ERC FUNDED PROJECTS

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

1 499 780 €

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

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

1 470 800 €

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

It has long been understood that genes contribute to phenotypes that are then the basis of selection. However, the nature and process of this relationship remains largely theoretical, and the relative contribution of change in gene expression and coding sequence to phenotypic diversification is unclear. The aim of this proposal is to fuse information about sexually dimorphic phenotypes, the mating systems and sexually antagonistic selective agents that shape sexual dimorphism, and the sex-biased gene expression patterns that encode sexual dimorphisms, in order to create a cohesive integrated understanding of the relationship between evolution, the genome, and the animal form. The primary approach of this project is to harnesses emergent DNA sequencing technologies in order to measure evolutionary change in gene expression and coding sequence in response to different sex-specific selection regimes in a clade of birds with divergent mating systems. Sex-specific selection pressures arise in large part as a consequence of mating system, however males and females share nearly identical genomes, especially in the vertebrates where the sex chromosomes house very small proportions of the overall transcriptome. This single shared genome creates sex-specific phenotypes via different gene expression levels in females and males, and these sex-biased genes connect sexual dimorphisms, and the sexually antagonistic selection pressures that shape them, with the regions of the genome that encode them. The Galloanserae (fowl and waterfowl) will be used to in the proposed project, as this clade combines the necessary requirements of both variation in mating systems and a well-conserved reference genome (chicken). The study species selected from within the Galloanserae for the proposal exhibit a range of sexual dimorphism and sperm competition, and this will be exploited with next generation (454 and Illumina) genomic and transcriptomic data to study the gene expression patterns that underlie sexual dimorphisms, and the evolutionary pressures acting on them. This work will be complemented by the development of mathematical models of sex-specific evolution that will be tested against the gene expression and gene sequence data in order to understand the mechanisms by which sex-specific selection regimes, arising largely from mating systems, shape the phenotype via the genome.

1 350 804 €

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

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

1 500 000 €

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

"A major outstanding challenge for evolutionary biology is to explain how novel adaptations arise. We propose to test whether developmental plasticity initiates evolutionary change in morphological, behavioural and social traits, using laboratory experiments, fieldwork and comparative analyses. Using burying beetles Nicrophorus spp as our model experimental system, we shall: 1) Test whether variation in parental provisioning during development induces correlated phenotypic change in adult body size and a suite of life history traits; whether these phenotypic changes can be genetically accommodated under experimental evolution (the Baldwin Effect); and whether changes induced by experimental evolution mimic natural variation in adult body size and life history strategy among Nicrophorus species; 2) Test whether parental provisioning has a canalizing effect on the developmental environment, potentially storing up cryptic genetic variation which might then be released as random new phenotypes, if offspring are exposed to a new developmental environment; 3) Investigate whether developmental trade-offs, induced by under-provisioning from parents, provide the first step towards the evolution of a novel interspecific mutualism. Is a second species recruited in adulthood to carry out the function of a structure that was under-nourished during development? 4) Using comparative analyses of data from the literature on insects, frogs, birds and mammals, we shall test whether the evolution of parental provisioning in a given lineage is positively correlated with the number of species in the lineage. Our proposal is original in focusing on developmental plasticity induced by variation in parental provisioning. Given the diverse and numerous species that provision their young, including several whose genomes have now been sequenced, this potentially opens up a rich new area for future work on the developmental mechanisms underlying evolutionary innovations."

1 499 914 €

Start date: 2012-11-01, End date: 2017-10-31

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

1 422 907 €

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

Cooling is essential for food and drinks, medicine, electronics and thermal comfort. Thermal changes due to pressure-driven phase transitions in fluids have long been used in vapour compression systems to achieve continuous refrigeration and air conditioning, but their energy efficiency is relatively low, and the working fluids that are employed harm the environment when released to the atmosphere. More recently, the discovery of large thermal changes due to pressure-driven phase transitions in magnetic solids has led to suggestions for environmentally friendly solid-state cooling applications. However, for this new cooling technology to succeed, it is still necessary to find suitable barocaloric (BC) materials that satisfy the demanding requirements set by applications, namely very large thermal changes in inexpensive materials that occur near room temperature in response to small applied pressures. I aim to develop new BC materials by exploiting phase transitions in non-magnetic solids whose structural and thermal properties are strongly coupled, namely ferroelectric salts, molecular crystals and hybrid materials. These materials are normally made from cheap abundant elements, and display very large latent heats and volume changes at structural phase transitions, which make them ideal candidates to exhibit extremely large BC effects that outperform those observed in state-of-the-art BC magnetic materials, and that match applications. My unique approach combines: i) materials science to identify materials with outstanding BC performance, ii) advanced experimental techniques to explore and exploit these novel materials, iii) materials engineering to create new composite materials with enhanced BC properties, and iv) fabrication of BC devices, using insight gained from modelling of materials and device parameters. If successful, my ambitious strategy will culminate in revolutionary solid-state cooling devices that are environmentally friendly and energy efficient.

1 467 521 €

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

The objective of the BEACON project is to (re-)introduce analog communications into the design of modern wireless networks. We argue that the extreme energy and latency constraints imposed by the emerging Internet of Everything (IoE) paradigm can only be met within a hybrid digital-analog communications framework. Current network architectures separate source and channel coding, orthogonalize users, and employ long block-length digital source and channel codes, which are either suboptimal or not applicable under the aforementioned constraints. BEACON questions these well-established design principles, and proposes to replace them with a hybrid digital-analog communications framework, which will meet the required energy and latency constraints while simplifying the encoding and decoding processes. BEACON pushes the performance of the IoE to its theoretical limits by i) exploiting signal correlations that are abundant in IoE applications, given the foreseen density of deployed sensing devices, ii) taking into account the limited and stochastic nature of energy availability due to, for example, energy harvesting capabilities, iii) using feedback resources to improve the end-to-end signal distortion, and iv) deriving novel converse results to identify fundamental performance benchmarks. The results of BEACON will not only shed light on the fundamental limits on the performance any coding scheme can achieve, but will also lead to the development of unconventional codes and communication protocols that can approach these limits, combining digital and analog communication techniques. The ultimate challenge for this project is to exploit the developed hybrid digital-analog networking theory for a complete overhaul of the physical layer design for emerging IoE applications, such as smart grids, tele-robotics and smart homes. For this purpose, a proof-of-concept implementation test-bed will also be built using software defined radios and sensor nodes.

