targeted interventions. It will then estimate a structural model of general practitioners’ acquisition and use of information under uncertainty about resistance in prescription choice, allowing counterfactual analysis of information-improving policies such as mandatory diagnostic testing. The large-scale and structural econometric analyses allow flexible identification of physician heterogeneity, which ABRSEIST will exploit to design and evaluate targeted, randomized information nudges in the field. The result will be improved rational use and a toolset applicable in contexts of antibiotic prescribing.

1 498 920 €

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

The Acts of the Ecumenical Councils of Late Antiquity include (purportedly) verbatim minutes of the proceedings, a formal framework and copies of relevant documents which were either (allegedly) read out during the proceedings or which were later attached to the Acts proper. Despite this unusual wealth of documentary evidence, the daunting nature of the Acts demanding multidisciplinary competency, their complex structure with a matryoshka-like nesting of proceedings from different dates, and the stereotype that their contents bear only on Christological niceties have deterred generations of historians from studying them. Only in recent years have their fortunes begun to improve, but this recent research has not always been based on sound principles: the recorded proceedings of the sessions are still often accepted as verbatim minutes. Yet even a superficial reading quickly reveals widespread editorial interference. We must accept that in many cases the Acts will teach us less about the actual debates than about the editors who shaped their presentation. This does not depreciate the Acts’ evidence: on the contrary, they are first-rate material for the rhetoric of persuasion and self-representation. It is possible, in fact, to take the investigation to a deeper level and examine in what manner the oral proceedings were put into writing: several passages in the Acts comment upon the process of note-taking and the work of the shorthand writers. Thus, the main objective of the proposed research project could be described as an attempt to trace the destinies of the Acts’ texts, from the oral utterance to the manuscript texts we have today. This will include the fullest study on ancient transcript techniques to date; a structural analysis of the Acts’ texts with the aim of highlighting edited passages; and a careful comparison of the various editions of the Acts, which survive in Greek, Latin, Syriac and Coptic, in order to detect traces of editorial interference.

1 497 250 €

Start date: 2016-05-01, End date: 2021-04-30

The cell cortex is a highly dynamic layer of crosslinked actin filaments and myosin molecular motors beneath the cell membrane. It plays a central role in large scale rearrangements that occur inside cells. Many molecular mechanisms contribute to cortex structure and dynamics. However, cell scale physical properties of the cortex are difficult to grasp. This is problematic because for large scale rearrangements inside a cell, such as coherent flow of the cell cortex, it is the cell scale emergent properties that are important for the realization of such events. I will investigate how the actomyosin cytoskeleton behaves at a coarse grained and cellular scale, and will study how this emergent active behaviour is influenced by molecular mechanisms. We will study the cell cortex in the one cell stage C. elegans embryo, which undergoes large scale cortical flow during polarization and cytokinesis. We will combine theory and experiment. We will characterize cortex structure and dynamics with biophysical techniques such as cortical laser ablation and quantitative photobleaching experiments. We will develop and employ novel theoretical approaches to describe the cell scale mechanical behaviour in terms of an active complex fluid. We will utilize genetic approaches to understand how these emergent mechanical properties are influenced by molecular activities. A central goal is to arrive at a coarse grained description of the cortex that can predict future dynamic behaviour from the past structure, which is conceptually similar to how weather forecasting is accomplished. To date, systematic approaches to link molecular scale physical mechanisms to those on cellular scales are missing. This work will open new opportunities for cell biological and cell biophysical research, by providing a methodological approach for bridging scales, for studying emergent and large-scale active mechanical behaviours and linking them to molecular mechanisms.

1 500 000 €

Start date: 2011-12-01, End date: 2017-08-31

Ageing is accompanied by ectopic white adipose tissue depositions in skeletal muscle and other anatomical locations, such as brown adipose tissue and the bone marrow. Ectopic fat accrual contributes to organ dysfunction, systemic insulin resistance, and other perturbations that have been implicated in metabolic diseases. This research proposal aims to identify the regulatory cues that control the development of ectopic progenitor cells that give rise to this type of fat. It is hypothesized that an age-related dysfunction of the stem cell niche leads to an imbalance between (1) tissue-specific stem cells and (2) fibroblast-like, primarily adipogenic progenitors that reside within many tissues. Novel methodologies that assess stem/progenitor cell characteristics on the single cell level will be combined with animal models of lineage tracing to determine the developmental origin of these adipogenic progenitors and processes that regulate their function. Notch signalling is a key signalling pathway that relies on direct physical interaction to control stem cell fate. It is proposed that impaired Notch activity contributes to the phenotypical shift of precursor cell distribution in aged tissues. Lastly, the role of the stem cell niche in ectopic adipocyte progenitor formation will be analyzed. External signals originating from the surrounding niche cells regulate the developmental fate of stem cells. Secreted factors and their role in the formation of ectopic adipocyte precursors during senescence will be identified using a combination of biochemical and systems biology approaches. Accomplishment of these studies will help to understand the basic processes of stem cell ageing and identify mechanisms of age-related functional decline in tissue regeneration. By targeting the population of tissue-resident adipogenic progenitor cells, therapeutic strategies could be developed to counteract metabolic complications associated with the ageing process.

1 496 444 €

Start date: 2013-03-01, End date: 2018-02-28

Host cytokines, chemokines and type I IFNs are critical effectors of the innate immune response to viral and bacterial pathogens. Several classes of germ-line encoded pattern recognition receptors have been identified, which sense non-self nucleic acids and trigger these responses. Recently NLRP-3, a member of the NOD-like receptor (NLR) family, has been shown to sense endogenous danger signals, environmental insults and the DNA viruses adenovirus and HSV. Activation of NLRP-3 induces the formation of a large multiprotein complex in cells termed inflammasome , which controls the activity of pro-caspase-1 and the maturation of pro-IL-1² and pro-IL18 into their active forms. NLRP-3, however, does not regulate these responses to double stranded cytosolic DNA. We identified the cytosolic protein AIM2 as the missing receptor for cytosolic DNA. AIM2 contains a HIN200 domain, which binds to DNA and a pyrin domain, which associates with the adapter molecule ASC to activate both NF-ºB and caspase-1. Knock down of AIM2 down-regulates caspase-1-mediated IL-1² responses following DNA stimulation or vaccinia virus infection. Collectively, these observations demonstrate that AIM2 forms an inflammasome with the DNA ligand and ASC to activate caspase-1. Our underlying hypothesis for this proposal is that AIM2 plays a central role in host-defence to cytosolic microbial pathogens and also in DNA-triggered autoimmunity. The goals of this research proposal are to further characterize the DNA ligand for AIM2, to explore the molecular mechanisms of AIM2 activation, to define the contribution of AIM2 to host-defence against viral and bacterial pathogens and to assess its function in nucleic acid triggered autoimmune disease. The characterization of AIM2 and its role in innate immunity could open new avenues in the advancement of immunotherapy and treatment of autoimmune disease.

