ERC FUNDED PROJECTS

Who are the people of Europe? This question is facing statisticians as they grapple with standardising national census methods so that their numbers can be assembled into a European population. Yet, by so doing—intentionally or otherwise—they also contribute to the making of a European people. This, at least, is the central thesis of ARITHMUS. While typically framed as a methodological or statistical problem, the project approaches this as a practical and political problem of assembling multiple national populations into a European population and people. Why is this both an urgent political and practical problem? Politically, Europe is said to be unable to address itself to a constituted polity and people, which is crucial to European integration. Practically, its efforts to constitute a European population are also being challenged by digital technologies, which are being used to diversify census methods and bringing into question the comparability of national population data. Consequently, over the next several years Eurostat and national statistical institutes are negotiating regulations for the 2020 census round towards ensuring 'Europe-wide comparability.' ARITHMUS will follow this process and investigate the practices of statisticians as they juggle scientific independence, national autonomy and EU comparability to innovate census methods. It will then connect this practical work to political questions of the making and governing of a European people and polity. It will do so by going beyond state-of-the art scholarship on methods, politics and science and technology studies. Five case studies involving discourse analysis and ethnographic methods will investigate the situated practices of EU and national statisticians as they remake census methods, arguably the most fundamental changes since modern censuses were launched over two centuries ago. At the same time it will attend to how these practices affect the constitution of who are the people of Europe.

1 833 649 €

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

This proposal details the mechanism-based discovery of ground-breaking new catalyst systems for a broad range of arylation processes that will be of immediate and long-lasting utility to the pharmaceutical, agrochemical, and materials chemistry industries. These industries have become highly dependent on coupling technologies employing homogeneous late transition metal catalysis and this reliance will grow further, particularly if the substrate scope can be broadened, the economics, in terms of reagents and catalyst, made more favourable, the reliability at scale-up improved, and the generation of side-products, of particular importance for optical and electronic properties of materials, minimized or eliminated. This proposal addresses these issues by conducting a detailed and comprehensive mechanistic investigation of direct arylation, so that a substantial expansion of the reaction scope can be achieved. At present, the regioselectivity can be very high, however catalyst turnover rates are moderate, and the arene is required to be in a fairly narrow window of activity. Specific aspects to be addressed in terms of mechanistic study are: catalyst speciation and pathways for deactivation; pathways for homocoupling; influence of anions and dummy ligands; protodemetalloidation pathways. Areas proposed for mechanism-informed development are: expansion of metalloid tolerance; expansion of arene scope; use of traceless activators and directors, new couplings via ligand exchange, the evolution of simpler / cheaper and more selective / active catalysts; expansion to oxidative double arylations (Ar-H + Ar’-H) with control, and without resort to super-stoichiometric bias. The long-term legacy of these studies will be detailed insight for current and emerging systems, as well as readily extrapolated information for the design of new, more efficient catalyst systems in academia, and their scaleable application in industry

2 114 223 €

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

The Arctic Ocean is a vast expanse of sea ice. Most of it is snow covered as are large continental regions for about half of the year. However, Global Change is arguably greatest in the Arctic, where temperatures have risen more than anywhere else in the last few decades. New record lows occurred in snow extent in June 2012 and sea ice extent in September 2012. Many observations show that widespread and sustained change is occurring in the Arctic driving this unique environmental system into a new state. This project focuses on the biogeochemical links between sea ice and snow and the composition and chemistry of the troposphere (the lowest ~10km of the atmosphere). This is an important topic because the concentrations of greenhouse gases and aerosol particles, which scatter sunlight directly and influence cloud properties, play key roles for our climate. Additionally, changes in the composition of the troposphere also affect the so-called oxidation capacity, the capability of the atmosphere to cleanse itself from pollutants. This project aims to deliver a step change improvement in our quantitative understanding of chemical exchanges between ocean, sea ice, snow and the atmosphere in polar regions, especially the Arctic and of Arctic tropospheric chemistry. Answering these fundamental questions is essential to predict future change in the Arctic and globally. To this end a unique sea ice chamber will be constructed in the laboratory and used to quantify exchange processes in sea ice. Furthermore a hierarchy of numerical models will be used, operating at different spatial and temporal scales and degree of process description from a very detailed 1D to a global Earth System model. This will allow a breakthrough in our understanding of the importance of the changes for the composition and oxidation capacity of the atmosphere and climate and will allow us to calculate adjusted Greenhouse Warming Potentials that include these processes.