1 496 350 €

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

Social interactions are multifaceted and subtle, yet we can almost instantaneously discern if two people are cooperating or competing, flirting or fighting, or helping or hindering each other. Surprisingly, the development and brain basis of this remarkable ability has remained largely unexplored. At the same time, understanding how we develop the ability to process and use social information from other people is widely recognized as a core challenge facing developmental cognitive neuroscience. The Becoming Social project meets this challenge by proposing the most complete investigation to date of the development of the behavioural and neurobiological systems that support complex social perception. To achieve this, we first systematically map how the social interactions we observe are coded in the brain by testing typical adults. Next, we investigate developmental change both behaviourally and neurally during a key stage in social development in typically developing children. Finally, we explore whether social interaction perception is clinically relevant by investigating it developmentally in autism spectrum disorder. The Becoming Social project is expected to lead to a novel conception of the neurocognitive architecture supporting the perception of social interactions. In addition, neuroimaging and behavioural tasks measured longitudinally during development will allow us to determine how individual differences in brain and behaviour are causally related to real-world social ability and social learning. The planned studies as well as those generated during the project will enable the Becoming Social team to become a world-leading group bridging social cognition, neuroscience and developmental psychology.

1 500 000 €

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

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

1 362 538 €

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

Can benefit-sharing address the equity deficit within the green economy? This project aims to investigate benefit-sharing as an under-theorised and little-implemented regulatory approach to the equity concerns (disregard for the special circumstances of developing countries and of indigenous peoples and local communities) in transitioning to the green economy. Although benefit-sharing is increasingly deployed in a variety of international environmental agreements and also in human rights and corporate accountability instruments, no comprehensive account exists of its conceptual and practical relevance to equitably address global environmental challenges. This project will be the first systematic evaluation of the conceptualisations and operationalisations of benefit-sharing as a tool for equitable change through the allocation among different stakeholders of economic and also socio-cultural and environmental advantages arising from natural resource use. The project will combine a comparative study of international law with empirical legal research, and include an inter-disciplinary study integrating political sociology in a legal enquiry on the role of “biocultural community protocols” that articulate and implement benefit-sharing at the intersection of international, transnational, national and indigenous communities’ customary law (global environmental law). The project aims to: 1. develop a comprehensive understanding of benefit-sharing in international law; 2. clarify whether and how benefit-sharing supports equity and the protection of human rights across key sectors of international environmental regulation (biodiversity, climate change, oceans, food and agriculture) that are seen as inter-related in the transition to the green economy; 3. understand the development of benefit-sharing in the context of global environmental law; and 4. clarify the role of transnational legal advisors (NGOs and bilateral cooperation partners) in the green economy.

1 481 708 €

Start date: 2013-11-01, End date: 2018-10-31

This project investigates the cross-fertilisation of Anglo/American and German literature and film during the Allied Occupation of Germany. It will be the first study to survey the cultural landscape of the British and American zones of Occupied Germany in any detail. By doing so it will offer a new interpretative framework for postwar culture, in particular in three areas: the history of the Allied Occupation of Germany; the history of postwar Anglophone and Germanophone literature (arguing the two were more intertwined than has previously been suggested); and the history of the relationship between postwar and Cold War. Combining Anglo-American and German literature and film history with critical analysis, cultural history and life-writing, this is a necessarily ambitious, multidisciplinary study which will open up a major new field of research.

1 414 601 €

Start date: 2013-09-01, End date: 2019-02-28

The agile and efficient flight of birds shows what flight performance is physically possible, and in theory could be achieved by unmanned air vehicles (UAVs) of the same size. The overall aim of this project is to enhance the performance of small scale UAVs by developing novel technologies inspired by understanding how birds are adapted to interact with airflows. Small UAVs have the potential to dramatically change current practices in many areas such as, search and rescue, surveillance, and environmental monitoring. Currently the utility of these systems is limited by their operational endurance and their inability to operate in strong turbulent winds, especially those that often occur in urban environments. Birds are adapted to be able to fly in these conditions and actually use them to their advantage to minimise their energy output. This project is composed of three tracks which contain elements of technology development, as well as scientific investigation looking at bird flight behaviour and aerodynamics. The first track looks at developing path planning algorithms for UAVs in urban environments based on how birds fly in these areas, by using GPS tracking and computational fluid dynamics alongside trajectory optimization. The second track aims to develop artificial wings with improved gust tolerance inspired by the features of feathered wings. Here, high speed video measurements of birds flying through gusts will be used alongside wind tunnel testing of artificial wings to discover what features of a bird’s wing help to alleviate gusts. The third track develops novel force and flow sensor arrays for autonomous flight control based on the sensor arrays found in flying animals. These arrays will be used to make UAVs with increased agility and robustness. This unique bird inspired approach uses biology to show what is possible, and engineering to find the features that enable this performance and develop them into functional technologies.

1 998 546 €

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

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

1 491 479 €

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

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

1 462 500 €

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

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

1 432 301 €

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

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

1 536 120 €

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

Biofilms are antibiotic-resistant, sessile bacterial communities that occupy most moist surfaces on Earth and represent a major mode of bacterial life. Another common feature of bacterial life is exposure to viral parasites (termed phages), which are a dominant force in bacterial population control throughout nature. Surprisingly, almost nothing is known about the interactions between biofilm-dwelling bacteria and phages. This proposal is designed to fill this gap using a combination of novel methodology, experimental systems, and mathematical modeling. We have recently developed a new microscopic imaging technique that allows us to image and track all individual cells and their gene expression inside biofilms. First, we will use this technique for tracking the population dynamics of bacteria and phages within biofilms at single cell resolution. By genetically manipulating bacterial hosts and their phages, and by varying environmental conditions, we will investigate the fundamental biological and physical determinants of phage spread within biofilm communities. Second, we will study how biofilms respond to phage attack on both intra-generational and evolutionary time scales, focusing in particular on proximate response mechanisms and the population dynamics of phage-resistant and phage-susceptible cells as a function of biofilm spatial structure. Lastly, we will combine our novel insights to engineer phages that manipulate the composition of biofilm communities, either by subtraction of particular bacterial species or by addition of novel phenotypes to existing biofilm community members. Altogether, the proposed research promises to uncover the major mechanistic and evolutionary elements of biofilm-phage interactions. This combined work will greatly enrich our knowledge of microbial ecology and motivate novel strategies for bacterial biofilm control, an increasingly urgent priority in light of widespread antibiotic resistance.