1 727 920 €

Start date: 2009-12-01, End date: 2014-11-30

Think about an enantioselective catalyst, which can switch its enantioselectivity and which can be imprinted and provides self-amplification by its own chiral reaction product. Think about a catalyst, which can be fine-tuned for efficient stereoselective synthesis of drugs and other materials, e.g. polymers. Highly promising reactions such as enantioselective autocatalysis (Soai reaction) and chiral catalysts undergoing dynamic interconversions, e.g. BIPHEP ligands, are still not understood. Their application is very limited to a few compounds, which opens the field for novel investigations. I propose the development of a smart or switchable chiral ligand undergoing dynamic interconversions. These catalysts will be tuned by their reaction product, and this leads to self-amplification of one of the stereoisomers. I propose a novel fundamental mechanism which has the potential to overcome the limitations of the Soai reaction, exploiting the full potential of enantioselective catalysis. As representatives of enantioselective self-amplifying stereodynamic catalysts a novel class of diazirine based ligands will be developed, their interconversion barrier is tuneable between 80 and 130 kJ/mol. Specifically, following areas will be explored: 1. Investigation of the kinetics and thermodynamics of the Soai reaction as a model reaction by analysis of large sets of kinetic data. 2. Ligands with diaziridine moieties with flexible structure will be designed and investigated, to control the enantioselectivity. 3. Design of a ligand receptor group for product interaction to switch the chirality. Study of self-amplification in enantioselective processes. 4. Enantioselective hydrogenations, Diels-Alder reactions, epoxidations and reactions generating multiple stereocenters will be targeted.

1 452 000 €

Start date: 2010-12-01, End date: 2016-05-31

"Traditionally, natural products are classified into ""natural product families"". Within a family all congeners display specific structure elements, owing to their common biosynthetic pathway. This suggests a bio-inspired or ""collective synthesis"", as has been devised by D: W. MacMillan. However, a biosynthetic pathway is confined to these structure elements, thus limiting synthesis with regard to structure diversification. In this research proposal the applicant exemplarily devises a strategic concept to overcome these limitations, by replacing the dogma of ""retrosynthetic analysis"" with ""structure pattern recognition"". This concept is termed ""Artificial Natural Product Systems Synthesis — ANaPSyS"", and aims to supersede the current ""logic of chemical synthesis"" as a standard practice in this field. ANaPSyS exclusively categorizes natural products based on structural relationships — regardless of biogenetic origin. The structure pattern analysis groups natural products according to their shared core structure, and thereof creates a common precursor called ""privileged intermediate (PI)"". This intermediate is resembled in each of these natural products and is architecturally less complex. As a result every member of this natural product group can originate from a different natural product family and is obtained via this ""privileged intermediate"", which serves as basis for the artificial synthetic network. With ANaPSyS a synthetic route is not restricted to a single target structure anymore (as in conventional synthesis). In comparison with bio-inspired synthesis, which is limited to a single natural product family, ANaPSyS enables the synthesis of a whole set of natural product families. With every synthesis accomplished, the network is upgraded — hence diversification leads to a rise in revenue. As a consequence, synthetic efficiency is drastically enhanced, therefore profoundly boosting and facilitating lead structure development. "

1 497 000 €

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

"Blood vessels pervade all tissues in the body to supply nutrients and oxygen. Aberrant vessel growth and function are hallmarks of cancer and cardiovascular diseases and they contribute to disease pathogenesis. Antiangiogenic therapeutics have reached the clinic, but limited efficacy and resistance raise unresolved challenges. The current limitations of angiogenic medicine call for a more integrated understanding of the angiogenic process that focuses not only on the instigators of vessel branching but also on mechanisms that sustain vessel growth. Recent insights into fundamental aspects of cell growth move metabolism into spotlight and establish how proliferating cells reprogram their metabolism to provide energy and building blocks for cell replication. During angiogenesis, endothelial cells (ECs) also convert between growth states: although mostly quiescent in adult tissues, ECs divide and migrate rapidly upon angiogenic stimulation. To allow growth of new vessel branches, ECs therefore need to adjust their metabolism to increase energy production and biosynthetic activity. However, the molecular mechanisms that coordinate EC metabolism with angiogenic signalling are not known to date. In this proposal, we put forth the hypothesis that metabolic regulation is a key component of the endothelial angiogenic machinery that is required to sustain vessel growth. Thus, this proposal aims (I) to define transcriptional circuits that link EC growth with metabolism, (II) to explore the regulation of these transcriptional networks by lysine acetylation, a nutrient-regulated protein modification with key functions in metabolism, and (III) to assess the role of sirtuin deacetylases for sensing endothelial energetics during vascular growth. Understanding the principles of angiogenesis-metabolism crosstalk will not only yield novel insights into the basic mechanisms of vessel formation but will also provide unprecedented opportunities for future drug development."

1 487 920 €

Start date: 2012-09-01, End date: 2017-08-31

"During the last decade, a strikingly successful cosmological concordance model has been established. With only six free parameters, nearly all observables, comprising millions of data points, may be fitted with outstanding precision. However, in this beautiful picture a few ""blemishes"" have turned up, apparently not consistent with the standard model: While the model predicts that the universe is isotropic (i.e., looks the same in all directions) and homogeneous (i.e., the statistical properties are the same everywhere), subtle hints of the contrary are now seen. For instance, peculiar preferred directions and correlations are observed in the cosmic microwave background; some studies considering nearby galaxies suggest the existence of anomalous large-scale cosmic flows; a study of distant quasars hints towards unexpected large-scale correlations. All of these reports are individually highly intriguing, and together they hint toward a more complicated and interesting universe than previously imagined -- but none of the reports can be considered decisive. One major obstacle in many cases has been the relatively poor data quality. This is currently about to change, as the next generation of new and far more powerful experiments are coming online. Of special interest to me are Planck, an ESA-funded CMB satellite currently taking data; QUIET, a ground-based CMB polarization experiment located in Chile; and various large-scale structure (LSS) data sets, such as the SDSS and 2dF surveys, and in the future Euclid, a proposed galaxy survey satellite also funded by ESA. By combining the world s best data from both CMB and LSS measurements, I will in the proposed project attempt to settle this question: Is our universe really anisotropic? Or are these recent claims only the results of systematic errors or statistical flukes? If the claims turn out to hold against this tide of new and high-quality data, then cosmology as a whole may need to be re-written."

1 500 000 €

Start date: 2011-01-01, End date: 2015-12-31

This is a proposal for research at the interface of analytic number theory, automorphic forms and algebraic geometry. Motivated by fundamental conjectures in number theory, classical problems will be investigated in higher order situations: general number fields, automorphic forms on higher rank groups, the arithmetic of algebraic varieties of higher degree. In particular, I want to focus on - computation of moments of L-function of degree 3 and higher with applications to subconvexity and/or non-vanishing, as well as subconvexity for multiple L-functions; - bounds for sup-norms of cusp forms on various spaces and equidistribution of Hecke correspondences; - automorphic forms on higher rank groups and general number fields, in particular new bounds towards the Ramanujan conjecture; - a proof of Manin's conjecture for a certain class of singular algebraic varieties. The underlying methods are closely related; for example, rational points on algebraic varieties will be counted by a multiple L-series technique.

1 004 000 €

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

Even after three decades of research on human-computer interaction (HCI), current general-purpose user interfaces (UI) still lack the ability to attribute mental states to their users, i.e. they fail to understand users' intentions and needs and to anticipate their actions. This drastically restricts their interactive capabilities. ANTICIPATE aims to establish the scientific foundations for a new generation of user interfaces that pro-actively adapt to users' future input actions by monitoring their attention and predicting their interaction intentions - thereby significantly improving the naturalness, efficiency, and user experience of the interactions. Realising this vision of anticipatory human-computer interaction requires groundbreaking advances in everyday sensing of user attention from eye and brain activity. We will further pioneer methods to predict entangled user intentions and forecast interactive behaviour with fine temporal granularity during interactions in everyday stationary and mobile settings. Finally, we will develop fundamental interaction paradigms that enable anticipatory UIs to pro-actively adapt to users' attention and intentions in a mindful way. The new capabilities will be demonstrated in four challenging cases: 1) mobile information retrieval, 2) intelligent notification management, 3) Autism diagnosis and monitoring, and 4) computer-based training. Anticipatory human-computer interaction offers a strong complement to existing UI paradigms that only react to user input post-hoc. If successful, ANTICIPATE will deliver the first important building blocks for implementing Theory of Mind in general-purpose UIs. As such, the project has the potential to drastically improve the billions of interactions we perform with computers every day, to trigger a wide range of follow-up research in HCI as well as adjacent areas within and outside computer science, and to act as a key technical enabler for new applications, e.g. in healthcare and education.

