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

Darwin’s theory of natural selection rests on the principle that fitness variation in natural populations has a heritable component, on which selection acts, thereby leading to evolutionary change. A fundamental and so far unresolved question for the field of evolutionary biology is to identify the genetic loci responsible for this fitness variation, thereby coming closer to an understanding of how variation is maintained in the face of continual selection. One important complicating factor in the search for fitness related genes however is the existence of separate sexes – theoretical expectations and empirical data both suggest that sexually antagonistic genes are common. The phrase “two sexes, one genome” nicely sums up the problem; selection may favour alleles in one sex, even if they have detrimental effects on the fitness of the opposite sex, since it is their net effect across both sexes that determine the likelihood that alleles persist in a population. This theoretical framework raises an interesting, and so far entirely unexplored issue: that in one sex the functional performance of some alleles is predicted to be compromised and this effect may account for some common human diseases and conditions which show genotype-sex interactions. I propose to explore the genetic basis of sex-specific fitness in a model organism in both laboratory and natural conditions and to test whether those genes identified as having sexually antagonistic effects can help explain the incidence of human diseases that display sexual dimorphism in prevalence, age of onset or severity. This multidisciplinary project directly addresses some fundamental unresolved questions in evolutionary biology: the genetic basis and maintenance of fitness variation; the evolution of sexual dimorphism; and aims to provide novel insights into the genetic basis of some common human diseases.

1 500 000 €

Start date: 2012-01-01, End date: 2016-12-31

Optical, electron and probe microscopes are enabling tools for discoveries and knowledge generation in nanoscale sicence and technology. High resolution –nanoscale or molecular-, noninvasive and label-free imaging of three-dimensional soft matter-liquid interfaces has not been achieved by any microscopy method. Force microscopy (AFM) is considered the second most relevant advance in materials science since 1960. Despite its impressive range of applications, the technique has some key limitations. Force microscopy has not three dimensional depth. What lies above or in the subsurface is not readily characterized. 3DNanoMech proposes to design, build and operate a high speed force-based method for the three-dimensional characterization soft matter-liquid interfaces (3D AFM). The microscope will combine a detection method based on force perturbations, adaptive algorithms, high speed piezo actuators and quantitative-oriented multifrequency approaches. The development of the microscope cannot be separated from its applications: imaging the error-free DNA repair and to understand the relationship existing between the nanomechanical properties and the malignancy of cancer cells. Those problems encompass the different spatial –molecular-nano-mesoscopic- and time –milli to seconds- scales of the instrument. In short, 3DNanoMech aims to image, map and measure with picoNewton, millisecond and angstrom resolution soft matter surfaces and interfaces in liquid. The long-term vision of 3DNanoMech is to replace models or computer animations of bimolecular-liquid interfaces by real time, molecular resolution maps of properties and processes.

2 499 928 €

Start date: 2014-02-01, End date: 2019-01-31

Crucial processes within cells depend on specific non-covalent interactions which mediate the assembly of proteins and other biomolecules. Deriving structural information to understand the function of these complex systems is the primary goal of Structural Biology. In this application, the recently developed LILBID method (Laser Induced Liquid Bead Ion Desorption) will be optimized for investigation of macromolecular complexes with a mass accuracy two orders of magnitude better than in 1st generation spectrometers. Controlled disassembly of the multiprotein complexes in the mass spectrometric analysis while keeping the 3D structure intact, will allow for the determination of complex stoichiometry and connectivity of the constituting proteins. Methods for such controlled disassembly will be developed in two separate units of the proposed LILBID spectrometer, in a collision chamber and in a laser dissociation chamber, enabling gas phase dissociation of protein complexes and removal of excess water/buffer molecules. As a third unit, a chamber allowing determination of ion mobility (IM) will be integrated to determine collisional cross sections (CCS). From CCS, unique information regarding the spatial arrangement of proteins in complexes or subcomplexes will then be obtainable from LILBID. The proposed design of the new spectrometer will offer fundamentally new possibilities for the investigation of non-covalent RNA, soluble and membrane protein complexes, as well as broadening the applicability of non-covalent MS towards supercomplexes.

1 264 477 €

Start date: 2014-02-01, End date: 2019-01-31

Quantum chemistry provides two approaches to molecular electronic-structure calculations: the systematically refinable but expensive many-body wave-function methods and the inexpensive but not systematically refinable Kohn Sham method of density-functional theory (DFT). The accuracy of Kohn Sham calculations is determined by the quality of the exchange correlation functional, from which the effects of exchange and correlation among the electrons are extracted using the density rather than the wave function. However, the exact exchange correlation functional is unknown—instead, many approximate forms have been developed, by fitting to experimental data or by satisfying exact relations. Here, a new approach to density-functional analysis and construction is proposed: the Lieb variation principle, usually regarded as conceptually important but impracticable. By invoking the Lieb principle, it becomes possible to approach the development of approximate functionals in a novel manner, being directly guided by the behaviour of exact functional, accurately calculated for a wide variety of chemical systems. In particular, this principle will be used to calculate ab-initio adiabatic connection curves, studying the exchange correlation functional for a fixed density as the electronic interactions are turned on from zero to one. Pilot calculations have indicated the feasibility of this approach in simple cases—here, a comprehensive set of adiabatic-connection curves will be generated and utilized for calibration, construction, and analysis of density functionals, the objective being to produce improved functionals for Kohn Sham calculations by modelling or fitting such curves. The ABACUS approach will be particularly important in cases where little experimental information is available—for example, for understanding and modelling the behaviour of the exchange correlation functional in electromagnetic fields.

2 017 932 €

Start date: 2011-03-01, End date: 2016-02-29

The deep-sea floor hosts a distinct microbial biome covering 67% of the Earth’s surface, characterized by cold temperatures, permanent darkness, high pressure and food limitation. The surface sediments are dominated by bacteria, with on average a billion cells per ml. Benthic bacteria are highly relevant to the Earth’s element cycles as they remineralize most of the organic matter sinking from the productive surface ocean, and return nutrients, thereby promoting ocean primary production. What passes the bacterial filter is a relevant sink for carbon on geological time scales, influencing global oxygen and carbon budgets, and fueling the deep subsurface biosphere. Despite the relevance of deep-sea sediment bacteria to climate, geochemical cycles and ecology of the seafloor, their genetic and functional diversity, niche differentiation and biological interactions remain unknown. Our preliminary work in a global survey of deep-sea sediments enables us now to target specific genes for the quantification of abyssal bacteria. We can trace isotope-labeled elements into communities and single cells, and analyze the molecular alteration of organic matter during microbial degradation, all in context with environmental dynamics recorded at the only long-term deep-sea ecosystem observatory in the Arctic that we maintain. I propose to bridge biogeochemistry, ecology, microbiology and marine biology to develop a systematic understanding of abyssal sediment bacterial community distribution, diversity, function and interactions, by combining in situ flux studies and different visualization techniques with a wide range of molecular tools. Substantial progress is expected in understanding I) identity and function of the dominant types of indigenous benthic bacteria, II) dynamics in bacterial activity and diversity caused by variations in particle flux, III) interactions with different types and ages of organic matter, and other biological factors.

3 375 693 €

Start date: 2012-06-01, End date: 2018-05-31

What processes shape vertebrate diversity through deep time? Approaches to this question can focus on many different factors, from life history and ecology to large-scale environmental change and extinction. To date, the majority of studies on the evolution of vertebrate diversity have focused on relatively simple metrics, specifically taxon counts or univariate measures, such as body size. However, multivariate morphological data provides a more complete picture of evolutionary and palaeoecological change. Morphological data can also bridge deep-time palaeobiological analyses with studies of the genetic and developmental factors that shape variation and must also influence large-scale patterns of evolutionary change. Thus, accurately reconstructing the patterns and processes underlying evolution requires an approach that can fully represent an organism’s phenome, the sum total of their observable traits. Recent advances in imaging and data analysis allow large-scale study of phenomic evolution. In this project, I propose to quantitatively analyse the deep-time evolutionary diversity of tetrapods (amphibians, reptiles, birds, and mammals). Specifically, I will apply and extend new imaging, morphometric, and analytical tools to construct a multivariate phenomic dataset for living and extinct tetrapods from 3-D scans. I will use these data to rigorously compare extinction selectivity, timing, pace, and shape of adaptive radiations, and ecomorphological response to large-scale climatic shifts across all tetrapod clades. To do so, I will quantify morphological diversity (disparity) and rates of evolution spanning over 300 million years of tetrapod history. I will further analyse the evolution of phenotypic integration by quantifying not just the traits themselves, but changes in the relationships among traits, which reflect the genetic, developmental, and functional interactions that shape variation, the raw material for natural selection.