1 494 963 €

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

This ERC-StG proposal, BIOMOF, outlines a dual strategy for the growth and processing of porous metal-organic framework (MOF) materials, inspired by the interfacial interactions that characterise highly controlled biomineralisation processes. The aim is to prepare MOF (bio)-composite materials of hierarchical structure and multi-modal functionality to address key societal challenges in healthcare, catalysis and energy. In order for MOFs to reach their full potential, a transformative approach to their growth, and in particular their processability, is required since the insoluble macroscopic micron-sized crystals resulting from conventional syntheses are unsuitable for many applications. The BIOMOF project defines chemically flexible routes to MOFs under mild conditions, where the added value with respect to wide-ranging experimental procedures for the growth and processing of crystalline controllably nanoscale MOF materials with tunable structure and functionality that display significant porosity for wide-ranging applications is extremely high. Theme 1 exploits protein vesicles and abundant biopolymer matrices for the confined growth of soluble nanoscale MOFs for high-end biomedical applications such as cell imaging and targeted drug delivery, whereas theme 2 focuses on the cost-effective preparation of hierarchically porous MOF composites over several length scales, of relevance to bulk industrial applications such as sustainable catalysis, separations and gas-storage. This diverse yet complementary range of applications arising simply from the way the MOF is processed, coupled with the versatile structural and physical properties of MOFs themselves indicates strongly that the BIOMOF concept is a powerful convergent new approach to applied materials chemistry.

1 492 970 €

Start date: 2010-11-01, End date: 2015-10-31

Enzymes created by Nature are still more selective and can be orders of magnitude more efficient than man-made catalysts, in spite of recent advances in the design of de novo catalysts and in enzyme redesign. The optimal engineering of either small molecular or of complex biological catalysts requires both (i) accurate quantitative computational methods capable of a priori assessing catalytic efficiency, and (ii) molecular design principles and corresponding algorithms to achieve, understand and control biomolecular catalytic function and mechanisms. Presently, the computational design of biocatalysts is challenging due to the need for accurate yet computationally-intensive quantum mechanical calculations of bond formation and cleavage, as well as to the requirement for proper statistical sampling over very many degrees of freedom. Pioneering enhanced sampling and analysis methods have been developed to address crucial challenges bridging the gap between the available simulation length and the biologically relevant timescales. However, biased simulations do not generally permit the direct calculation of kinetic information. Recently, I and others pioneered simulation tools that can enable not only accurate calculations of free energies, but also of the intrinsic molecular kinetics and the underlying reaction mechanisms as well. I propose to develop more robust, automatic, and system-tailored sampling algorithms that are optimal in each case. I will use our kinetics-based methods to develop a novel theoretical framework to address catalytic efficiency and to establish molecular design principles to key design problems for new bio-inspired nanocatalysts, and to identify and characterize small molecule modulators of enzyme activity. This is a highly interdisciplinary project that will enable fundamental advances in molecular simulations and will unveil the physical principles that will lead to design and control of catalysis with Nature-like efficiency.

1 499 999 €

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

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

1 494 368 €

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

Xenon biosensors have an outstanding potential to increase the significance of magnetic resonance imaging (MRI) in molecular imaging and to combine the advantages of MRI with the high sensitivity of hyperpolarized Xe-129 and the specificity of a functionalized contrast agent. Based on new detection schemes (Hyper-CEST method) in Xe MRI, this novel concept in molecular diagnostics will be made available for biomedical applications. The advancement focuses on high-sensitivity in vitro diagnostics for localization of tumour cells in cell cultures and first demonstrations on animal models based on a transferrin-functionalized biosensor. Such a sensor will enable detection of subcutaneous tumours at high sensitivity without any background signal. More detailed work on the different available Hyper-CEST contrast parameters focuses on an absolute quantification of new molecular markers that will improve non-invasive tumour diagnostics significantly. NMR detection of functionalized Xe biosensors have the potential to close the sensitivity gap between modalities of nuclear medicine like PET/SPECT and MRI without using ionizing radiation or making compromises in penetration depth like in optical methods.

1 848 600 €

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

The centromere is one of the most important chromosomal elements. It is required for proper chromosome segregation in mitosis and meiosis and readily recognizable as the primary constriction of mitotic chromosomes. Proper centromere function is essential to ensure genome stability; therefore understanding centromere identity is directly relevant to cancer biology and gene therapy. How centromeres are established and maintained is however still an open question in the field. In most organisms this appears to be regulated by an epigenetic mechanism. The key candidate for such an epigenetic mark is CENH3 (CENP-A in mammals, CID in Drosophila), a centromere-specific histone H3 variant that is essential for centromere function and exclusively found in the nucleosomes of centromeric chromatin. Using a biosynthetic approach of force-targeting CENH3 in Drosophila to non-centromeric DNA, we were able to induce centromere function and demonstrate that CENH3 is sufficient to determine centromere identity. Here we propose to move this experimental setup across evolutionary boundaries into human cells to develop improved human artificial chromosomes (HACs). We will make further use of this unique setup to dissect the function of targeted CENH3 both in Drosophila and human cells. Contributing centromeric components and histone modifications of centromeric chromatin will be characterized in detail by mass spectroscopy in Drosophila. Finally we are proposing to develop a technique that allows high-resolution mapping of proteins on repetitive DNA to help further characterizing known and novel centromere components. This will be achieved by combining two independently established techniques: DNA methylation and DNA fiber combing. This ambitious proposal will significantly advance our understanding of how centromeres are determined and help the development of improved HACs for therapeutic applications in the future.