1 499 625 €

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

Social bonding success in life impacts on health, survival and fitness. It is proposed that early and later social experience as well as heritable factors determine social bonding abilities in adulthood, although the relative influence of each is unclear. In humans, the resulting uncertainty likely impedes psychological and psychiatric assessment and therapy. One problem hampering progress for human studies is that social bonding success is hard to objectively quantify, particularly in adults. I propose to directly address this problem by determining the key influences on social bonding abilities in chimpanzees, our closest living relative, where social bonding success can be objectively quantified, and is defined as number of affiliative relationships maintained over time with high rates of affiliation. Objectives. This project will quantify the relative impact of early and later social experience as well as heritable factors on social hormone levels, social cognition and social bonding success in 270 wild and captive chimpanzees, using both cohort and longitudinal data. This will reveal the degree of plasticity in social cognition and bonding behaviour throughout life. Finally, it will evaluate the potential for using endogenous hormone levels as non-invasive biomarkers of social bonding success, as well as identifying social contexts that act as strong natural social hormone releasers. Outcomes. This project will expose what makes some better at social bonding than others. Specifically, it will show the extent to which later social experience can compensate for early social experience or heritable factors in terms of adult social bonding success, the latter being a key factor in determining health and happiness in life. This project also offers the potential for using hormonal biomarkers in clincial settings, as objective assessment of changes in relationships over time, and in therapy by engaging in social behaviours that act as strong social hormone releasers.

1 495 000 €

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

Deregulated apoptotic signaling in hematopoietic stem and progenitor cells (HSPCs) strongly contributes to the pathogenesis and phenotypes of congenital bone marrow failure and myelodysplastic syndromes (MDS) and their progression to acute myeloid leukemia (AML). HSPCs are highly susceptible to apoptosis during bone marrow failure and early MDS, but AML evolution selects for apoptosis resistance. Little is known about the main apoptotic players and their regulators. ApoptoMDS will investigate the impact of apoptotic deregulation for pathogenesis, correlate apoptotic susceptibility with the kinetics of disease progression and characterize the mechanism by which apoptotic susceptibility turns into resistance. ApoptoMDS will draw on a large collection of patient-derived samples and genetically engineered mouse models to investigate disease progression in serially transplanted and xenotransplanted mice. How activated DNA damage checkpoint signaling contributes to syndrome phenotypes and HSPC hypersusceptibility to apoptosis will be assessed. Checkpoint activation confers a competitive disadvantage, and HSPCs undergoing malignant transformation are under high selective pressure to inactivate it. Checkpoint abrogation mitigates the hematological phenotype, but increases the risk of AML evolution. ApoptoMDS aims to analyze if inhibiting apoptosis in HSPCs from bone marrow failure and early-stage MDS can overcome the dilemma of checkpoint abrogation. Whether inhibiting apoptosis is sufficient to improve HSPC function will be tested on several levels and validated in patient-derived samples. How inhibiting apoptosis in the presence of functional checkpoint signaling influences malignant transformation kinetics will be assessed. If, as hypothesized, inhibiting apoptosis both mitigates hematological symptoms and delays AML evolution, ApoptoMDS will pave the way for novel therapeutic approaches to expand the less severe symptomatic period for patients with these syndromes.

1 372 525 €

Start date: 2015-06-01, End date: 2020-05-31

The project is the first comprehensive study to assess contemporary parenting norms and practices and their diffusion. The project develops a comparative framework to study prevalent motherhood and fatherhood norms, images, identities and behaviour in current societies. The project will focus on how parenting roles are constructed by professionals, welfare states, and popular media, and will assess how cultural and institutional norms and images are perceived and realized by expecting and new parents. In 4 subprojects this study investigates 1) How standards of 'good' mothering and fathering are perceived, shaped and disseminated by professionals (gynaecologists, midwives, family councils); 2) How welfare states, labour markets and family policies target at mothers and fathers roles as earners and care givers, and how this has changed in recent decades; 3) How images of mothers and fathers roles have been portrayed in print media from 1980 until 2010; 4) How (expecting) mothers and fathers perceive, embody and represent parenting norms and images in their own work and family roles; 5) How new parents divide paid and unpaid work and how these divisions shape career patterns over the life course; 6) How these patterns differ cross-nationally. The international collaboration includes Sweden, the Netherlands, Germany, Italy, the Czech Republic, and Poland. The aim of this project is to develop a contemporary sociology of adult sex roles and parenting norms: A theory of the social creation of parenting norms and a comprehensive framework to study empirically the change of men's and women's roles, identities and practices as earners and care givers in the early phase of family formation. By combining expert interviews, policy analysis and content analysis of print media with analyses of qualitative and quantitative data on (nascent) parents, the project will address the diverse layers associated with changing gender roles and parenting norms over the adult life course.

1 393 751 €

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

This proposal aims to unravel mysteries at the frontier of number theory and other areas of mathematics and physics. The main focus will be to understand and exploit “modularity” of q-hypergeometric series. “Modular forms are functions on the complex plane that are inordinately symmetric.” (Mazur) The motivation comes from the wide-reaching applications of modularity in combinatorics, percolation, Lie theory, and physics (black holes). The interplay between automorphic forms, q-series, and other areas of mathematics and physics is often two-sided. On the one hand, the other areas provide interesting examples of automorphic objects and predict their behavior. Sometimes these even motivate new classes of automorphic objects which have not been previously studied. On the other hand, knowing that certain generating functions are modular gives one access to deep theoretical tools to prove results in other areas. “Mathematics is a language, and we need that language to understand the physics of our universe.”(Ooguri) Understanding this interplay has attracted attention of researchers from a variety of areas. However, proofs of modularity of q-hypergeometric series currently fall far short of a comprehensive theory to describe the interplay between them and automorphic forms. A recent conjecture of W. Nahm relates the modularity of such series to K-theory. In this proposal I aim to fill this gap and provide a better understanding of this interplay by building a general structural framework enveloping these q-series. For this I will employ new kinds of automorphic objects and embed the functions of interest into bigger families A successful outcome of the proposed research will open further horizons and also answer open questions, even those in other areas which were not addressed in this proposal; for example the new theory could be applied to better understand Donaldson invariants.

1 240 500 €

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

"Archaea constitute the third domain of life and are believed to be close to the origin of life. They comprise a diverse group of micro-organisms that combine bacterial and eukaryotic features, but also employ many novel mechanisms. They possess a unique cell envelope with a cytoplasmic membrane of ether lipids surrounded by a proteinaceous S-layer and various cell appendages such as flagella, pili and more unusual structures. Studies have shown that the archaeal flagellum is an unique structure as it functionally resembles the bacterial flagellum, but structurally it is a simple type IV pilus. Moreover, we have shown that this type IV pilus can rotate. Therefore I propose to name the archaeal flagellum, the archaellum, as it is fundamentally different from the bacterial flagellum. In this proposal I aim to understand the assembly and mechanism of rotation of the archaellum of the thermocacidophilic crenarchaen Sulfolobus acidocaldarius by using biochemical, genetic and biophysical methods. The main milestons are: - Biochemical and structural characterization of all archaellum subunits - To understand the assembly pathway of the archaellum and the interactions of its different subunits - To understand how rotation of the filament is achieved and which subunits are important for this movement This work will identify a new, relatively simple motor complex that has evolved from primordial type IV pili assembly machineries and therefore uncover general principles of macromolecular assemblies at cellular surfaces and a novel mechanism to generate mechanical force that can be translated into movement."