1 482 818 €

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

The goal of this project is to demonstrate that novel aspects of the molecular basis of Darwinian adaptation can be discovered if the polygenic basis of adaptation is taken into account. This project will use the genome-wide distribution of cis-regulatory variants to discover the molecular pathways that are optimized during adaptation via accumulation of small effect mutations. Current approaches include scans for outlier genes with strong population genetics signatures of selection, or large effect QTL associating with fitness. They can only reveal a small subset of the molecular changes recruited along adaptive paths. Here, instead, the distribution of small effect mutations will be used to make inferences on the targets of polygenic adaptation across divergent populations in each of the two closely related species, A. thaliana and A. lyrata. These species are both found at diverse latitudes and show sign of local adaptation to climatic differences. Mutations affecting cis-regulation will be identified in leaves of plants exposed to various temperature regimes triggering phenotypic responses of adaptive relevance. Their distribution in clusters of functionally connected genes will be quantified. The phylogeographic differences in the distribution of the mutations will be used to disentangle neutral from adaptive clusters of functionally connected genes in each of the two species. This project will identify the molecular pathways subjected collectively to natural selection and provide a completely novel view on adaptive landscapes. It will further examine whether local adaptation occurs by convergent evolution of molecular systems in plants. This approach has the potential to find broad applications in ecology and agriculture.

1 683 120 €

Start date: 2015-09-01, End date: 2020-08-31

Sex differences in life span and aging are ubiquitous across the animal kingdom and represent a long-standing challenge in evolutionary biology. In most species, including humans, sexes differ not only in how long they live and when they start to senesce, but also in how they react to environmental interventions aimed at prolonging their life span or decelerating the onset of aging. Therefore, sex differences in life span and aging have important implications beyond the questions posed by fundamental science. Both evolutionary reasons and medical implications of sex differences in demographic, reproductive and physiological senescence are and will be crucial targets of present and future research in the biology of aging. Here I propose a two-step approach that can provide a significant breakthrough in our understanding of the biological basis of sex differences in aging. First, I propose to resolve the age-old conundrum regarding the role of sexspecific mortality rate in sex differences in aging by developing a series of targeted experimental evolution studies in a novel model organism – the nematode, Caenorhabditis remanei. Second, I address the role of intra-locus sexual conflict in the evolution of aging by combining novel methodology from nutritional ecology – the Geometric Framework – with artificial selection approach using the cricket Teleogryllus commodus and the fruitfly Drosophila melanogaster. I will directly test the hypothesis that intra-locus sexual conflict mediates aging by restricting the adaptive evolution of diet choice. By combining techniques from evolutionary biology and nutritional ecology, this proposal will raise EU’s profile in integrative research, and contribute to the training of young scientists in this rapidly developing field.

1 391 904 €

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

Mitochondria are often referred to as the “power houses” of eukaryotic cells. All eukaryotes were thought to have mitochondria of some form until 2016, when the first eukaryote thriving without mitochondria was discovered by our laboratory – a flagellate Monocercomonoides. Understanding cellular functions of these cells, which represent a new functional type of eukaryotes, and understanding the circumstances of the unique event of mitochondrial loss are motivations for this proposal. The first objective focuses on the cell physiology. We will perform a metabolomic study revealing major metabolic pathways and concentrate further on elucidating its unique system of iron-sulphur cluster assembly. In the second objective, we will investigate in details the unique case of mitochondrial loss. We will examine two additional potentially amitochondriate lineages by means of genomics and transcriptomics, conduct experiments simulating the moments of mitochondrial loss and try to induce the mitochondrial loss in vitro by knocking out or down genes for mitochondrial biogenesis. We have chosen Giardia intestinalis and Entamoeba histolytica as models for the latter experiments, because their mitochondria are already reduced to minimalistic “mitosomes” and because some genetic tools are already available for them. Successful mitochondrial knock-outs would enable us to study mitochondrial loss in ‘real time’ and in vivo. In the third objective, we will focus on transforming Monocercomonoides into a tractable laboratory model by developing methods of axenic cultivation and genetic manipulation. This will open new possibilities in the studies of this organism and create a cell culture representing an amitochondriate model for cell biological studies enabling the dissection of mitochondrial effects from those of other compartments. The team is composed of the laboratory of PI and eight invited experts and we hope it has the ability to address these challenging questions.

1 935 500 €

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

Molecular structure elucidation is of great importance in synthetic chemistry, pharmacy, life sciences, energy and environmental sciences, and technology applications. To date structure elucidation by atomic force microscopy (AFM) has been demonstrated for a few, small and mainly planar molecules. In this project high-risk, high-impact scientific questions will be solved using structure elucidation with the AFM employing a novel tool and novel methodologies. A combined low-temperature scanning tunneling microscope/atomic force microscope (LT-STM/AFM) with high throughput and in situ electrospray deposition method will be developed. Chemical resolution will be achieved by novel measurement techniques, in particular the usage of different and novel tip functionalizations and combination with Kelvin probe force microscopy. Elements will be identified using substructure recognition provided by a database that will be erected and by refined theory and simulations. The developed tools and techniques will be applied to molecules of increasing fragility, complexity, size, and three-dimensionality. In particular samples that are challenging to characterize with conventional methods will be studied. Complex molecular mixtures will be investigated molecule-by-molecule taking advantage of the single-molecule sensitivity. The absolute stereochemistry of molecules will be determined, resolving molecules with multiple stereocenters. The operation of single molecular machines as nanocars and molecular gears will be investigated. Reactive intermediates generated with atomic manipulation will be characterized and their on-surface reactivity will be studied by AFM.

2 000 000 €

Start date: 2016-06-01, End date: 2021-05-31

Our ability to predict adaptation and the response of populations to selection is limited. Solving this issue is a fundamental challenge of evolutionary ecology with implications for applied sciences such as conservation, and agronomy. Non genetic inheritance (NGI; e.g., ecological niche transmission) is suspected to play a foremost role in adaptive evolution but such hypothesis remains untested. Using quantitative genetics in wild plant populations, experimental evolution, and epigenetics, we will assess the role of NGI in the adaptive response to selection of plant populations. The ANGI project will follow the subsequent research program: (1) Using long-term survey data, we will measure natural selection in wild populations of Antirrhinum majus within its heterogeneous array of micro-habitats. We will calculate the fitness gain provided by multiple traits and stem elongation to plants growing in bushes where they compete for light. Stem elongation is known to depend on epigenetic variation. (2) Using a statistical approach that we developed, we will estimate the quantitative genetic and non genetic heritability of traits. (3) We will identify phenotypic changes caused by fitness that are based on genetic variation and NGI and assess their respective roles in adaptive evolution. (4) In controlled conditions, we will artificially select for increased stem elongation in clonal lineages, thereby excluding DNA variation. We will quantify the non genetic response to selection and test for a quantitative epigenetic signature of selection. (5) We will build on our results to generate an inclusive theory of genetic and non genetic natural selection. ANGI builds on a confirmed expertise in selection experiments, quantitative genetics and NGI. In addition, the availability of survey data provides a solid foundation for the achievement of this project. Our ambition is to shed light on original mechanisms underlying adaptation that are an alternative to genetic selection.

1 999 970 €

Start date: 2016-03-01, End date: 2021-02-28

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

1 562 000 €

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

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

2 000 000 €

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

Here we propose a first step toward a direct reconstruction of the evolutionary history of human infectious disease agents by obtaining genome wide data of historic pathogens. Through an extensive screening of skeletal collections from well-characterized catastrophe, or emergency, mass burials we plan to detect and sequence pathogen DNA from various historic pandemics spanning at least 2,500 years using a general purpose molecular capture method that will screen for hundreds of pathogens in a single assay. Subsequent experiments will attempt to reconstruct full genomes from all pathogenic species identified. The molecular fossil record of human pathogens will provide insights into host adaptation and evolutionary rates of infectious disease. In addition, human genomic regions relating to disease susceptibility and immunity will be characterized in the skeletal material in order to observe the direct effect that pathogens have made on the genetic makeup of human populations over time. The results of this project will allow a multidisciplinary interpretation of historical pandemics that have influenced the course of human history. It will provide priceless information for the field of history, evolutionary biology, anthropology as well as medicine and will have direct consequences on how we manage emerging and re-emerging infectious disease in the future.