1 755 960 €

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

Iridescence is a form of structural colour which changes hue according to the angle from which it is viewed. Blue iridescence caused by multilayers has been described on the leaves of taxonomically diverse species such as the lycophyte Selaginella uncinata and the angiosperm Begonia pavonina. While much is known about the role of leaf pigment colour, the adaptive role of leaf iridescence is unknown. Hypotheses have been put forward including 1) iridescence acts as disruptive camouflage against herbivores 2) it enhances light sensing and capture in low light conditions 3) it is a photoprotective mechanism to protect shade-adapted plants against high light levels. These hypotheses are not mutually exclusive: each function may be of varying importance in different environments. To understand any one function, we need a interdisciplinary approach considering all three potential functions and their interactions. The objective of my research would be to test these hypotheses, using animal behavioural and plant physiological methods, to determine the functions of leaf iridescence and how the plant has adapted to the reflection of developmentally vital wavelengths. Use of molecular and bioinformatics methods will elucidate the genes that control the production of this potentially multifunctional optical phenomenon. This research will provide a pioneering study into the generation, developmental impact and adaptive significance of iridescence in leaves. It would also answer questions at the frontiers of several fields including those of plant evolution, insect vision, methods of camouflage, the generation and role of animal iridescence, and could also potentially inspire synthetic biomimetic applications.

1 118 378 €

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

"The body is ubiquitous in perceptual experience and is central to our sense of self and personal identity. Disordered body representations are central to several serious psychiatric and neurological disorders. Thus, identifying factors which contribute to the formation and maintenance of body representations is crucial for understanding how body representation goes awry in disease, and how it might be corrected by potential novel therapeutic interventions. Several types of sensory signals provide information about the body, making the body the multisensory object, par excellence. Little is known, however, about how information from somatosensation and from vision is integrated to construct the rich body representations we all experience. This project fills this gap in current understanding by determining how the brain builds body representations (BODYBUILDING). A hierarchical model of body representation is proposed, providing a novel theoretical framework for understanding the diversity of body representations and how they interact. The key motivating hypothesis is that body representation is determined by the dialectic between two major cognitive processes. First, from the bottom-up, somatosensation represents the body surface as a mosaic of discrete receptive fields, which become progressively agglomerated into larger and larger units of organisation, a process I call fusion. Second, from the top-down, vision starts out depicting the body as an undifferentiated whole, which is progressively broken into smaller parts, a process I call segmentation. Thus, body representation operates from the bottom-up as a process of fusion of primitive elements into larger complexes, as well as from the top-down as a process of segmentation of an initially undifferentiated whole into more basic parts. This project uses a combination of psychophysical, electrophysiological, and neuroimaging methods to provide fundamental insight into how we come to represent our body."

1 497 715 €

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

More than 30 million people are living with diabetes in the EU, with a prevalence expected to grow to over 10% of the adult population by the year 2030. Type 2 diabetes is a major cause of cardiovascular disease related death and disability, substantially increasing the risk of myocardial infarction, stroke and peripheral arterial disease. Recent landmark trials, showing that intensive glucose control does not improve cardiovascular outcomes and may increase mortality in some circumstances, provide a compelling rationale for intense research aimed at developing novel therapeutic strategies. Type 2 diabetes is underpinned by resistance to the effects of insulin, which I have shown in endothelial cells causes reduced bioavailability of the anti-atherosclerotic molecule nitric oxide and leads to accelerated atherosclerosis. The cellular effects of insulin are mirrored by insulin-like growth factor factor-1, the bioavailability of which at its receptor is in turn is regulated by a family of high affinity binding proteins (IGFBP). Epidemiological studies demonstrate and inverse association between one of these binding proteins, IGFBP1, and diabetes-related cardiovascular risk. I have recently demonstrated that IGFBP1 when expressed in mice can ameliorate insulin resistance, obesity and atherosclerosis. In endothelial cells, I showed that IGFBP1 upregulates the production of nitric oxide indepenedently of IGF. These findings suggest that IGFBP1 may be a ‘protective’ endogenous protein and that increasing circulating levels may be a therapeutic strategy to prevent development of diabetes and cardiovascular disease. In this proposal I will address this hypothesis by employing state of the art studies in cells and novel gene modified mice to unravel the molecular basis of the protective effects of IGFBP1 and to investigate the possibility of exploiting the IGF-IGFBP axis to prevent cardiovascular disease in the setting of diabetes and obesity.

1 493 543 €

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

We and others have recently delineated the molecular architecture of a new feedback pathway in brain synapses, which operates as a synaptic circuit breaker. This pathway is supposed to use a group of lipid messengers as retrograde synaptic signals, the so-called endocannabinoids. Although heterogeneous in their chemical structures, these molecules along with the psychoactive compound in cannabis are thought to target the same effector in the brain, the CB1 receptor. However, the molecular catalog of these bioactive lipids and their metabolic enzymes has been expanding rapidly by recent advances in lipidomics and proteomics raising the possibility that these lipids may also serve novel, yet unidentified physiological functions. Thus, the overall aim of our research program is to define the molecular and anatomical organization of these endocannabinoid-mediated pathways and to determine their functional significance. In the present proposal, we will focus on understanding how these novel pathways regulate synaptic and extrasynaptic signaling in hippocampal neurons. Using combination of lipidomic, genetic and high-resolution anatomical approaches, we will identify distinct chemical species of endocannabinoids and will show how their metabolic enzymes are segregated into different subcellular compartments in cell type- and synapse-specific manner. Subsequently, we will use genetically encoded gain-of-function, loss-of-function and reporter constructs in imaging experiments and electrophysiological recordings to gain insights into the diverse tasks that these new pathways serve in synaptic transmission and extrasynaptic signal processing. Our proposed experiments will reveal fundamental principles of intercellular and intracellular endocannabinoid signaling in the brain.