1 464 317 €

Start date: 2013-02-01, End date: 2018-01-31

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

Supramolecular assemblies – formed by the self-assembly of hundreds of protein subunits – are part of bacterial nanomachines involved in key cellular processes. Important examples in pathogenic bacteria are pili and type 3 secretion systems (T3SS) that mediate adhesion to host cells and injection of virulence proteins. Structure determination at atomic resolution of such assemblies by standard techniques such as X-ray crystallography or solution NMR is severely limited: Intact T3SSs or pili cannot be crystallized and are also inherently insoluble. Cryo-electron microscopy techniques have recently made it possible to obtain low- and medium-resolution models, but atomic details have not been accessible at the resolution obtained in these studies, leading sometimes to inaccurate models. I propose to use solid-state NMR (ssNMR) to fill this knowledge-gap. I could recently show that ssNMR on in vitro preparations of Salmonella T3SS needles constitutes a powerful approach to study the structure of this virulence factor. Our integrated approach also included results from electron microscopy and modeling as well as in vivo assays (Loquet et al., Nature 2012). This is the foundation of this application. I propose to extend ssNMR methodology to tackle the structures of even larger or more complex homo-oligomeric assemblies with up to 200 residues per monomeric subunit. We will apply such techniques to address the currently unknown 3D structures of type I pili and cytoskeletal bactofilin filaments. Furthermore, I want to develop strategies to directly study assemblies in a native-like setting. As a first application, I will study the 3D structure of T3SS needles when they are complemented with intact T3SSs purified from Salmonella or Shigella. The ultimate goal of this proposal is to establish ssNMR as a generally applicable method that allows solving the currently unknown structures of bacterial supramolecular assemblies at atomic resolution.

1 456 000 €

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

Despite considerable efforts aimed at prevention and treatment, the prevalence of obesity and type 2 diabetes has increased at an alarming rate worldwide over recent decades. Given the urgent need to develop safe and efficient anti-obesity drugs, the scientific community has to intensify efforts to better understand the mechanisms involved in the pathogenesis of obesity. Based on human genome-wide association studies and targeted mouse mutagenesis models, it has recently emerged that the brain controls most aspects of systemic metabolism and that obesity may be a brain disease. I have recently shown that like neurons, astrocytes also respond to circulating nutrients, and they cooperate with neurons to efficiently regulate energy metabolism. So far, the study of brain circuits controlling energy balance has focused on neurons, ignoring the presence and role of astrocytes. Importantly, our studies were the first to describe that exposure to a high-fat, highsugar (HFHS) diet triggers hypothalamic astrogliosis prior to significant body weight gain, indicating a potentially important role in promoting obesity. Overall, my recent findings suggest a novel model in which astrocytes are actively involved in the central nervous system (CNS) control of metabolism, likely including active crosstalk between astrocytes and neurons. To test this hypothetical model, I propose to develop a functional understanding of astroglia-neuronal communication in the CNS control of metabolism focusing on: 1) dissecting the ability of astrocytes to release gliotransmitters to neurons, 2) assessing how astrocytes respond to neuronal activity, and 3) determining if HFHS-induced astrogliosis interrupts this crosstalk and contributes to the development of obesity and type 2 diabetes. These studies aim to uncover the molecular underpinnings of astrocyte-neuron inputs regulating metabolism in health and disease so as to inspire and enable novel therapeutic strategies to fight diabetes and obesity.

1 499 938 €

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

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

The ongoing miniaturization in nanotechnology and functional materials puts an ever increasing focus on the development of three-dimensional (3D) nanostructures, such as quantum dot arrays, structured nanowires, or non-trivial topological magnetic textures such as skyrmions, which permit a better performance of logical or memory devices in terms of speed and energy efficiency. To develop and advance such technologies and to improve the understanding of the underlying fundamental solid state physics effects, the nondestructive and quantitative 3D characterization of physical, e.g., electric or magnetic, fields down to atomic resolution is indispensable. Current nanoscale metrology methods only inadequately convey this information, e.g., because they probe surfaces, record projections, or lack resolution. AToM will provide a ground-breaking tomographic methodology for current nanotechnology by mapping electric and magnetic fields as well as crucial properties of the underlying atomic structure in solids, such as the chemical composition, mechanical strain or spin configuration in 3D down to atomic resolution. To achieve that goal, advanced holographic and tomographic setups in the Transmission Electron Microscope (TEM) are combined with novel computational methods, e.g., taking into account the ramifications of electron diffraction. Moreover, fundamental application limits are overcome (A) by extending the holographic principle, requiring coherent electron beams, to quantum state reconstructions applicable to electrons of any (in)coherence; and (B) by adapting a unique in-situ TEM with a very large sample chamber to facilitate holographic field sensing down to very low temperatures (6 K) under application of external, e.g., electric, stimuli. The joint development of AToM in response to current problems of nanotechnology, including the previously mentioned ones, is anticipated to immediately and sustainably advance nanotechnology in its various aspects.

1 499 602 €

Start date: 2017-01-01, End date: 2021-12-31

Quantum information science and atom optics are among the most active fields in modern physics. In recent years, many theoretical efforts have been made to combine these two fields. Recent experimental progresses have shown the in-principle possibility to perform scalable quantum information processing (QIP) with linear optics and atomic ensembles. The main purpose of the present project is to use atomic qubits as quantum memory and exploit photonic qubits for information transfer and processing to achieve efficient linear optics QIP. On the one hand, utilizing the interaction between laser pulses and atomic ensembles we will experimentally investigate the potentials of atomic ensembles in the gas phase to build quantum repeaters for long-distance quantum communication, that is, to develop a new technological solution for quantum repeaters making use of the effective qubit-type entanglement of two cold atomic ensembles by a projective measurement of individual photons by spontaneous Raman processes. On this basis, we will further investigate the advantages of cold atoms in an optical trap to enhance the coherence time of atomic qubits beyond the threshold for scalable realization of quantum repeaters. Moreover, building on our long experience in research on multi-photon entanglement, we also plan to perform a number of significant experiments in the field of QIP with particular emphasis on fault-tolerant quantum computation, photon-loss-tolerant quantum computation and cluster-state based quantum simulation. Finally, by combining the techniques developed in the above quantum memory and multi-photon interference experiments, we will further experimentally investigate the possibility to achieve quantum teleportation between photonic and atomic qubits, quantum teleportation between remote atomic qubits and efficient entanglement generation via classical feed-forward. The techniques that will be developed in the present project will lay the basis for future large scale

1 435 000 €

Start date: 2008-07-01, End date: 2013-12-31

Collective electron motion can unfold on attosecond time scales in nanoplasmonic systems, as defined by the inverse spectral bandwidth of the plasmonic resonant region. Similarly, in dielectrics or semiconductors, the laser-driven collective motion of electrons can occur on this characteristic time scale. Until now, such collective electron dynamics has not been directly observed on its natural, attosecond timescale. In ATTOCO, the attosecond, sub-cycle dynamics of strong-field driven collective electron dynamics in clusters and nanoparticles will be explored. Moreover, we will explore field-dependent processes induced by strong laser fields in nanometer sized matter, such as the metallization of dielectrics, which has been recently proposed theoretically. In order to map the collective electron motion we will apply the attosecond nanoplasmonic streaking technique, which has been proposed and developed theoretically. In this approach, the temporal resolution is achieved by limiting the emission of high energetic, direct photoelectrons to a sub-cycle time window using attosecond XUV pulses phase-locked to a driving few-cycle near-infrared field. Kinetic energy spectra of the photoelectrons recorded for different delays between the excitation field and the ionizing XUV pulse will allow extracting the spatio-temporal electron dynamics. ATTOCO offers the capability to measure field-induced material changes in real-time and to gain novel insight into collective electron dynamics. In particular, we aim to learn from ATTOCO in detail, how the collective electron motion is established, how the collective motion is driven by the strong external field and over which pathways and timescale the collective motion decays. ATTOCO provides also a major step in the development of lightwave (nano-)electronics, which may push the frontiers of electronics from multi-gigahertz to petahertz frequencies. If successfully accomplished, this development will herald the potential scalability of electron-based information technologies to lightwave frequencies, surpassing the speed of current computation and communication technology by many orders of magnitude.