1 474 560 €

Start date: 2013-01-01, End date: 2017-12-31

Arboviruses infect millions of people each year, however, mechanisms that drive viral emergence and maintenance remain largely unknown. A combination of host factors (e.g., human mobility), mosquito factors (e.g., abundance) and viral factors (e.g., transmissibility) interconnect to drive spread. Further, for endemic arboviruses, complex patterns of population immunity, built up over many years, appear key to the emergence of particular lineages. To disentangle the contribution of these different drivers, we need detailed data from the same pathogen system over a long time period from the same location. In addition, we need new methods, which can integrate these different data sources and allow appropriate mechanistic inferences. In this project, I will use the most globally prevalent arbovirus, dengue virus, as a case study. I will focus on Thailand where all four dengue serotypes have circulated endemically for decades and excellent long-term data and isolates exist, to address two fundamental questions: i) How do population-level patterns of immunity evolve over time and what is their impact on strain dynamics? I will use mechanistic models applied to historic serotype-specific case data to reconstruct the evolving immune profile of the population and explore the impact of immunity on viral diversity using sequences from archived isolates from each year over a 50-year period. ii) How do human behaviors, vector densities interact with immunity to dictate spread? I will work with geolocated full genome sequences from across Thailand and use detailed data on how people move, their contact patterns, their immunity profiles and mosquito distributions to study competing hypotheses of how arboviruses spread. I will compare the key drivers of dengue spread with that found for outbreaks of Zika and chikungunya. This proposal addresses fundamental questions about the mechanisms that drive arboviral emergence and spread that will be relevant across disease systems.

1 499 896 €

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

With the advent of new sequencing technologies, population geneticists now have access to more data than ever before. We have access to thousands of human genomes from a diverse set of populations around the globe, and, thanks to advances in DNA extraction and library preparation, we now are beginning to have access to ancient DNA sequence data. These data have greatly improved our knowledge of human history, human adaptation to different environments and human disease. Genome-wide studies have highlighted many genes or genomic loci that may play a role in adaptive or disease related phenotypes of biological importance. With these collections of modern and ancient sequence data we want to answer a key evolutionary question: how do human adaptations arise? We strongly believe that the state-of-the-art methodologies for uncovering signatures of adaptation are blind to potential modes of adaptation because they are lacking two critical components – more complete integration of multiple population haplotype data (including archaic, ancient and modern samples), and an account of population interactions that facilitate adaptation. Therefore I plan to develop new methods to detect shared selective events across populations by creating novel statistical summaries, and to detect admixture-facilitated adaptation which we believe is likely a common mode of natural selection. We will apply these tools to new datasets to characterize the interplay of natural selection, archaic and modern admixture in populations in the Americas and make a comparative analysis of modern and ancient European samples to understand the origin and changing profile of adaptive archaic alleles. As a result our work will reveal evolutionary processes that have played an important role in human evolution and disease.

1 500 000 €

Start date: 2020-01-01, End date: 2024-12-31

The objective of the present scientific proposal is the implementation of a novel approach in selective and asymmetric heterogeneous catalysis. We aim to exploit the structure and chirality of small, supported metal and bimetal clusters for triggering selective and enantioselective reactions. Our Ansatz is beyond doubt of fundamental nature. Although chemistry and in particular catalysis evolved on a largely empirical basis in the past, we strongly believe the complexity of the challenges at hand to make this a less ideal approach. In consequence, developing selective and asymmetric cluster catalysis will be based on a detailed molecular understanding and will not only require intense methodological developments for the synthesis and characterization of asymmetric catalysts and the detection of chiral and isomeric product molecules but also make use of innovative basic science in the fields of surface chemistry, cluster science, spectroscopy and kinetics. As complex as the involved challenges are, we aim at mastering the following ground-breaking steps: (a) development of cutting-edge spectroscopic methodologies for the isomer and enantiomer sensitive in situ detection of product molecules. (b) preparation and characterization of isomer- and enantioselective heterogeneous catalysts based on chiral metal clusters or molecule-cluster-complexes. (c) investigations of the selectivity and enantioselectivity of cluster based heterogeneous catalysts and formulation of concepts for understanding the observed selective and asymmetric chemistry. Besides the importance of the science carried out within this proposal, the proposed experimental methodology will also open up opportunities in other fields of chemistry like catalysis, analytical chemistry, spectroscopy, surface science, and nanomaterials.

2 301 600 €

Start date: 2010-04-01, End date: 2015-03-31

A technological revolution is currently taking place making it possible to noninvasively study metabolism in mammals (incl. humans) in vivo with unprecedented temporal and spatial resolution. Central to these developments is the phenomenon of hyperpolarization, which transiently enhances the magnetic resonance (MR) signals so much that real-time metabolic imaging and spectroscopy becomes possible. The first clinical translation of hyperpolarization MR technology has recently been demonstrated with prostate cancer patients. I have played an active role in these exciting developments, through design and construction of hyperpolarization MR setups that are defining the cutting-edge for in vivo preclinical metabolic studies. However, important obstacles still exist for the technology to fulfill its enormous potential. With this highly interdisciplinary proposal, I will overcome the principal drawbacks of current hyperpolarization technology, namely: 1) A limited time window for hyperpolarized MR detection; 2) The conventional use of potentially toxic polarizing agents; 3) The necessity to use supra-physiological doses of metabolic substrates to reach detectable MR signal I will develop a novel hyperpolarization instrument making use of photoexcited compounds as polarizing agents to produce hyperpolarized solutions containing exclusively endogenous compounds. It will become possible to deliver hyperpolarized solutions in a quasi-continuous manner, permitting infusion of physiological doses and greatly increasing sensitivity. I will also use a complementary isotope imaging technique, the so-called CryoNanoSIMS (developed at my institution over the last year), which can image isotopic distributions in frozen tissue sections and reveal the localization of injected substrates and their metabolites with subcellular spatial resolution. Case studies will include liver and brain cancer mouse models. This work is pioneering and will create a new frontier in molecular imaging.

2 199 146 €

Start date: 2016-09-01, End date: 2021-08-31

The goal of ATOMICAR is to achieve the ultimate sensitivity limit in heterogeneous catalysis: Quantitative measurement of chemical turnover on a single catalytic nanoparticle. Most heterogeneous catalysis occurs on metal nanoparticle in the size range of 3 nm - 10 nm. Model studies have established that there is often a strong coupling between nanoparticle size & shape - and catalytic activity. The strong structure-activity coupling renders it probable that “super-active” nanoparticles exist. However, since there is no way to measure catalytic activity of less than ca 1 million nanoparticles at a time, any super-activity will always be hidden by “ensemble smearing” since one million nanoparticles of exactly identical size and shape cannot be made. The state-of-the-art in catalysis benchmarking is microfabricated flow reactors with mass-spectrometric detection, but the sensitivity of this approach cannot be incrementally improved by six orders of magnitude. This calls for a new measurement paradigm where the activity of a single nanoparticle can be benchmarked – the ultimate limit for catalytic measurement. A tiny batch reactor is the solution, but there are three key problems: How to seal it; how to track catalytic turnover inside it; and how to see the nanoparticle inside it? Graphene solves all three problems: A microfabricated cavity with a thin SixNy bottom window, a single catalytic nanoparticle inside, and a graphene seal forms a gas tight batch reactor since graphene has zero gas permeability. Catalysis is then tracked as an internal pressure change via the stress & deflection of the graphene seal. Crucially, the electron-transparency of graphene and SixNy enables subsequent transmission electron microscope access with atomic resolution so that active nanoparticles can be studied in full detail. ATOMICAR will re-define the experimental limits of catalyst benchmarking and lift the field of basic catalysis research into the single-nanoparticle age.