1 638 000 €

Start date: 2009-11-01, End date: 2014-10-31

"Conscious experiences normally result from the flow of external input into our sensory systems. However, our minds are also able to create conscious percepts in the absence of any sensory stimulation; these internally generated percepts are referred to as mental images, and they have many similarities with real visual percepts; consequently, mental imagery is often referred to as “seeing in the mind’s eye”. Mental imagery is also believed to be closely related to working memory, a mechanism which can maintain “offline” representations of visual stimuli no longer in the observer’s view, as both involve internal representations of previously seen visual attributes. Indeed, visual imagery is often thought of as a conscious window into the content of memory representations. Imagery, working memory, and conscious perception are thus thought to rely on very similar mechanisms. However, in everyday life we are generally able to keep apart the constructs of our imagination from real physical events; this begs the question of how the brain distinguishes internal mental images from externally induced visual percepts. To answer this question, the proposed work aims to isolate the cortical mechanisms associated uniquely with WM and imagery independently of each other and independently of the influence of external conscious percepts. Furthermore, by the use of neuroimaging and brain stimulation, we aim to determine the cortical mechanisms which keep apart internally generated and externally induced percepts, in both health and disease. This is a question of great clinical interest, as the ability to distinguish the perceived from the imagined is impoverished in psychotic disorders. In addition to revealing the mechanisms underlying this confusion, the present project aims to alleviate it in psychotic patients by the use of brain stimulation. The project will thus significantly improve our understanding of these cognitive processes and will also have clinical implications."

1 280 680 €

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

We are currently witnessing a paradigm shift in our understanding of human brain function, moving towards a clearer description of cortical processing. Sensory systems are no longer considered as 'passively recording' but rather as dynamically anticipating and adapting to the rapidly changing environment. These new ideas are encompassed in the predictive coding framework, and indeed in a unifying theory of the brain (Friston, 2010). In terms of brain computation, a predictive model is created in higher cortical areas and communicated to lower sensory areas through feedback connections. Based on my pioneering research I propose experiments that are capable of ‘brain-reading’ cortical feedback– which would contribute invaluable data to theoretical frameworks. The proposed research project will advance our understanding of ongoing brain activity, contextual processing, and cortical feedback - contributing to what is known about general cortical functions. By providing new insights as to the information content of cortical feedback, the proposal will fill one of the most important gaps in today’s knowledge about brain function. Friston’s unifying theory of the brain (Friston, 2010) and contemporary models of the predictive-coding framework (Hawkins and Blakeslee, 2004;Mumford, 1992;Rao and Ballard, 1999) assign feedback processing an essential role in cortical processing. Compared to feedforward information processing, our knowledge about feedback processing is in its infancy. The proposal introduces parametric and explorative brain reading designs to investigate this feedback processing. The chief goal of my proposal will be precision measures of cortical feedback, and a more ambitious objective is to read mental images and inner thoughts.

1 494 714 €

Start date: 2012-12-01, End date: 2017-11-30

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

1 500 000 €

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

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

1 434 250 €

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

I propose a programme of precision tests of the Standard Model of particle physics to be carried out using the LHCb experiment at CERN. The proposal is focussed on studies of CP violation - differences between the behaviour of particles and antiparticles that are fundamental to understanding why the Universe we see today is made up of matter, not antimatter. The innovative feature of this research is the use of Dalitz plot analyses to improve the sensitivity to interesting CP violation effects. Recently I have developed a number of new methods to search for CP violation based on this technique. These methods can be used at LHCb and will extend the physics reach of the experiment beyond what was previously considered possible. I propose to create a small research team, based at the University of Warwick, to develop these methods and to make a number of precise measurements of CP violation parameters using the LHCb experiment. By comparing the results with the Standard Model predictions for these parameters, effects due to non-standard particles can be observed or highly constrained. The results of this work have the potential to redefine the direction of this research field. They will be essential to develop theories of particle physics that go beyond the Standard Model and attempt to address great unanswered questions, such as the origin of the matter--antimatter asymmetry of the Universe.

1 682 800 €

Start date: 2010-02-01, End date: 2016-01-31

Recent advances in magnetic resonance (MR) acquisition technology are providing us with images of the human brain of increasing detail and resolution. While these images hold promise to greatly increase our understanding of such a complex organ, the neuroimaging community relies on tools (e.g. SPM, FSL, FreeSurfer) which, being over a decade old, were designed to work at much lower resolutions. These tools do not consider brain substructures that are visible in present-day scans, and this inability to capitalize on the vast improvement of MR is hampering progress in the neuroimaging field. In this ambitious project, which lies at the nexus of medical histology, neuroscience, biomedical imaging, computer vision and statistics, we propose to build a set of next-generation computational tools that will enable neuroimaging studies to take full advantage of the increased resolution of modern MR technology. The core of the tools will be an ultra-high resolution probabilistic atlas of the human brain, built upon multimodal data combining from histology and ex vivo MR. The resulting atlas will be used to analyze in vivo brain MR scans, which will require the development of Bayesian segmentation methods beyond the state of the art. The developed tools, which will be made freely available to the scientific community, will enable the analysis of MR data at a superior level of structural detail, opening completely new opportunities of research in neuroscience. Therefore, we expect the tools to have a tremendous impact on the quest to understand the human brain (in health and in disease), and ultimately on public health and the economy.

1 450 075 €

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

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

1 499 549 €

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

Music and language share similar properties and are processed in overlapping brain regions. As a common information-bearing element in music and language, pitch plays an essential role in encoding musical melodies, signifying linguistic functions, and conveying emotions through music and speech. However, two distinct neurodevelopmental disorders, congenital amusia (CA) and autism spectrum disorders (ASD), affecting millions of people in Europe and worldwide, may selectively impair individuals’ ability to process musical, linguistic, and emotional pitch. To date, it remains unclear why individuals with CA and ASD exhibit significant differences in music, speech, and emotion processing. Under our Delicate Form-Function Balance Hypothesis, we will conduct a series of behavioural and neurophysiological experiments to test the central hypothesis that normal musical, linguistic, and emotional functioning requires a delicate balance in the encoding and decoding of form and function in musical, speech, and emotional communication, with musical communication centred on form and linguistic and emotional communication focused on function. Most critically, we hypothesize that the differences in music, speech, and emotional processing in CA and ASD are rooted not only in pitch and cognitive abilities, but also in the balance between form and function for each domain. Addressing three specific aims regarding the impacts of cognitive processing styles, pitch processing skills, and language background (tone vs. non-tonal) on the behavioural and neurophysiological characteristics of music, language, and emotion processing in CA and ASD, this research will not only help reveal the underlying mechanisms of the two defining aspects of human cognition, music and language, but also form a laboratory for testing key hypotheses about the bio-behavioural manifestations of human neurodevelopmental disorders in music and language processing.