1 498 500 €

Start date: 2013-06-01, End date: 2018-05-31

I suggest that perceptions of diversity and disagreement voiced in the on-line political discussion may play a key role in mobilizing citizens to voice their views and take action in authoritarian regimes. The empirical focus is the Chinese Internet. Subjective perceptions of group discussion among participants can significantly differ from the objective content of the discussion. These perceptions can have an independent effect on political engagement. Novel is also that I will study which technological settings (blogs, Weibo (Twitter), public hearings, etc) facilitate these perceptions. I will address these novel issues by specifying the conditions and causal mechanisms that facilitate the rise of online public opinion. As an expansion to prior work, I will study passive in addition to active participants in online discussion. This is of particular interest because passive participants outnumber active participants. My overall aim is to deepen our knowledge of how participants experience online political discussion in stabilizing or destabilizing authoritarian rule. To this end, I propose to work with one post-doc and two PhD research assistants on four objectives: Objective 1 is to explore what kinds of people engage in online discussions and differences between active and passive participants. Objective 2 is to understand how the technological settings that create the conditions for online discussion differ from each other. Objective 3 is to assess how active and passive participants see the diversity and disagreement in the discussion in these settings. Objective 4 is to assess whether citizens take action upon online political discussion depending on how they see it. I will produce the first nationally representative survey on the experiences of participants in online political discussion in China. In addition to academics, this knowledge is of interest to policy-makers, professionals, and journalists aiming to understand authoritarian politics and media

1 499 780 €

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

Embedded Control software plays a critical role in many safety-critical applications. For instance, modern vehicles use interacting software and hardware components to control steering and braking. Control software forms the main core of autonomous transportation, power networks, and aerospace. These applications are examples of cyber-physical systems (CPS), where distributed software systems interact tightly with spatially distributed physical systems with complex dynamics. CPS are becoming ubiquitous due to rapid advances in computation, communication, and memory. However, the development of core control software running in these systems is still ad hoc and error-prone and much of the engineering costs today go into ensuring that control software works correctly. In order to reduce the design costs and guaranteeing its correctness, I aim to develop an innovative design process, in which the embedded control software is synthesized from high-level correctness requirements in a push-button and formal manner. Requirements for modern CPS applications go beyond conventional properties in control theory (e.g. stability) and in computer science (e.g. protocol design). Here, I propose a compositional methodology for automated synthesis of control software by combining compositional techniques from computer science (e.g. assume-guarantee rules) with those from control theory (e.g. small-gain theorems). I will leverage decomposition and abstraction as two key tools to tackle the design complexity, by either breaking the design object into semi-independent parts or by aggregating components and eliminating unnecessary details. My project is high-risk because it requires a fundamental re-thinking of design techniques till now studied in separate disciplines. It is high-gain because a successful method for automated synthesis of control software will make it finally possible to develop complex yet reliable CPS applications while considerably reducing the engineering cost.

1 470 800 €

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

Early life immune balance is essential for survival and establishment of healthy immunity in later life. We aim to define how age-dependent regulation of dendritic cell (DC) development contributes to this crucial immune balance. DCs are versatile controllers of immunity that in neonates are qualitatively distinct from adults. Why such age-dependent differences exist is unclear but newborn DCs are considered underdeveloped and functionally immature. Using ontogenetic tracing of conventional DC precursors, I have found a previously unappreciated developmental heterogeneity of DCs that is particularly prominent in young mice. Preliminary data indicate that distinct waves of DC poiesis contribute to the functional differences between neonatal and adult DCs. I hypothesize that the neonatal DC compartment is not immature but rather that DC poiesis is developmentally regulated to create essential age-dependent immune balance. Further, I have identified a unique situation in early life to address a fundamental biological question, namely to what extent cellular function is pre-programmed by developmental origin (nature) versus environmental factors (nurture). In this proposal, we will first use novel models to fate map the origin of the DC compartment with age. We will then define to what extent cellular origin determines age-dependent functions of DCs in immunity. Using innovative comparative gene expression profiling and integrative epigenomic analysis the cell intrinsic mechanisms regulating the age-dependent functions of DCs will be characterized. Because environmental factors in utero and after birth critically influence immune balance, we will finally define the impact of maternal infection and metabolic disease, as well as early microbial encounter on DC poiesis. Characterizing how developmentally regulated DC poiesis shapes the unique features of early life immunity will provide novel insights into immune development that are vital to advance vaccine strategies.

1 500 000 €

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

Exciting findings from animal electrophysiological research in the last years suggest that an increased rate of body movements results in an enhanced response of neurons within the visual system despite the absence of visual changes. It is unclear why such modulation occurs in areas which process visual input. In humans, little is known about the influence of body movements on sensory brain areas mainly due to the technical challenges of measuring brain responses during pronounced muscle activity. However, psychophysical studies in humans show that also percept and perceptual demands are connected to the rate of movements. These two lines of evidence suggest a general link between rhythmic body movements and perceptual processes. The main aim of the proposed research is to decode the relationship between body movements and percept and to identify the underlying mechanism. To this end human non-invasive recordings from electro- and magnetoencephalography (EEG, MEG) as well as invasive human and animal multi-electrode recordings collected during movement execution will be analyzed. Directly relating perceptual processes and their underlying neuronal oscillations to rhythmic body movements offers an approach circumventing some of the methodological problems. This research could uncover a new mechanism of how our system modulates perceptual processes through body movements. The proof of such a mechanism would constitute a ground-breaking step in understanding perception during natural behavior. We need to keep in mind that in the awake state our body is constantly in motion. However, up to now, the vast majority of studies which investigate sensory brain responses are conducted under strict movement suppression. Besides facilitating exciting new insights, this research can strengthen the assumption that the knowledge we have gathered about artificial situations generalizes to our natural behavior.