1 496 000 €

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

"The goal of the present proposal is to realize measurements of electronic dynamics in polyatomic molecules with attosecond temporal resolution (1 as = 10^-18s). We propose to study electronic rearrangements following photoexcitation, charge migration in a molecular chain induced by ionization and non-adiabatic multi-electron dynamics in an intense laser field. The grand question addressed by this research is the characterization of electron correlations which control the shape, properties and function of molecules. In all three proposed projects, a time-domain approach appears to be the most suitable since it reduces complex molecular dynamics to the purely electronic dynamics by exploiting the hierarchy of motional time scales. Experimentally, we propose to realize an innovative experimental setup. A few-cycle infrared (IR) pulse will be used to generate attosecond pulses in the extreme-ultraviolet (XUV) by high-harmonic generation. The IR pulse will be separated from the XUV by means of an innovative interferometer. Additionally, it will permit the introduction of a controlled attosecond delay between the two pulses. We propose to use the attosecond pulses as a tool to look inside individual IR- or UV-field cycles to better understand light-matter interactions. Time-resolved pump-probe experiments will be carried out on polyatomic molecules by detecting the energy and angular distribution of photoelectrons in a velocity-map imaging spectrometer. These experiments are expected to provide new insights into the dynamics of multi-electron systems along with new results for the validation and improvement of theoretical models. Multi-electron dynamics is indeed a very complex subject on its own and even more so in the presence of strong laser fields. The proposed experiments directly address theses challenges and are expected to provide new insights that will be beneficial to a wide range of scientific research areas."

1 999 992 €

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

Why is the world green? Because predators control herbivores, allowing plants to flourish. This >50 years old answer to the deceptively simple question remains controversial. After all, plants are also protected from herbivores physically and by secondary chemistry. My goal is to test novel aspects of the “green world hypothesis”: ● How the importance of top-down effects varies with forest diversity and productivity along a latitudinal gradient? ● How the key predators, birds, bats and ants, contribute to top-down effects individually and in synergy? I strive to understand this because: ● While there is evidence that predators reduce herbivore abundance and enhance plant growth, the importance of top-down control is poorly understood across a range of forests. ● The importance of key predatory groups, and their antagonistic and synergic interactions, have been rarely studied, despite their potential impact on ecosystem dynamics in changing world. I wish to achieve my goals by: ● Factorial manipulations of key insectivorous predators (birds, bats, ants) to measure their effects on lower trophic levels in forest understories and canopies, accessed by canopy cranes, along latitudinal gradient spanning 75o from Australia to Japan. ● Studying compensatory effects among predatory taxa on herbivore and plant performance. Why this has not been done before: ● Factorial experimental exclusion of predatory groups replicated on a large spatial scale is logistically difficult. ● Canopy crane network along a latitudinal gradient has only recently become available. I am in excellent position to succeed as I have experience with ● foodweb experiments along an elevation gradient in New Guinea rainforests, ● study of bird, bat and arthropod communities. If the project is successful, it will: ● Allow understanding the importance of predators from temperate to tropical forests. ● Establish a network of experimental sites along a network of canopy cranes open for follow-up research.

1 455 032 €

Start date: 2018-12-01, End date: 2023-11-30

All levels of life entail cooperation and conflict. Genes cooperate to build up a functional genome, which can yet be undermined by selfish genetic elements. Humans and animals cooperate to build up societies, which can yet be subverted by cheats. There is a long-standing interest among biologists to comprehend the tug-of-war between cooperation and conflict. Recently, research on bacteria was successful in identifying key factors that can tip the balance in favour or against cooperation. Bacteria cooperate through the formation of protective biofilms, cell-to-cell communication, and the secretion of shareable public goods. However, the advantage of bacteria being fast replicating units, easily cultivatable in high numbers, is also their disadvantage: they are small and imperceptible, such that measures of cooperation typically rely on averaged responses across millions of cells. Thus, we still know very little about bacterial cooperation at the biological relevant scale: the individual cell level. Here, I present research using the secretion of public goods in the opportunistic human pathogen Pseudomonas aeruginosa, to tackle this issue. I will explore new dimensions of bacterial cooperation by asking whether bacteria engage in collective-decision making to find optimal group-level solutions; whether bacteria show division of labour to split up work efficiently; and whether bacteria can distinguish between trustworthy and cheating partners. The proposed research will make two significant contributions. First, it will reveal whether bacteria engage in complex forms of cooperation (collective decision-making, division of labour, partner recognition), which have traditionally been associated with higher organisms. Second, it will provide insights into the evolutionary stability of cooperation – key knowledge for designing therapies that interfere with virulence-inducing public goods in infections, and the design of stable public-good based remediation processes.

1 994 981 €

Start date: 2016-09-01, End date: 2021-08-31

Natural selection is supposed to keep lethal alleles (dysfunctional or deleted copies of crucial genes) in check. Yet, in a balanced lethal system the frequency of lethal alleles is inflated. Because two forms of a chromosome carry distinct lethal alleles that are reciprocally compensated for by functional genes on the alternate chromosome form, both chromosome forms – and in effect their linked lethal alleles – are required for survival. The inability of natural selection to purge balanced lethal systems appears to defy evolutionary theory. How do balanced lethal systems originate and persist in nature? I suspect the answer to this pressing but neglected research question can be found in the context of supergenes in a balanced polymorphism – a current, hot topic in evolutionary biology. Chromosome rearrangements can lock distinct beneficial sets of alleles (i.e. supergenes) on two chromosome forms by suppressing recombination. Now, balancing selection would favour possession of both supergenes. However, as a consequence of suppressed recombination, unique lethal alleles could become fixed on each supergene, with natural selection powerless to prevent collapse of the arrangement into a balanced lethal system. I aim to explain the evolution of balanced lethal systems in nature. As empirical example I will use chromosome 1 syndrome, a balanced lethal system observed in newts of the genus Triturus. My research team will: Reconstruct the genomic architecture of this balanced lethal system at its point of origin [PI project]; Conduct comparative genomics with related, unaffected species [PhD project]; Determine gene order of the two supergenes involved [Postdoc project I]; and Model the conditions under which this balanced lethal system could theoretically have evolved [Postdoc project II]. Solving the paradox of chromosome 1 syndrome will allow us to understand balanced lethal systems in general and address the challenges they pose to evolutionary theory.

1 499 869 €

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

Speciation is a central process in evolution that involves the origin of barriers to gene flow between populations. Species are typically isolated by several barriers and assembly of multiple barriers separating the same populations seems to be critical to the evolution of strong reproductive isolation. Barriers resulting from direct selection can become coincident through a process of coupling while reinforcement can add barrier traits that are not under direct selection. In the presence of gene flow, these processes are opposed by recombination. While recent research using the latest sequencing technologies has provided much increased knowledge of patterns of differentiation and the genetic basis of local adaptation, it has so far added little to understanding of the coupling and reinforcement processes. In this project, I will focus on the accumulation of barriers to gene exchange and the processes underlying increasing reproductive isolation. I will use the power of natural contact zones, combined with novel manipulative experiments, to separate the processes that underlie patterns of differentiation and introgression. The Littorina saxatilis model system allows me to do this with both local replication and a contrast between distinct spatial contexts on a larger geographic scale. I will use modelling to determine how processes interact and to investigate the conditions most likely to promote coupling and reinforcement. Overall, the project will provide major new insights into the speciation process, particularly revealing the requirements for progress towards complete reproductive isolation.