1 488 814 €

Start date: 2016-12-01, End date: 2021-11-30

Craniosynostosis is a group of congenital craniofacial abnormalities consisting in premature fusion (ossification) of one or more cranial sutures during infancy. This results in growth restriction perpendicular to the axis of the suture and promotes growth parallel to it, causing physical deformation of the cranial and facial skeleton, as well as distortion of the underling brain, with potential detrimental effects on its function: visual loss, sleep apnoea, feeding and breathing difficulties, and neurodevelopment delay. Conventional management of craniosynostosis involves craniofacial surgery delivered by excision of the prematurely fused sutures, multiple bone cuts and remodelling of the skull deformities, with the primary goal of improving patient function, while normalising their appearance. Cranial vault remodelling surgical procedures, aided by internal and external devices, have proven functionally and aesthetically effective in correcting skull deformities, but final results remain unpredictable and often suboptimal because of an incomplete understanding of the biomechanical interaction between the device and the skull. The overall aim of this grant is to create a validated and robust computational framework that integrates patient information and device design to deliver personalised care in paediatric craniofacial surgery in order to improve clinical outcomes. A virtual model of the infant skull with craniosynostosis, including viscoelastic properties and mechano-biology regulation, will be developed to simulate device implantation and performance over time, and will be validated using clinical data from patient populations treated with current devices. Bespoke new devices will be designed allowing for pre-programmed 3D shapes to be delivered with continuous force during the implantation period. Patient specific skull models will be used to virtually test and optimise the personalised devices, and to tailor the surgical approach for each individual case.

1 498 772 €

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

Non-invasive genomic analysis of cancer can revolutionize the study of tumour evolution, heterogeneity, and drug resistance. Clinically applied, this can transform current practice in cancer diagnosis and management. Cell-free DNA in plasma contains tumour-specific sequences. This circulating tumour DNA (ctDNA) is a promising source of genomic and diagnostic information, readily accessible non-invasively. The study of ctDNA is therefore timely and of great importance. But it is also very challenging. Measurement can be complex, and high-quality samples are not easily obtained. Though progress has been made, much remains to be discovered. My lab pioneered the use of targeted sequencing to analyse mutations in ctDNA. We recently developed a ground-breaking paradigm for analysing evolving cancer genomes in plasma DNA, combining ctDNA quantification with exome-sequencing of serial plasma samples. Applied to extensive sets of clinical samples my lab has characterized, this will enable large-scale exploration of acquired drug resistance with unprecedented resolution. CancerExomesInPlasma aims to use ctDNA for genome-wide analysis of tumour evolution, as a means for non-invasive, unbiased discovery of genes and pathways involved in resistance to cancer therapy.

1 769 380 €

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

Cancer screening and the diagnostics industry: a comparative analysis of the political economy of diagnostic innovation A decade after the Human Genome Project, major public and private investments continue to fuel expectations of a genomic revolution in biomedicine. The freight of expectations surrounding the new “age of diagnostics” is accompanied by much uncertainty about how public policy should steer diagnostic innovation, with much debate about inter alia the harms of creating diagnostic monopolies through gene patenting, and the risks of under- or over-regulation. However, due to the paucity of research on diagnostic innovation, policy deliberation is driven more by anecdote and expert opinion than empirical evidence. With a specific focus on screening/early detection of cancer, this project will map industry dynamics, technological trajectories and regulatory developments in Europe and the USA from 1996 to the present day. Combining quantitative and qualitative methods, the project’s innovative dimensions include a new conceptual model of socio-technical transition in the diagnostics sector, and the first integrative analysis linking scientometric data on the interactions between public and private actors in the diagnostic research domain with comparative transnational analysis of regulatory decision-making. Through a novel integration of conceptual insights from the literature on biomedicalisation and scholarship on socio-technical regime change, this project aims to advance both fields of research by applying a new multi-scale, multi-level model of socio-technical transition. The project will provide unprecedented insight into the factors shaping the development of a new generation of molecular diagnostic tests, and examine how these technologies are reconfiguring disease categories and redrawing the boundaries between health and sickness. We will establish a platform of theory and methods for a broader programme of work on diagnostic innovation.

1 347 992 €

Start date: 2017-04-01, End date: 2021-09-30

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

1 480 826 €

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

This project centres ‘the carceral archipelago’ in the history of the making of the modern world. It analyses the relationships and circulations between and across convict transportation, penal colonies and labour, migration, coercion and confinement. It incorporates all the global powers engaged in transportation for the purpose of expansion and colonization - Europe, Russia, Latin America, China, Japan – over the period from Portugal’s first use of convicts in North Africa in 1415 to the dissolution of Stalin’s gulags in 1960. It uses an innovative theoretical base to shift convict transportation out of the history of crime and punishment into the new questions being raised by global and postcolonial history. The project maps for the first time global networks of transportation and penal colonies. It undertakes case study archival research on relatively unexplored convict flows, and on the mobility of ideas and practices around transportation and other modes of confinement. It analyses its findings within the broader literature, including on transportation but also debates around the definition of freedom/ unfreedom, the importance of circulating labour, and global divergence and convergence. It redefines what we mean by ‘transportation,’ explores penal transportation as an engine of global change, de-centres Europe in historical analysis, and defines long-term impacts on economy, society and identity. It places special stress on investigating whether a transnational approach to the topic gives us a fresh theoretical starting point for studying global history that moves beyond ‘nation’ or ‘empire.’ The project lies at the intersections of national, colonial and global history, and economic, social and cultural history. It will be of wide interest to scholars of labour, migration, punishment and confinement; comparative and global history; diaspora, creolization and cultural translation; and museum and heritage studies.