1 422 907 €

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

There is an apparent lack of non-metallic 2D-matrials for the construction of electronic devices, as only five materials of the “graphene family” are known: graphene, hBN, BCN, fluorographene, and graphene oxide – none of them with a narrow bandgap close to commercially used silicon. This ERC-StG proposal, BEGMAT, outlines a strategy for design, synthesis, and application of layered, functional materials that will go beyond this exclusive club. These materials “beyond graphene” (BEG) will have to meet – like graphene – the following criteria: (1) The BEG-materials will feature a transfer of crystalline order from the molecular (pm-range) to the macroscopic level (cm-range), (2) individual, free-standing layers of BEG-materials can be addressed by mechanical or chemical exfoliation, and (3) assemblies of different BEG-materials will be stacked as van der Waals heterostructures with unique properties. In contrast to the existing “graphene family”, (4) BEG-materials will be constructed in a controlled way by covalent organic chemistry in a bottom-up approach from abundant precursors free of metals and critical raw materials (CRMs). Moreover – and unlike – many covalent organic frameworks (COFs), (5) BEG-materials will be fully aromatic, donor-acceptor systems to ensure that electronic properties can be addressed on macroscopic scale. The potential to make 2D materials “beyond graphene” is a great challenge to chemical bond formation and material design. In 2014 the applicant has demonstrated the feasibility of the concept to expand the “graphene family” with triazine-based graphitic carbon, a compound highlighted as an “emerging competitor for the miracle material” graphene. Now, the PI has the opportunity to build a full-scale research program on layered functional materials that offers unique insights into controlled, covalent linking-chemistry, and that addresses practicalities in device manufacture, and structure-properties relationships.

1 362 538 €

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

For many optimization problems that arise in logistics, information retrieval, and other contexts the classical theory of algorithms has lost its grip on reality because it is based on a pessimistic worst-case perspective, in which the performance of an algorithm is solely measured by its behavior on the worst possible input. This does not take into consideration that worst-case inputs are often rather contrived and occur only rarely in practical applications. It led to the situation that for many problems the classical theory is not able to differentiate meaningfully between different algorithms. Even worse, for some important problems it recommends algorithms that perform badly in practice over algorithms that work well in practice only because the artificial worst-case performance of the latter ones is bad. We will study classic optimization problems (traveling salesperson problem, linear programming, etc.) as well as problems coming from machine learning and information retrieval. All these problems have in common that the practically most successful algorithms have a devastating worst-case performance even though they clearly outperform the theoretically best algorithms. Only in recent years a paradigm shift towards a more realistic and robust algorithmic theory has been initiated. This project will play a major role in this paradigm shift by developing and exploring novel theoretical approaches (e.g. smoothed analysis) to reconcile theory and practice. A more realistic theory will have a profound impact on the design and analysis of algorithms in the future, and the insights gained in this project will lead to algorithmic tools for large-scale optimization problems that improve on existing ad hoc methods. We will not only work theoretically but also test the applicability of our theoretical considerations in experimental studies.

1 235 820 €

Start date: 2012-10-01, End date: 2017-09-30

Organic semiconducting molecules often make for very good luminescent materials. Fundamental excitations are localized on single molecules, which is in stark contrast to inorganic semiconductors, such that exchange interactions lead to energetically distinct singlet and triplet states. The singlet-excited state is the origin of conventional fluorescence. However, once an excitation is in the molecular triplet state, emission of photons is very unlikely, because spin conservation needs to be broken. Here, non-radiative recombination outcompetes the radiative. Recent research efforts led to the discovery of highly efficient biluminescence. Here, in addition to the fluorescence from the singlet state, the phosphorescence (triplet state emission) is unlocked by suppression of non-radiative channels at room temperature. The dynamics of both states is vastly different with nanosecond fluorescence and millisecond phosphorescence. If both channels are highly luminescent, then there is no room for loss channels. Within BILUM, the virtually unexplored phenomenon of biluminescence will be the central point: On the basic science side, efforts will be focussed on the detailed understanding of structure-property relationships that are key for efficient dual state emission. At the same time, with a curiosity driven engineering approach, known bilumophores will be carefully tested in different scenarios to set the ground for future applications. Biluminescence has the potential to access non-radiative triplet states that are in many cases system limiting, to serve as ultra-broadband emitters, to introduce persistent (ultra long-lived) emission, to store photonic energy, and to allow optical sensing with internal reference emission – all on the molecular level. New bilumophores will be identified through systematic screening that will employ quantum chemical calculations and developed through organic synthesis.

1 462 500 €

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

The most energetic electromagnetic phenomena in the Universe are believed to be powered by the collision of two neutron stars, the smallest and densest stars on which surface gravity is about 2 billion times stronger than gravity on Earth. However, a definitive identification of neutron star mergers as central engines for short-gamma-ray bursts and kilonovae transients is possible only by direct gravitational-wave observations. The latter provide us with unique information on neutron stars' masses, radii, and spins, including the possibility to set the strongest observational constraints on the unknown equation-of-state of matter at supranuclear densities. Neutron stars binary mergers are among the main targets for ground-based gravitational-wave interferometers like Advanced LIGO and Virgo, which start operations this year. The astrophysical data analysis of the signals emitted by these sources requires the availability of accurate waveform models, which are missing to date. Hence, the theoretical understanding of the gravitational spectrum is a necessary and urgent step for the development of a gravitational-based astrophysics in the next years. This project aims at developing, for the first time, a precise theoretical model for the complete gravitational spectrum of neutron star binaries, including the merger and postmerger stages of the coalescence process. Building on the PI's unique expertise and track record, the proposed research exploits synergy between analytical and numerical methods in General Relativity. Results from state of the art nonlinear 3D numerical relativity simulations will be combined with the most advanced analytical framework for the relativistic two-body problem. The model developed here will be used in the first gravitational-wave observations and will dramatically impact multimessenger astrophysics.

1 432 301 €

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

In the last decades, Materials Sciences and Life Sciences, two highly dynamically evolving and interdisciplinary research areas, have been influencing natural and engineering sciences significantly, creating new challenges and opportunities. A prime example for an increasing synergetic overlap of Materials and Life Sciences is provided by biomedical and bioengineering applications, which are of great academic, but also of steadily increasing societal and commercial interest. Bridging the traditional borders of disciplinary thinking in these areas has become one of today’s most challenging tasks for scientists. One group of key materials that are of great importance to biomedical engineering and bioengineering are advanced oxide and non-oxide ceramics with specific functionalities towards biological environments, so-called Bioceramics. The interplay at the interface of ceramics-protein-cells/bacteria is very complex and requires multiscale and interdisciplinary approaches. This expertise, that is under continuous development in my Bioceramics group, encompasses materials processing, shaping, surface functionalisation and cells/bacteria evaluation at the same time. The comprehensive research environment and expertise provides a unique opportunity to engineer materials/surfaces with immediate subsequent biological evaluation in order to achieve an extremely short development time. A centre of focus is the contribution of electrostatic and hydrophilic/hydrophobic interactions to the overall biocompatibility and -activity. The proposed research project includes four closely interrelated subprojects, addressing the following topics: “Interaction of surface functionalised ceramic particles with proteins”, “Cytotoxicity of functionalised oxide particles”, “Fabrication and testing of functionalised porous Al2O3 as filters for water cleaning and bioengineering applications” and “Novel functional scaffold composites for bone tissue engineering”.

1 536 120 €

Start date: 2009-01-01, End date: 2013-12-31

Primary energy conversion in nature is powered by highly efficient enzymes that capture chemical or light energy and transduce it into other energy forms. These processes are catalyzed by coupled transfers of protons and electrons (PCET), but their fundamental mechanistic principles are not well understood. In order to obtain a molecular-level understanding of the functional elements powering biological energy conversion processes, we will study the catalytic machinery of one of the largest and most intricate enzymes in mitochondria and bacteria, the respiratory complex I. This gigantic redox-driven proton-pump functions as the entry point for electrons into aerobic respiratory chains, and it employs the energy released from a chemical reduction process to transport protons up to 200 Å away from its active site. Its molecular structure from bacteria and eukaryotes was recently resolved, but the origin of this remarkable action-at-a-distance effect still remains unclear. We employ and develop multi-scale quantum and classical molecular simulation techniques in combination with de novo-protein design methodology to identify and isolate the functional elements that catalyze the long-range PCET reactions in complex I. To fully understand the natural PCET-elements, we will further engineer central parts of this machinery into artificial protein frameworks, with the goal of designing modules for redox-driven proton pumps from first principles. The project aims to establish a fundamental understanding of nature's toolbox of catalytic elements, to elucidate how the complex biochemical environment contributes to the catalytic effects, and to provide blueprints that can guide the design of man-made enzymes for sustainable energy technology.