2 499 927 €

Start date: 2016-09-01, End date: 2021-08-31

The development of longer lasting, higher energy density and cheaper rechargeable batteries represents one of the major technological challenges of our society, batteries representing the limiting components in the shift from gasoline-powered to electric vehicles. They are also required to enable the use of more (typically intermittent) renewable energy, to balance demand with generation. This proposal seeks to develop and apply new NMR metrologies to determine the structure and dynamics of the multiple electrode-electrolyte interfaces and interphases that are present in these batteries, and how they evolve during battery cycling. New dynamic nuclear polarization (DNP) techniques will be exploited to extract structural information about the interface between the battery electrode and the passivating layers that grow on the electrode materials (the solid electrolyte interphase, SEI) and that are inherent to the stability of the batteries. The role of the SEI (and ceramic interfaces) in controlling lithium metal dendrite growth will be determined in liquid based and all solid state batteries. New DNP approaches will be developed that are compatible with the heterogeneous and reactive species that are present in conventional, all-solid state, Li-air and redox flow batteries. Method development will run in parallel with the use of DNP approaches to determine the structures of the various battery interfaces and interphases, testing the stability of conventional biradicals in these harsh oxidizing and reducing conditions, modifying the experimental approaches where appropriate. The final result will be a significantly improved understanding of the structures of these phases and how they evolve on cycling, coupled with strategies for designing improved SEI structures. The nature of the interface between a lithium metal dendrite and ceramic composite will be determined, providing much needed insight into how these (unwanted) dendrites grow in all solid state batteries. DNP approaches coupled with electron spin resonance will be use, where possible in situ, to determine the reaction mechanisms of organic molecules such as quinones in organic-based redox flow batteries in order to help prevent degradation of the electrochemically active species. This proposal involves NMR method development specifically designed to explore a variety of battery chemistries. Thus, this proposal is interdisciplinary, containing both a strong emphasis on materials characterization, electrochemistry and electronic structures of materials, interfaces and nanoparticles, and on analytical and physical chemistry. Some of the methodology will be applicable to other materials and systems including (for example) other electrochemical technologies such as fuel cells and solar fuels and the study of catalysts (to probe surface structure).

3 498 219 €

Start date: 2019-10-01, End date: 2024-09-30

During the course of eukaryote evolution, photosynthesis was propagated from primary eukaryotic algae to non-photosynthetic organisms through multiple secondary endosymbiotic events. Collectively referred to as “secondary algae”, these photosynthetic organisms account for only 1-2% of the total global biomass, but produce a far larger part of the global annual fixation of carbon on Earth. ATP is the universal chemical energy carrier in living cells. In photosynthetic eukaryotes, it is produced by two major cellular processes: photosynthesis and respiration taking place in chloroplasts and mitochondria, respectively. Both processes support the production of biomass and govern gas (O2 and CO2) exchanges. On the other hand, anaerobic fermentative enzymes have also been identified in several primary and secondary algae. The regulation modes and interactions of respiration, photosynthesis and fermentation are fairly well understood in primary green algae. Conversely, the complex evolutionary history of secondary algae implies a great variety of original regulatory mechanisms that have been barely investigated to date. Over the last years my laboratory has developed and optimized a range of multidisciplinary approaches that now allow us, within the frame of the BEAL (BioEnergetics in microALgae) project, to (i) characterize and compare the photosynthetic regulation modes by biophysical approaches, (ii) use genetic and biochemical approaches to gain fundamental knowledge on aerobic respiration and anaerobic fermentative pathways, and (iii) investigate and compare interconnections between respiration, photosynthesis, and fermentation in organisms resulting from distinct evolutionary scenarios. On a long term, these developments will be instrumental to unravel bioenergetics constraints on growth in microalgae, a required knowledge to exploit the microalgal diversity in a biotechnological perspective, and to understand the complexity of the marine phytoplankton.

1 837 625 €

Start date: 2016-06-01, End date: 2021-05-31

We propose focused theory developments and applications, which aim to substantially advance our ability to model and understand the behavior of molecules in complex environments. From a large repertoire of possible environments, we have chosen to concentrate on experimentally-relevant situations, including molecular fluctuations in electric and optical fields, disordered molecular crystals, solvated (bio)molecules, and molecular interactions at/through low-dimensional nanostructures. A challenging aspect of modeling such realistic environments is that both molecular electronic and nuclear fluctuations have to be treated efficiently at a robust quantum-mechanical level of theory for systems with 1000s of atoms. In contrast, the current state of the art in the modeling of complex molecular systems typically consists of Newtonian molecular dynamics employing classical force fields. We will develop radically new approaches for electronic and nuclear fluctuations that unify concepts and merge techniques from quantum-mechanical many-body Hamiltonians, statistical mechanics, density-functional theory, and machine learning. Our developments will be benchmarked using experimental measurements with terahertz (THz) spectroscopy, atomic-force and scanning tunneling microscopy (AFM/STM), time-of-flight (TOF) measurements, and molecular interferometry. Our final goal is to bridge the accuracy of quantum mechanics with the efficiency of force fields, enabling large-scale predictive quantum molecular dynamics simulations for complex systems containing 1000s of atoms, and leading to novel conceptual insights into quantum-mechanical fluctuations in large molecular systems. The project goes well beyond the presently possible applications and once successful will pave the road towards having a suite of first-principles-based modeling tools for a wide range of realistic materials, such as biomolecules, nanostructures, disordered solids, and organic/inorganic interfaces.

1 811 650 €

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

Biomimetic Organocatalysis – Development of Novel Synthetic Catalytic Methodology and Technology The objective of the proposed research is the design and development of unprecedented preassembled, modular, molecular factories. Inspiration comes from nature’s non-ribosomal peptide synthetases (NRPSs) and polyketide synthetases (PKSs). These large multifunctional enzymes possess catalytic modules with the capacity for recognition, activation and modification required for sequential biosynthesis of complex peptides and polyketides. Using nature as a role model we intend to design and prepare such catalyst “factories” synthetically and apply them in novel cascade reaction sequences. The single catalytic modules employed will be based on organocatalytic procedures, including enamine-, iminium-, as well as hydrogen bonding activation processes, but the potential scope is limitless. Organocatalysts have so far never been applied in a combined fashion utilizing their different activation mechanisms in multiple reaction cascades. Therefore, it is our intention to firstly demonstrate that such a production line approach is feasible and that these new catalyst systems can be applied in the synthesis of valuable enantiopure, biologically active, building blocks and natural products. Additionally, the extensive possibilities to vary organocatalyst modules in sequence will lead to science mimicking nature in its diversity.

999 960 €

Start date: 2008-09-01, End date: 2012-08-31

Many significant global challenges in catalysis for energy and sustainable chemistry have already been solved in nature. Metalloenzymes within microorganisms catalyse the transformation of carbon dioxide into simple carbon building blocks or fuels, the reduction of dinitrogen to ammonia under ambient conditions and the production and utilisation of dihydrogen. Catalytic sites for these reactions are necessarily based on metals that are abundant in the environment, including iron, nickel and molybdenum. However, attempts to generate biomimetic catalysts have largely failed to reproduce the high activity, stability and selectivity of enzymes. Proton and electron transfer and substrate binding are all finely choreographed, and we do not yet understand how this is achieved. This project develops a suite of new experimental infrared (IR) spectroscopy tools to probe and understand mechanisms of redox metalloenzymes in situ during electrochemically-controlled steady state turnover, and during electron-transfer-triggered transient studies. The ability of IR spectroscopy to report on the nature and strength of chemical bonds makes it ideally suited to follow the activation and transformation of small molecule reactants at metalloenzyme catalytic sites, binding of inhibitors, and protonation of specific sites. By extending to the far-IR, or introducing mid-IR-active probe amino acids, redox and structural changes in biological electron relay chains also become accessible. Taking as models the enzymes nitrogenase, hydrogenase, carbon monoxide dehydrogenase and formate dehydrogenase, the project sets out to establish a unified understanding of central concepts in small molecule activation in biology. It will reveal precise ways in which chemical events are coordinated inside complex multicentre metalloenzymes, propelling a new generation of bio-inspired catalysts and uncovering new chemistry of enzymes.

1 997 286 €

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

Increases in nutrient availability and temperature, and changes in precipitation patterns and biodiversity are important components of global environmental change. Thus, it is imperative to understand their impacts on the functioning of natural ecosystems. Substantial research efforts are being currently devoted to predict how biodiversity will respond to global change. However, little is known on the relative importance of biodiversity against other attributes of biotic communities, such as species cover and spatial pattern, as a driver of ecosystem processes. Furthermore, the effects of global change on the relationships between these attributes and ecosystem functioning are virtually unknown. This project aims to evaluate the relationships between community attributes (species richness, composition, evenness, cover, and spatial pattern) and key processes related to ecosystem functioning under different global change scenarios. Its specific objectives are to: i) evaluate the relative importance of community attributes as drivers of ecosystem functioning, ii) assess how multiple global change drivers will affect key ecosystem processes, iii) test whether global change drivers modify observed community attributes-ecosystem functioning relationships, iv) develop models to forecast global change effects on ecosystem functioning, and v) set up protocols for the establishment of mitigation actions based on the results obtained. They will be achieved by integrating experimental and modeling approaches conducted with multiple biotic communities at different spatial scales. Such integrated framework has not been tackled before, and constitutes a ground breaking advance over current research efforts on global change. This proposal will also open the door to new research lines exploring the functional role of community attributes and their importance as modulators of ecosystem responses to global change.