1 492 870 €

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

In the epoch of Gaia, fundamental stellar properties will be made widely available for large numbers of stars. These properties are expected to unleash a new wave of discovery in the field of astrophysics. But while many properties of stars are measurable, meaningful Helium abundances (Y) remain elusive and as a result fundamental properties are not accurate. Helium enrichment laws, which underpin most stellar properties, link initial Y to initial metallicity, but these relations are very uncertain with gradients (dY/dZ) spanning the range 1 to 3. This uncertainty is the initial Y problem and this is a bottleneck that must be overcome to unleash the true potential of Gaia. Without measurements of initial Y for all stars we need to find alternative observables that trace out the evolution of initial Y. We will search for better tracers using the power of asteroseismology as a calibrator. Asteroseismic measures of Helium will be used to construct a map from observable properties (fundamental, chemical or even dynamical) back to initial Helium. This is a challenge that can only be solved through the use of the latest asteroseismic techniques coupled to a rigorous yet flexible statistical scheme. I am uniquely qualified in the cutting edge methods of asteroseismology and the application of advanced multi-level statistical models. The intersection of these two skill sets will allow me to solve the initial Helium problem. The motivation for a timely solution to this problem could not be stronger. We have just entered an age of large asteroseismic datasets, vast spectroscopic surveys, and the billion star program of Gaia. The next wave of scientific breakthroughs in stellar physics, exoplanetary science, and Galactic archeology will be held back unless accurate fundamental stellar properties are available. We can only produce these accurate properties with a reliable map of stellar Helium.

1 496 203 €

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

Responding to climate change has profound implications for behaviour; yet policies to achieve this change have met with limited success. A key challenge for environmental social scientists is the need to move forward in understanding how to bring about change in consumption, community and political behaviours, which is commensurate to the scale of the climate change challenge. One promising area is ‘behavioural spillover’, the notion that taking up a new behaviour (e.g., recycling) may lead to adoption of other, more environmentally beneficial, behaviours. Such a notion appears to hold the promise of changing a suite of behaviours in a cost-effective way. Yet despite robust theoretical principles (e.g., self-perception theory) underpinning behavioural spillover, there is little empirical research. The proposed research intends to produce a step-change in behavioural and sustainability science by undertaking a mixed-method, cross-cultural study of pro-environmental behavioural spillover in order to open up new ways of promoting sustainable lifestyle change and significantly broadening our understanding of behaviour within individuals and cultures. There are three objectives for the research: 1. To examine ways in which pro-environmental behaviour, lifestyles and spillover are understood and develop within different cultures; 2. To understand drivers of behavioural consistency and spillover effects across contexts, including home and work, and cultures; and 3. To develop a theoretical framework for behavioural spillover and test interventions to promote spillover across different contexts and cultures. Three Work Packages will address these objectives: 1. Defining and understanding spillover: Focus groups with biographical questions and card sorts [Years 1-2] 2. Examining drivers of spillover: Cross-national survey with factor, correlation and regression analyses [Years 2-3] 3. Developing theory and testing interventions: Laboratory and field experiments [Years 3-5]

1 486 563 €

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

The present research project focuses on an unjustly neglected corpus of late-medieval sources, the administrative and fiscal accounts (‘computi’) of the castellanies – basic administrative units – of the county of Savoy. I propose a holistic model of analysis that can fully capitalise on the unusual wealth of detail of the Savoyard source material, in order to illuminate some key topics in late-medieval institutional and socio-economic history, from the development of state institutions through administrative and fiscal reform – with particular attention to the transition from personal to institutional accountability – to the question of socio-economic growth, decline, and recovery during the turbulent period of the late-thirteenth to the late-fourteenth century. More broadly, my research into these topics aims to contribute to our understanding of the late-medieval origins of European modernity. The advances of pragmatic literacy, record-keeping, and auditing practices will be analysed with the aid of anthropological and social scientific theories of practice. By comparing the Savoyard ‘computi’ with their sources of inspiration, from the Anglo-Norman pipe rolls to the Catalan fiscal records, the project aims to highlight the creative adaptation of imported administrative models, and thus to contribute to our knowledge of institutional transfers in European history. The project will develop an inclusive frame of analysis in which the ‘computi’ will be read against the evidence from enfeoffment charters, castellany surveys (‘extente’), and the records of direct taxation (‘subsidia’). The serial data will be analysed by building a database; the findings of quantitative analysis will be verified by case studies of the individuals and families (many from the middle social strata) that surface in the fiscal records.

671 875 €

Start date: 2015-05-01, End date: 2020-04-30

The aim of CATALIGHT is to use sunlight as a source of energy in order to trigger chemical reactions by harvesting photons with plasmonic nanoparticles and channelling the energy into catalytic materials. Plasmonic-catalytic devices would allow efficient harvest, transport, and injection of solar energy into molecules. To achieve this, imaging the energy flow at the nanoscale will be crucial for establishing the true potential of plasmonics, both in the context of yielding fundamental knowledge about the light-into-chemical energy conversion processes, and for moving from active towards efficient reactive devices within nanoscale environments. CATALIGHT has roots in three underlying components, making this project an interwoven effort to break new grounds in a crucial field for the further development of nanoscale energy manipulation: A) Super-resolution imaging of the energy-flow at the nanoscale – with a view to unravel the most efficient mechanisms to guide solar energy into catalytic materials using plasmonic structures as photon harvesters. B) Scaling-up this process through the fabrication of hierarchical photocatalytic colloids – using image-learning for the design of colloidal sources for energy manipulation. C) Light-into-chemical energy conversion – boosting efficiencies in environmental and industrial catalytic processes using tailored photocatalysts. The outcomes of this project will not only yield a substantial amount of fundamental knowledge in these crucial areas for the further development of the field, but also provide directly exploitable results for the applied sciences, particularly photocatalysis and fuel cells.