1 494 368 €

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

The aim of this transdisciplinary project is to develop and analyse multiscale mathematical models of pattern formation in multicellular systems controlled by the dynamics of intracellular signalling pathways and cell-to-cell communication and to develop new mathematical methods for the modelling of such complex processes. This aim will be achieved through a close collaboration with experimental groups and comprehensive analytical investigations of the mathematical problems arising in the modelling of these biological processes. The mathematical methods and techniques to be employed will be the analysis of systems of partial differential equations, asymptotic analysis, as well as methods of dynamical systems. These techniques will be used to formulate the models and to study the spatio-temporal behaviour of solutions, especially stability and dependence on characteristic scales, geometry, initial data and key parameters. Advanced numerical methods will be applied to simulate the models. This comprehensive methodology goes beyond the state-of-the-art, since usually the analyses are limited to a single aspect of model behaviour. Groundbreaking impacts envisioned are threefold: (i) The project will contribute to the understanding of mechanisms of structure formation in the developmental process, in the context of recently discovered signalling pathways. In addition, some of the factors and mechanisms playing a role in developmental processes, such as Wnt signalling, are implicated in carcinogenesis, for instance colon and lung cancer. (ii) Accurate quantitative and predictive mathematical models of cell proliferation and differentiation are important for the control of tumour growth and tissue egeneration; (iii) Qualitative analysis of multiscale mathematical models of biological phenomena generates challenging mathematical problems and, therefore, the project will lead to the development of new mathematical theories and tools.

750 000 €

Start date: 2008-09-01, End date: 2013-08-31

Blood and bone are closely intertwined. Their intrinsic regenerative capacities are disturbed in many hematological and musculoskeletal diseases. Re-establishing the regenerative potential is the key to cure these diseases by regenerative medicine. Multipotent stem cells of both tissues – hematopoietic stem cells (HSCs) for blood and mesenchymal stem/stromal (MSCs) for bone – are the basis for their regenerative capacity. While it is well established that HSCs are influenced by the bone marrow in their natural environment including MSCs and their progeny, surprisingly little attention has been paid to the reciprocal relationship. The hypothesis of the current proposal is that only when taking both tissues and their mutual crosstalk into account, we will be able to understand how the regenerative potential of blood and bone is impaired in disease and how it can be re-established with novel treatment strategies. For this purpose we need to understand the early events of disease onset and progression. Due to the limitations of such studies in human beings and animals, I propose to develop human in vitro models of healthy bone marrow, which can be induced to develop hematological and musculoskeletal diseases with high incidence, namely leukemia, multiple myeloma and bone metastasis. Previously my team and I developed a simplified bone marrow analog that bases on macroporous, cell-laden biomaterials with tunable physical, biochemical and biological properties. This versatility will enable us to create biomimetic human in vitro models of the human bone marrow in health and disease, which are ground-breaking in their applicability to investigate how the regenerative balance of bone marrow is maintained in health and disturbed in the different kinds of diseases – a prerequisite to develop novel regenerative treatments – as well as their scalability and thus suitability as in vitro test systems for screening of novel drugs or treatments.

1 499 920 €

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

The potential and boundaries of the human mind is determined by dynamic interactions between the environment and the individual genetic architecture. However, despite several breakthroughs, the genetic revolution has not provided a coherent account of the development of the mind and its disorders, and the missing heritability is large across human traits. One explanation of this impasse is the complexity of the gene-environment interactions. Current knowledge about the determinants of a healthy mind is largely based on studies whose modus operandi is to treat the environment as a static entity, neglecting to consider the crucial fact that environmental inputs and their genetic interactions vary dramatically between life phases. The objective of BRAINMINT is to provide this missing link by zeroing in on two major life transitions, namely adolescence and pregnancy. These phases are characterized by temporarily increased brain plasticity, offering windows for adaptation and growth, but also host the emergence of common mental disorders. I propose that a multi-level investigation with this dark side of brain plasticity as the axis mundi will add a mechanistic understanding of this link between growth and vulnerability. I will test the main hypothesis that mechanisms that boost neuroplasticity promote adaptation to a dynamic environment, but at the cost of increased risk of psychopathology if exposed to a combination of genetic and environmental triggers. To this end I will utilize cutting-edge longitudinal brain imaging, electrophysiology, rich cognitive and clinical data, immune markers, gene expression and genetics. I will leverage on massive imaging data (n>40,000) and novel tools to increase power and generalizability and improve brain- and gene-based predictions of complex traits. Aiming to help resolving one of the modern day enigmas, BRAINMINT is a pioneering and high risk/high gain effort to find mechanisms of brain plasticity that support and harm the brain.

1 446 113 €

Start date: 2019-08-01, End date: 2024-07-31

Synchronization of brain rhythms to the rhythms of sounds is a foundational mechanism for auditory perception. However, we know very little about why brain–environment synchrony might fail, leading to auditory perception problems like impaired speech comprehension that negatively impact quality of life. The proposed research program fills this knowledge gap in three stages: 1) Predicting auditory perception, and individual differences thereof, from the fit between neural dynamics and environment; 2) Perturbing the relationship between brain and environment to experimentally test the limits of and protective factors for brain–environment synchronization; 3) Translating gained knowledge to understand age-related dysfunctions in brain–environment synchrony and auditory perception. Stage 1 uses behavioural and neural properties of neural oscillators – brain regions and networks that generate rhythmic neural activity – to predict individual differences in brain–environment synchronization. Stage 2 assesses when and why auditory perception fails, and how auditory perception might be insulated by good brain–environment fit and neural flexibility, by challenging the brain’s ability to adapt to auditory rhythms. Stage 2 has strong potential to provide insight into compensatory listening strategies that may be adopted when neural entrainment is effortful or impossible. Stage 3 places special emphasis on listening difficulties that develop with age, and tests the hypotheses that 1) speech comprehension difficulties stem from reduced neural entrainment in older age, and 2) reduced entrainment for older adults results from age-related changes to neural flexibility. Noninvasive brain stimulation will be used to temporarily remedy these deficits by improving brain–environment synchrony. The research program will account for much currently unexplained individual variance in auditory perception, and will inspire novel interventions to support auditory perception in advancing age.

1 500 000 €

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

Despite their many successes and great computational power and speed, why are machines still so blatantly outperformed by humans in uncertain environments that require flexible sensorimotor behavior like playing football or navigating a disaster zone? Answering this question requires understanding the mathematical principles of biological sensorimotor control and learning. Over the recent years Bayes-optimal actor models have widely become the gold standard in the mathematical understanding of sensorimotor processing in well-controlled laboratory tasks. However, these models quickly become intractable for real-world problems because they ignore the computational effort required to search for the Bayes-optimum. What is therefore needed is a framework of sensorimotor processing that takes the limited information-processing capacity of bounded rational actors into account and that explains their robust real-world performance. It is the aim of BRISC to establish such a framework by drawing out theoretical predictions and gathering experimental evidence in human motor control, in particular to understand (i) how single bounded rational actors deviate from Bayes-optimal behavior in motor tasks, (ii) how multiple bounded rational actors organize themselves to solve motor tasks that no individual can solve by themselves and (iii) how this drives the emergence of hierarchical control structures that simultaneously process multiple degrees of abstraction at different time scales. Understanding how abstract concepts are formed autonomously from the sensorimotor stream based on resource allocation principles will establish an essential missing link between high-level symbolic and low-level perceptual processing. These advances will provide a decisive step towards a framework for robust and flexible sensorimotor processing, which is not only essential for understanding the fundamental principles of intelligent behavior, but it is also of potentially great technological value.