1 463 374 €

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

Heterogeneous biomolecular mechanisms at the surface of cellular membranes are often fundamental to generate function and dysfunction in living systems. These processes are governed by transient and dynamical macromolecular interactions that pose tremendous challenges to current analytical tools, as the majority of these methods perform best in the study of well-defined and poorly dynamical systems. This proposal aims at a radical innovation in the characterisation of complex processes that are dominated by structural order and disorder, including those occurring at the surface of biological membranes such as cellular signalling, the assembly of molecular machinery, or the regulation vesicular trafficking. I outline a programme to realise a vision where the combination of experiments and theory can delineate a new analytical platform to study complex biochemical mechanisms at a multiscale level, and to elucidate their role in physiological and pathological contexts. To achieve this ambitious goal, my research team will develop tools based on the combination of nuclear magnetic resonance (NMR) spectroscopy and molecular simulations, which will enable probing the structure, dynamics, thermodynamics and kinetics of complex protein-protein and protein-membrane interactions occurring at the surface of cellular membranes. The ability to advance both the experimental and theoretical sides, and their combination, is fundamental to define the next generation of methods to achieve our transformative aims. We will provide evidence of the innovative nature of the proposed multiscale approach by addressing some of the great questions in neuroscience and elucidate the details of how functional and aberrant biological complexity is achieved via the fine tuning between structural order and disorder at the neuronal synapse.

1 999 945 €

Start date: 2019-06-01, End date: 2024-05-31

The overall objective of the proposal is to develop enabling chemical technologies to address two important problems in biology: detect in a nondestructive fashion gene expression or microRNA sequences in vivo and, secondly, study the role of multivalency and spatial organization in carbohydrate recognition. Both of these projects exploit the programmable pre-organization of peptide nucleic acid (PNA) to induce a chemical reaction in the first case or modulate a ligand-receptor interaction in the second case. For nucleic acid detection, a DNA or RNA fragment will be utilized to bring two PNA fragments bearing reactive functionalities in close proximity thereby promoting a reaction. Two types of reactions are proposed, the first one to release a fluorophore for imaging purposes and the second one to release a drug as an “intelligent” therapeutic. If affinities are programmed such that hybridization is reversible, the template can work catalytically leading to large amplifications. As a proof of concept, this method will be used to measure the transcription level of genes implicated in stem cell differentiation and detect mutations in oncogenes. For the purpose of studying multivalent carbohydrate ligand architectures, the challenge of chemical synthesis has been a limiting factor. A supramolecular approach is proposed herein where different arrangements of carbohydrates can be displayed in a well organized fashion by hybridizing PNA-tagged carbohydrates to DNA templates. This will be used not only to control the distance between multiple ligands or to create combinatorial arrangements of hetero ligands but also to access more complex architectures such as Hollyday junctions. The oligosaccharide units will be prepared using de novo organoctalytic reactions. This technology will be first applied to probe the recognition events between HIV and dendritic cells which promote HIV infection.

1 249 980 €

Start date: 2008-07-01, End date: 2013-06-30

Recent intensive research on the laser spectroscopy of neutral gas-phase biomolecules has yielded a detailed picture of their structures and conformational preferences away from the complications of the bulk environment. In contrast, work on ionic systems has been sparse despite the fact that many important molecular groups are charged under physiological conditions. To address this probelm, we have developed a custom-built laser spectrometer, which incorporates a distincitive electrospray ionisation (ESI) cluster ion source, dedicated to producing biological anions (ATP,oligonucleotides) and their microsolvated clusters for structural characterization. Many previous laser spectrometers with ESI sources have suffered from producing "hot" congested spectra as the ions were produced at ambient temperatures. This is a particularly serious limitation for spectroscopic studies of biomolecules, since these systems can possess high internal energies due tothe presence of numerous low frequency modes. Our spectrometer overcomes this problem by exploiting the newly developed physics technique of "buffer gas cooling" to produce cold ESI molecular ions. In this proposal, we now seek to exploit the new laser-spectrometer to perform detailed spectroscopic interrogations of ESI generated biomolecular anions and clusters. In addition to traditional ion-dissociation spectroscopies, we propose to develop two new laser spectroscopy techniques (Two-color tuneable IR spectroscopy and Dipole-bound excited state spectroscopy) to give the broadest possible structural characterizations of the systems of interest. Studies will focus on ATP/GTP-anions, olignonucleotides, and sulphated and carboxylated sugars. These methodologies will provide a general approach for performing temperature-controlled spectroscopic characterizations of isolated biological ions, with measurements on the corresponding micro-solvated clusters providing details of how the molecules are perturbed by solvent.

1 250 000 €

Start date: 2008-10-01, End date: 2015-06-30

During the past decades the PI has helped shape the research field of computer simulation of biomolecular systems at the atomic level. He has carried out one of the first molecular dynamics (MD) simulations of proteins, and has since then contributed many different methodological improvements and developed one of the major atomic-level force fields for simulations of proteins, carbohydrates, nucleotides and lipids. Methodology and force field have been implemented in a set of programs called GROMOS (GROningen MOlecular Simulation package), which is currently used in hundreds of academic and industrial research groups from over 50 countries on all continents. It is proposed to develop a next generation of molecular models, force fields, multi-scaling simulation methodology and software for biomolecular simulations which is at least an order of magnitude more accurate in terms of energetics, and which is 1000 times more efficient through the use of coarse-grained molecular models than the currently available software and models.

1 320 000 €

Start date: 2008-11-01, End date: 2014-09-30

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

This project addresses a key issue in fundamental research - one that has challenged ecologists ever since Darwin s time that is why some species are common, and others rare, and why, despite marked turnover at the level of individual species abundances, the structure of a community is generally conserved through time. Its aim is to examine the temporal dynamics of species abundance distributions (SADs), and to assess the capacity of these distributions to withstand change (resistance) and to recover from change (resilience). These are topical and important questions given the increasing impact that humans are having on the natural world. There are three components to the research. First, we will model SADs and predict responses to a range of events including climate change and the arrival of invasive species. A range of modeling approaches (including neutral, niche and statistical) will be adopted; by incorporating temporal turnover in hitherto static models we will advance the field. Second, we will test predictions concerning the resistance and resilience of SADs by a comparative analysis of existing data sets (that encompass communities in terrestrial, freshwater and marine environments for ecosystems extending from the poles to the tropics) and through a new field experiment that quantifies temporal turnover across a community (unicellular organisms to vertebrates) in relation to factors both natural (dispersal limitation) and anthropogenic (human disturbance) thought to shape SADs. In the final part of the project we will apply these new insights into the temporal dynamics of SADs to two important conservation challenges. These are 1) the conservation of biodiversity in a heavily utilized European landscape (Fife, Scotland) and 2) the conservation of biodiversity in Mamirauá and Amaña reserves in Amazonian flooded forest. Taken together this research will not only shed new light on the structure of ecological communities but will also aid conservation.

1 812 782 €

Start date: 2010-08-01, End date: 2016-01-31

The standard variational principles (VPs) are cornerstones of quantum mechanics, and one can hardly overestimate their usefulness as tools for generating approximations to the time-independent and time-dependent Schröodinger equations. The aim of the proposal is to study and apply a generalization of these, the bivariational principles (BIVPs), which arise naturally when one does not assume a priori that the system Hamiltonian is Hermitian. This unconventional approach may have transformative impact on development of ab initio methodology, both for electronic structure and dynamics. The first objective is to establish the mathematical foundation for the BIVPs. This opens up a whole new axis of method development for ab initio approaches. For instance, it is a largely ignored fact that the popular traditional coupled cluster (TCC) method can be neatly formulated with the BIVPs, and TCC is both polynomially scaling with the number of electrons and size-consistent. No “variational” method enjoys these properties simultaneously, indeed this seems to be incompatible with the standard VPs. Armed with the BIVPs, the project aims to develop new and understand existing ab initio methods. The second objective is thus a systematic multireference coupled cluster theory (MRCC) based on the BIVPs. This is in itself a novel approach that carries large potential benefits and impact. The third and last objective is an implementation of a new coupled-cluster type method where the orbitals are bivariational parameters. This gives a size-consistent hierarchy of approximations to multiconfiguration Hartree--Fock. The PI's broad contact with and background in scientific disciplines such as applied mathematics and nuclear physics in addition to quantum chemistry increases the feasibility of the project.