1 500 000 €

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

According to string theory, coherent sheaves on three-dimensional Calabi-Yau spaces encode fundamental properties of the universe. On the other hand, they have a purely mathematical definition. We will develop and use the new field of categorified Donaldson-Thomas (DT) theory, which counts these objects. Via the powerful perspective of noncommutative algebraic geometry, this theory has found application in recent years in a wide variety of contexts, far from classical algebraic geometry. Categorification has proved tremendously powerful across mathematics, for example the entire subject of algebraic topology was started by the categorification of Betti numbers. The categorification of DT theory leads to the replacement of the numbers of DT theory by vector spaces, of which these numbers are the dimensions. In the area of categorified DT theory we have been able to prove fundamental conjectures upgrading the famous wall crossing formula and integrality conjecture in noncommutative algebraic geometry. The first three projects involve applications of the resulting new subject: 1. Complete the categorification of quantum cluster algebras, proving the strong positivity conjecture. 2. Use cohomological DT theory to prove the outstanding conjectures in the nonabelian Hodge theory of Riemann surfaces, and the subject of Higgs bundles. 3. Prove the comparison conjecture, realising the study of Yangian quantum groups and the geometric representation theory around them as a special case of DT theory. The final objective involves coming full circle, and applying our recent advances in noncommutative DT theory to the original theory that united string theory with algebraic geometry: 4. Develop a generalised theory of categorified DT theory extending our results in noncommutative DT theory, proving the integrality conjecture for categories of coherent sheaves on Calabi-Yau 3-folds.

1 239 435 €

Start date: 2017-11-01, End date: 2022-10-31

Medicinal chemistry requires more efficient and diverse methods for the asymmetric synthesis of chiral scaffolds. Over 60% of the world’s top selling small molecule drug compounds are chiral and, of these, approximately 80% are marketed as single enantiomers. There is a compelling correlation between drug candidate “chiral complexity” and the likelihood of progression to the marketplace. Surprisingly, and despite the tremendous advances made in catalysis over the past several decades, the “chiral complexity” of drug discovery libraries has actually decreased, while, at the same time, for the reasons mentioned above, the “chiral complexity” of marketed drugs has increased. Since the mid-1990s, there has been a notable acceleration of this “complexity divergence”. Consequently, there is now an urgent need to provide efficient processes that directly access privileged chiral scaffolds. It is our philosophy that catalysis holds the key here and new processes should be based upon platforms that can exert control over both absolute and relative stereochemistry. In this proposal we outline the development of a range of N-heteroannulation processes based upon the catalytic generation and trapping of unique or unusual classes of organometallic intermediate derived from transition metal insertion into C-C and C-N sigma-bonds. We will provide a variety of enabling methodologies and demonstrate applicability in flexible total syntheses of important natural product scaffolds. The processes proposed are synthetically flexible, operationally simple and amenable to asymmetric catalysis. Likely starting points, based upon preliminary results, will set the stage for the realisation of aspirational and transformative goals. Through the study of the organometallic intermediates involved here, there is potential to generalise these new catalytic manifolds, such that this research will transcend N heterocyclic chemistry to provide enabling methods for organic chemistry as a whole.

1 548 738 €

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

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

Dikes and sills are large sheet-like intrusions transporting and storing magma in the Earth’s crust. When propagating, they generate seismicity and deformation and may lead to volcanic eruption. The physics of magma-filled structures is similar to that of any fluid-filled reservoir, such as oil fields and CO2 reservoirs created by sequestration. This project aims to address old and new unresolved challenging questions related to dike propagation, sill emplacement and in general to the dynamics of fluid and gas-filled reservoirs. I propose to focus on crustal deformation, induced seismicity and external stress fields to study the signals dikes and sills produce, how they grow and why they reactivate after years of non-detected activity. I will combine experimental, numerical and analytical techniques, in close cooperation with volcano observatories providing us with the data necessary to validate our models. In the lab, I will simulate magma propagation injecting fluid into solidified gelatin. I will also contribute to a project, currently under evaluation, on the monitoring of a CO2 sequestration site. At the same time, I will address theoretical aspects, extending static models to dynamic cases and eventually developing a comprehensive picture of the multi faceted interaction between external stress field, magma and rock properties, crustal deformation and seismicity. I also plan, besides presenting my team’s work in the major national and international geophysical conferences, to produce, with technical support from the media services of DKRZ (Deutsches Klimarechenzentrum), an audiovisual teaching DVD illustrating scientific advances and unresolved issues in magma dynamics, in the prediction of eruptive activity and in the physics of reservoirs.

1 507 679 €

Start date: 2010-07-01, End date: 2015-06-30

A critical question in neuroscience is to understand how neurons wire up to form a functional network. During the wiring of the brain it is important to establish mechanisms that act as safeguards to control and stabilize neuronal excitability in the face of large, chronic changes in neuronal or network activity. This is especially true for developing systems that undergo rapid and large scale forms of plasticity, which could easily lead to large imbalances in activity. If left unchecked, they could lead the network to its extremes: a complete loss of signal or epileptic-like activity. For this reason neurons employ different strategies to maintain their excitability within reasonable bounds. This proposal will focus on two crucial sites for neuronal information processing and integration: the synapse and the axon initial segment (AIS). Both sites undergo important structural and functional rearrangements in response to chronic activity changes, thus controlling the input-output function of a neuron and allowing the network to function efficiently. This proposal will explore novel forms of plasticity that occur during development and which are key to establishing a functional network. They range from understanding the role of activity during synapse formation to how pre- and postsynaptic structure and function become matched during development. Finally, it tackles a novel form of plasticity that lies downstream of synaptic inputs and is responsible for setting the threshold of action potential firing: the axon initial segment. Here, chronic changes in network activity results in a physical relocation of the AIS along the axon, which in turn alters the excitability of the neuron. This proposal will focus on the central issue of how a neuron alters both its input (synapses) and output (AIS) during development to maintain its activity levels within a set range and allow a functional network to form.

1 500 000 €

Start date: 2012-03-01, End date: 2017-02-28