1 434 250 €

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

The oral cavity is the gateway to the lower respiratory tract, and oral bacteria are likely to play a role in lung health. This may be the case for pathogens as well as commensal bacteria and the balance between species. The oral bacterial community of patients with periodontitis is dominated by gram-negative bacteria and a higher lipopolysaccharide (LPS) activity than in healthy microbiota. Furthermore, bacteria with especially potent pro-inflammatory LPS have been shown to be more common in the lungs of asthmatic than in healthy individuals. The working hypothesis of BRuSH is that microbiome communities dominated by LPS-producing bacteria which induce a particularly strong pro-inflammatory immune response in the host, will have a negative effect on respiratory health. I will test this hypothesis in two longitudinally designed population-based lung health studies. I aim to identify whether specific bacterial composition and types of LPS producing bacteria in oral and dust samples predict lung function and respiratory health over time; and if the different types of LPS-producing bacteria affect LPS in saliva saliva and dust. BRuSH will apply functional genome annotation that can assign biological significance to raw bacterial DNA sequences. With this bioinformatics tool I will cluster microbiome data into various LPS-producers: bacteria with LPS with strong inflammatory effects and others with weak- or antagonistic effects. The epidemiological studies will be supported by mice-models of asthma and cell assays of human bronchial epithelial cells, by exposing mice and bronchial cells to chemically synthesized Lipid A (the component that drive the LPS-induced immune responses) of various potency. The goal of BRuSH is to prove a causal relationship between oral microbiome and lung health, and gain knowledge that will enable us to make oral health a feasible target for intervention programs aimed at optimizing lung health and preventing respiratory disease.

1 499 938 €

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

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

The Earth's climate system contains a highly complex interplay of numerous components, such as atmospheric greenhouse gases, ice sheets, and ocean circulation. Due to nonlinearities and feedbacks, changes to the system can result in rapid transitions to radically different climate states. In light of rising greenhouse gas levels there is an urgent need to better understand climate at such tipping points. Reconstructions of profound climate changes in the past provide crucial insight into our climate system and help to predict future changes. However, all proxies we use to reconstruct past climate depend on assumptions that are in addition increasingly uncertain back in time. A new kind of temperature proxy, the carbonate ‘clumped isotope’ thermometer, has great potential to overcome these obstacles. The proxy relies on thermodynamic principles, taking advantage of the temperature-dependence of the binding strength between different isotopes of carbon and oxygen, which makes it independent of other variables. Yet, widespread application of this technique in paleoceanography is currently prevented by the required large sample amounts, which are difficult to obtain from ocean sediments. If applied to the minute carbonate shells preserved in the sediments, this proxy would allow robust reconstructions of past temperatures in the surface and deep ocean, as well as global ice volume, far back in time. Here I propose to considerably decrease sample amount requirements of clumped isotope thermometry, building on recent successful modifications of the method and ideas for further analytical improvements. This will enable my group and me to thoroughly ground-truth the proxy for application in paleoceanography and for the first time apply it to aspects of past climate change across major climate transitions in the past, where clumped isotope thermometry can immediately contribute to solving long-standing first-order questions and allow for major progress in the field.

1 877 209 €

Start date: 2015-08-01, End date: 2020-07-31

Climate change may be undermining the stock of seasonal representations that society draws on to understand and live according to the weather. The CALENDARS project studies how modern society represents seasons, and how these representations shape institutions and help people live with seasonal change. The project opens an important emerging field in climate adaptation research by examining the representations of ‘normal’ seasons underlying key institutions, assesses their quality for successful adaptation to rapid climate change, and analyses facilitators and barriers to adopting representations more flexibly to new climates. It contributes a novel perspective on how to transform our institutions – from schools to farmer cooperatives – from the foundational culture and representations up, to better fit the changing seasonal cycles we are experiencing. CALENDARS empirically explores the relationship between different institutions’ ideas of seasons and their successful adaptation through an in-depth comparative study of a set of institutions in two local communities, in Norway and New Zealand. It is steered by an overall objective to: ‘Advance knowledge and understanding of how seasonal representations shape and are shaped by institutions, and critically appraise the quality of these representations for contributing to successful adaptation to seasonal change’. Conceptually, CALENDARS looks at representations as continuously ‘co-produced’ at the boundary of nature and society, and society and institutions. It tests a novel reconceptualisation of co-production as a prism; with each of the project’s three phases looking at the complex processes by which representations emerge through different ‘lenses’ of co-production. Methodologically, the project tests the feasibility of a novel basket of bespoke methods spanning narrative interviews, calendar boundary objects and collaborative sustainability science.

1 489 426 €

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

The change from reproduction by outbreeding to selfing is one of the most frequent evolutionary transitions in plants. This transition is generally accompanied by changes in flower morphology and function, termed the selfing syndrome, including a reduction in flower size and a more closed flower structure. While the loss of self-incompatibility is relatively well understood, little is known about the molecular basis of the associated morphological changes and their evolutionary history. We will address these problems using the species pair Capsella grandiflora (the ancestral outbreeder) and C. rubella (the derived selfing species) as a genetically tractable model. We have established recombinant inbred lines from a cross of C. grandiflora x C. rubella and mapped quantitative trait loci affecting flower size and flower opening. Using this resource, the proposal will address four objectives. (1) We will isolate causal genes underlying the variation in flower size and opening, by combining genetic mapping with next-generation sequencing. (2) We will characterize the developmental and molecular functions of the isolated genes in Capsella and Arabidopsis. (3) We will dissect the molecular basis of the different allelic effects of the causal genes to determine which kinds of mutations have led to the morphological changes. (4) Based on population-genetic analyses of the isolated genes, the evolutionary history of the morphological changes will be retraced. Together, these strands of investigation will provide a detailed understanding of general processes underlying morphological evolution in plants.

1 480 826 €

Start date: 2010-12-01, End date: 2016-11-30

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

The impressive progress in synthetic organic chemistry during the past century has propelled this discipline to its current central place as the key enabling technology in the physical and life sciences. Despite these remarkable advances, our ability to construct molecules of even moderate structural complexity remains unsatisfactory, since these syntheses continue to be inefficient, rely on a high number of reaction steps, and generate undesired, often toxic waste. These features led to the general need for greener transformations that will stimulate the development of more sustainable chemical industries. Conventional approaches in synthetic organic chemistry make use of starting materials displaying specific functional groups, the installation of which results in costly reaction and purification steps. Therefore, an environmentally-sound and economically-attractive alternative is represented by the direct functionalization of ubiquitous carbon-hydrogen (C–H) bonds. These transition-metal-catalyzed processes avoid prefunctionalization strategies, prevent the formation of undesired waste, and thus enable an overall streamlining of organic synthesis. While considerable recent progress has been accomplished in C–H bond functionalizations, available methodologies continue to be limited in scope, and key challenges are still to be overcome. Establishing a full set of sustainable C–H bond functionalization protocols will undeniably have a tremendous impact on various applied areas, such as drug discovery, chemical industries or material sciences.

1 499 338 €

Start date: 2012-10-01, End date: 2017-09-30