1 499 572 €

Start date: 2015-04-01, End date: 2020-03-31

Early vertebrate evolution involved a series of drastic structural reorganisations as new features were added and elaborated. The fossil record illuminates this evolutionary history more directly than inferences from the diversity of living forms, but the fossils usually consist only of bones whereas many of the most important and interesting changes occurred in the soft anatomy. Traditional approaches to reconstructing the musculature and other soft tissues of fossil vertebrates rely on subjective tools, like the visual identification of rough bone textures thought to indicate muscle attachments, and generally leave a lot to be desired. Here I propose a wholly novel and radically more objective approach to the identification of soft-tissue contacts, using holotomographic synchrotron CT at sub-micron resolutions to identify these contacts by the three-dimensional micro-architecture of the bone. A pilot study has already shown that such scans (performed at the ESRF synchrotron facility in Grenoble) are capable of imaging key features such as arrested growth surfaces and probable Sharpey s fibres in 380 million year old fossils. We will undertake a systematic review of the three-dimensional bone micro-architectures associated with different soft-tissue contacts in living vertebrates, and the use this as a key to reconstruct the soft-tissue contacts on fossil bones with unprecedented accuracy. This will permit us to produce far more reliable reconstructions of the soft anatomy than has hitherto been possible. Our findings will inform other areas of palaentology, particularly functional morphology, and will also be of great importance to evolutionary developmental biology.

1 046 782 €

Start date: 2009-04-01, End date: 2014-03-31

Although various aspects of biomineralisation in corals have been studied for decades, the basic mechanism of precipitation of the aragonite skeleton remains enigmatic. Two parallel lines of inquiry have emerged: geochemist models of calcification that are directly related to seawater carbonate chemistry at thermodynamic equilibrium. Here, the role of the organisms in the precipitation reaction is largely ignored. The second line is based on biological considerations of the biomineralisation process, which focuses on models of biophysical processes far from thermodynamic equilibrium that concentrate calcium ions, anions and proteins responsible for nucleation in specific compartments. Recently, I identified and cloned a group of highly acidic proteins derived the common stony coral, Stylophora pistillata. All of the cloned proteins precipitate aragonite in seawater at pH 8.2 and 7.6 in-vitro. However, it is not at all clear if the expression of these proteins in-vivo is sufficient for the formation of an aragonite skeleton at seawater pH values below ~7.8. Here using a combination of molecular, biophysical, genomic, and cell biological approaches, we proposed to test the core hypothesis that, unless wounded or otherwise having skeletal material exposed directly to seawater, stony zooxanthellate corals will continue to calcify at pH values projected for the CO2 emissions scenarios for 2100. Specifically, the objectives of Ca2Coral are to: 1) Use functional genomics to identify the key genes and proteins involved both in the organic matrix and skeleton formation in the adult holobiont and during its larval development. 2) Use a genetics approach to elucidate the roles of specific proteins in the biomineralisation process. 3) Use ultra-high resolution imaging and spectroscopic analysis at different pH levels to elucidate the biomineralisation pathways and mineral precursor in corals in the adult holobiont and during its larval development.

1 499 741 €

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

Ultrafast laser methods will be employed to examine the dynamics of chemical and photochemical reactions in liquid solutions. By contrasting the solution phase dynamics with those observed for isolated collisions in the gas phase, the fundamental role of solvent on chemical pathways will be explored at a molecular level. The experimental studies will be complemented by computational simulations that explicitly include treatment of the effects of solvent on reaction energy pathways and reactant and product motions. The research addresses a major challenge in Chemistry to understand the role of solvent on the mechanisms of chemical reactions. Questions that will be examined include how the solvent modifies reaction barriers and other regions of the reaction potential energy surface (PESs), alters the couplings between PESs, most importantly at conical intersections between electronic states, influences and constrains the dynamical stereochemistry of passage through transition states, and dissipates excess product energy. The experimental strategy will be to obtain absorption spectra of transient species with lifetimes of ~100 fs – 1000 ps using broad bandwidth light sources in the infrared, visible and ultraviolet regions. Time-evolutions of such spectra reveal the formation and decay of short-lived species that might be highly reactive radicals or internally (vibrationally and electronically) excited molecules. The transient species decay by reaction or energy loss to the solvent. Statistical mechanical theories of reactions in solution treat such processes using linear response theory, but the experimental data will challenge this paradigm by seeking evidence for breakdown of the linear response interaction of solvent and solute on short timescales because of microscopic chemical dynamics that perturb the solvent structure. The work will build on our pioneering experiments at the Rutherford Appleton Laboratory that prove the feasilbility of the methods.

2 666 684 €

Start date: 2012-02-01, End date: 2017-01-31

Carbon and water in its various states of matter make up a substantial proportion of our Universe. The two materials are highly dissimilar with respect to their chemical and physical properties. Elemental carbon is even often referred to as a hydrophobic, ‘water-hating’ material. Yet, the two materials often coexist and critical processes take place at the interface between these unlike chemical species. This includes the hydration shells of hydrophobic moieties in biomolecules, clathrate hydrate materials where water molecules crystallise around hydrophobic guest species as well as icy comets which are often black due to the presence of carbon at their surfaces. The aim of the CARBONICE project is to investigate the interface and interplay between water and carbon in detail. Using new and innovative experimental strategies, the water molecule will be placed in a variety of different yet highly relevant carbon environments. This will give us unprecedented insights into how water hydrates hydrophobic species which is highly important in the context of hydrophobic interactions. Investigations into how carbon species influence phase transitions of ice will give new insights into crystallisation phenomena but will also reveal the factors that lead to the formation of either ferro- or antiferroelectric ices. Creating carbon – ice composites in the lab as they exist on comets will enable us to understand the complex weather cycles on comets and may help explaining the unusual surface features recently identified by the Rosetta space probe. In summary, this truly multidisciplinary project opens up a new spyhole to critically important processes at the water – carbon interface. The results will have an impact on the space, atmospheric and general materials sciences but will also be highly relevant with respect to further optimising the computer models of water as well as understanding the properties of water in nano-confinements and how it drives biological processes.

1 999 806 €

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

Nanoparticles with etched substrate channels are proposed as a simplified enzyme mimic, nanozymes, for electrocatalysis providing concave catalytically active sites together with the local modulation of electrolyte composition. This concept will be extended to bimetallic core-shell structures with etched channels to provide locally confined catalyst surfaces with varying selectivity. The first catalytic reaction at the channel entrance selectively generates a product, which is further converted in a follow-up reaction catalysed at the core material at the bottom of the channel. The endeavour to locally assemble catalysts with different properties in nano-confined reaction volumes to actualise cascade reaction pathways will be extended to layered nanoparticle structures. Together with an anisotropic provision of a gaseous reactant through a hydrophobic/hydrophilic phase boundary of specifically designed gas diffusion electrodes multi-step catalytic cascade reactions become feasible. The development and extensive evaluation of multi-catalyst gas-diffusion electrodes using operando electrochemistry/spectroscopy and nano-electrochemical tools as well as multi flow-through electrolysers will provide the fundamental knowledge concerning the relative location of different catalyst particles, which synergistically perform chemical cascade reaction with high selectivity and at high current densities. These gas-diffusion electrodes will be integrated in novel electrolyser concepts targeting CO2 recycling at high current density in alkaline solution under suppression of H2 competition with previously unprecedented selectivity for the formation of higher hydrocarbons envisioning contributions to a closed carbon cycle economy and a substantial decrease of CO2 emission. Additionally, a novel tree-type rotating electrolyser design is proposed for the removal of hazardous gaseous pollutants from air e.g. at street crossings in cities as exemplified by NOx reduction to N2 or NH3.

2 499 462 €

Start date: 2019-09-01, End date: 2024-08-31

With this proposal the PI capitalises on his recent breakthroughs in transition metal catalysed carbene (migratory) insertion reactions to build up a new research line for controlled catalytic preparation of a variety of new functionalised (co)polymers with expected special material properties. Metallo-carbenes are well-known intermediates in olefin cyclopropanation and olefin metathesis, but the PI recently discovered that their chemistry is far richer. He demonstrated for the first time that metallo-carbenoids can be used in transition metal catalysed insertion polymerisation to arrive at completely new types of stereoregular carbon-chain polymers functionalised at each carbon of the polymer backbone. Rhodium mediated polymerisation of carbenes provides the means to prepare new materials with yet unknown properties. It also provides a valuable alternative to prepare practically identical polymers as in the desirable (but still unachievable) highly stereo-selective (co)polymerisation of functionalised olefins, representing the ‘holey-grail’ in world-wide TM polymerisation catalysis research. The mechanism and scope of this remarkable new discovery will be investigated and new, improved catalysts will be developed for the preparation of novel materials based on homo- and copolymerisation of a variety of carbene precursors. Copolymerisation of carbenes and other reactive monomers will also be investigated and the properties of all new materials will be investigated. In addition the team will try to uncover new reactions in which carbene insertion reactions play a central role. DFT calculations suggest that the transition state (TS) of the new carbene polymerisation reaction is very similar to the TS’s of a variety of carbonyl insertion reactions. Based on this analogy, the team will investigate several new carbene insertion reactions, potentially leading to new, useful polymeric materials and new synthetic routes to prepare small functional organic molecules.

1 250 000 €

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

The aim of this project is to understand and control the fundamental physical properties of novel carbon nanomaterials: carbon nanotubes and graphene. By a combination of complementary methods, i.e. vibrational spectroscopy, scanning probe microscopy, and theoretical modelling, a comprehensive understanding of the electronic, vibrational, optical properties, and their connection with the material’s structure will be obtained. A diagnostics “toolbox” will be established on the materials in their most unperturbed, ideal states. Taking the results as reference, the materials will be studied under conditions relevant when incorporated into devices. These include imperfections of the materials and interaction with different environments, with other carbon nanotubes/graphene, and with extrinsic materials introduced during device processing. The gained insight and understanding on a fundamental level will also advance technological routes for scaling up carbon-nanomaterial electronic device fabrication, which is still lacking sufficient control over selectivity towards the desired physical properties. Control over the electronic and optical properties will be sought through deliberately induced interactions and chemical functionalization of the materials. The project benefits from close collaborations between experimental and theoretical physics, chemistry, and materials science.

1 468 960 €

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

Endosymbiosis is a key phenomenon that has played a critical role in shaping biological diversity, driving gene transfer and generating cellular complexity. During the process of endosymbiosis, one cell is integrated within another to become a critical component of the recipient, changing its characteristics and allowing it to chart a distinct evolutionary trajectory. Endosymbiosis was fundamentally important to the origin and evolution of eukaryotic cellular complexity, because an endosymbiotic event roots the diversification of all known eukaryotes and endosymbiosis has continually driven the diversification of huge sections of the eukaryotic tree of life. Little is known about how nascent endosymbioses are established or how they go on to form novel cellular compartments known as endosymbiotic organelles. Paramecium bursaria is a single celled protist that harbours multiple green algae within to form a phototrophic endosymbiosis. This relationship is nascent as the partners can be separated, grown separately, and the endosymbiosis reinitiated. This project will identify, for the first time, the gene functions that enable one cell to incubate another within to form a stable endosymbiotic interaction. To identify and explore which host genes control endosymbiosis in P. bursaria we have developed RNAi silencing technology. In the proposed project we will conduct genome sequencing, followed by a large-scale RNAi knockdown screening experiment, to identify host genes that when silenced perturb the endosymbiont population. Having identified candidate genes, we will investigate the localisation and function of the host encoded proteins. This project will significantly change our current understanding of the evolutionary phenomenon of endosymbiosis by identifying the cellular adaptations that drive these interactions, advancing our understanding of how these important moments in evolution occur and how core cellular systems can diversify in function.

2 602 483 €

Start date: 2019-06-01, End date: 2024-05-31

In the biomedical sciences, where endless combinatorial diversity of genes, proteins and synthetic molecules is involved, miniaturisation has not simply allowed an increase in the speed at which experiment can be performed: it has given birth to new areas such as combinatorial chemistry and biology, proteomics, genomics, and more recently, systems and synthetic biology. In all these areas, the synthesis, assay and analysis of large molecular ensembles has become the essence of experimental progress. However, it is the systematic analysis of the enormous amounts of data generated that will ultimately lead to an understanding of fundamental chemical and biological problems. This proposal deals with approaches in which libraries of molecules are employed to give such mechanistic insight – into how enzyme catalysis is brought about in proteins and polymeric enzyme models and into the molecular recognition and cell biology of drug delivery reagents. In each case considerable technical challenges are involved in the way diversity is brought about and probed: ranging from either using the tools of synthetic chemistry to using gene repertoires in emulsion microdroplet reactors with femtolitre volumes, handled in microfluidic devices.

563 848 €

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

The sensory mechanisms that allow birds to perceive the direction of the Earth’s magnetic field for the purpose of navigation are only now beginning to be understood. One of the two leading hypotheses is founded on magnetically sensitive photochemical reactions in the retina. It is thought that transient photo-induced radical pairs in cryptochrome, a blue-light photoreceptor protein, act as the primary magnetic sensor. Experimental and theoretical support for this mechanism has been accumulating over the last few years, qualifying chemical magnetoreception for a place in the emerging field of Quantum Biology. In this proposal, we aim to determine the detailed principles of efficient chemical sensing of weak magnetic fields, to elucidate the biophysics of animal compass magnetoreception, and to explore the possibilities of magnetic sensing technologies inspired by the coherent dynamics of entangled electron spins in cryptochrome-based radical pairs. We will: (a) Establish the fundamental structural, kinetic, dynamic and magnetic properties that allow efficient chemical sensing of Earth-strength magnetic fields in cryptochromes. (b) Devise new, sensitive forms of optical spectroscopy for this purpose. (c) Design, construct and iteratively refine non-natural proteins (maquettes) as versatile model systems for testing and optimising molecular magnetoreceptors. (d) Characterise the spin dynamics and magnetic sensitivity of maquette magnetoreceptors using specialised magnetic resonance and optical spectroscopic techniques. (e) Develop efficient and accurate methods for simulating the coherent spin dynamics of realistic radical pairs in order to interpret experimental data, guide the implementation of new experiments, test concepts of magnetoreceptor function, and guide the design of efficient sensors. (f) Explore the feasibility of electronically addressable, organic semiconductor sensors inspired by radical pair magnetoreception.

2 997 062 €

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

Proteins hosting regions highly enriched in one or few amino acids, the so-called Low-Complexity Regions (LCR), are very common in eukaryotes and play crucial roles in biology. Homorepeats, a subfamily of LCR that present stretches of the same amino acid, perform very specialized functions facilitated by the localized enrichment of the same physicochemical property. In contrast, numerous severe pathologies have been associated to abnormally long repetitions. Despite the relevance of homorepeats, their high-resolution characterization by traditional structural biology techniques is hampered by the degeneracy of the amino acid environments and their intrinsic flexibility. In chemREPEAT, I will develop strategies to incorporate isotopically labelled and unnatural amino acids at specific positions within homorepeats that will overcome present limitations. These labelled positions will be unique probes to investigate for first time the structure and dynamics of homorepeats at atomic level using complementary biophysical techniques. Computational tools will be specifically developed to derive three-dimensional conformational ensembles of homorepeats by synergistically integrating experimental data. chemREPEAT strategies will be developed on huntingtin (Htt), the prototype of repetitive protein. Htt hosts a glutamine tract that is linked with Huntington’s disease (HD), a deadly neuropathology appearing in individuals with more than 35 consecutive Glutamine residues that represent a pathological threshold. The application of the developed approaches to several Htt constructions with different number of Glutamines will reveal the structural bases of the pathological threshold in HD and the role played by the regions flanking the Glutamine tract. The strategies designed in chemREPEAT will expand present frontiers of structural biology to unveil the structure/function relationships for LCRs. This capacity will pave the way for a rational intervention in associated diseases.

1 999 844 €

Start date: 2015-09-01, End date: 2020-08-31