1 192 911 €

Start date: 2014-05-01, End date: 2016-09-30

Asthma exacerbations represent a high unmet medical need in particular in young children. Human Rhinoviruses (HRV) are the main triggers of these exacerbations. Till now Th2 cells were considered the main initiating effector cell type in asthma in general and asthma exacerbations in particular. However, exaggerated Th2 cell activities alone do not explain all aspects of asthma and exacerbations. Building on our recent discovery of type 2 human innate lymphoid cells (ILC2) capable of promptly producing high amounts of IL-5, IL-9 and IL-13 upon activation and on mouse data pointing to an essential role of these cells in asthma and asthma exacerbations, ILC2 may be the main initiating cells in asthma exacerbations in humans. Thus we hypothesize that HRV directly or indirectly stimulate ILC2s to produce cytokines driving the effector functions leading to the end organ effects that characterize this debilitating disease. Targeting ILC2 and HRV in parallel will provide a highly attractive therapeutic option for the treatment of asthma exacerbations. In depth study of the mechanisms of ILC2 differentiation and function will lead to the design effective drugs targeting these cells; thus the first two objectives of this project are: 1) To unravel the lineage relationship of ILC populations and to decipher the signal transduction pathways that regulate the function of ILCs, 2) to test the functions of lung-residing human ILCs and the effects of compounds that affect these functions in mice which harbour a human immune system and human lung epithelium under homeostatic conditions and after infections with respiratory viruses. The third objective of this project is developing reagents that target HRV; to this end we will develop broadly reacting highly neutralizing human monoclonal antibodies that can be used for prophylaxis and therapy of patients at high risk for developing severe asthma exacerbations.

2 499 593 €

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

In the 90s, two landmark observations brought to a paradigm shift about the role of astrocytes in brain function: 1) astrocytes respond to signals coming from other cells with transient Ca2+ elevations; 2) Ca2+ transients in astrocytes trigger release of neuroactive and vasoactive agents. Since then, many modulatory astrocytic actions and mechanisms were described, forming a complex - partly contradictory - picture, in which the exact roles and modes of astrocyte action remain ill defined. Our project wants to bring light into the “language of astrocytes”, i.e. into how they communicate with neurons and, ultimately, address their role in brain computations and cognitive behavior. To this end we will perform 4 complementary levels of analysis using highly innovative methodologies in order to obtain unprecedented results. We will study: 1) the subcellular organization of astrocytes underlying local microdomain communications by use of correlative light-electron microscopy; 2) the way individual astrocytes integrate inputs and control synaptic ensembles using 3D two-photon imaging, genetically-encoded Ca2+ indicators, optogenetics and electrophysiology; 3) the contribution of astrocyte ensembles to behavior-relevant circuit operations using miniaturized microscopes capturing neuronal/astrocytic population dynamics in freely-moving mice during memory tests; 4) the contribution of astrocytic signalling mechanisms to cognitive behavior using a set of new mouse lines with conditional, astrocyte-specific genetic modification of signalling pathways. We expect that this combination of groundbreaking ideas, innovative technologies and multilevel analysis makes our project highly attractive to the neuroscience community at large, bridging aspects of molecular, cellular, systems and behavioral neuroscience, with the goal of leading from a provocative hypothesis to the conclusive demonstration of whether and how “the language of astrocytes” participates in memory and cognition.

2 513 896 €

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

At every moment in time, the brain receives a vast amount of sensory information about the environment. This makes attention, the process by which we select currently relevant stimuli for processing and ignore irrelevant input, a fundamentally important brain function. Studies in primates have yielded a detailed description of how attention to a stimulus modifies the responses of neuronal ensembles in visual cortex, but how this modulation is produced mechanistically in the circuit is not well understood. Neuronal circuits comprise a large variety of neuron types, and to gain mechanistic insights, and to treat specific diseases of the nervous system, it is crucial to characterize the contribution of different identified cell types to information processing. Inhibition supplied by a small yet highly diverse set of interneurons controls all aspects of cortical function, and the central hypothesis of this proposal is that differential modulation of genetically-defined interneuron types is a key mechanism of attention in visual cortex. To identify the interneuron types underlying attentional modulation and to investigate how this, in turn, affects computations in the circuit we will use an innovative multidisciplinary approach combining genetic targeting in mice with cutting-edge in vivo 2-photon microscopy-based recordings and selective optogenetic manipulation of activity. Importantly, a key set of experiments will test whether the observed neuronal mechanisms are causally involved in attention at the level of behavior, the ultimate readout of the computations we are interested in. The expected results will provide a detailed, mechanistic dissection of the neuronal basis of attention. Beyond attention, selection of different functional states of the same hard-wired circuit by modulatory input is a fundamental, but poorly understood, phenomenon in the brain, and we predict that our insights will elucidate similar mechanisms in other brain areas and functional contexts.

1 466 505 €

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

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

1 499 780 €

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

"X-ray crystallography yields atomic-resolution 3D images of the whole spectrum of molecules ranging from small inorganic clusters to large protein complexes constituting the macromolecular machinery of life. Life is not static, and many of the most important reactions in chemistry and biology are light induced and occur on ultrafast timescales. These have been studied with high time resolution primarily by ultrafast laser spectroscopy, but they reduce the vast complexity of the process to a few reaction coordinates. Here we develop attosecond serial crystallography and spectroscopy, to give a full description of ultrafast processes atomically resolved in real space and on the electronic energy landscape, from co-measurement of X-ray and optical spectra, and X-ray diffraction. This technique will revolutionize our understanding of structure and function at the atomic and molecular level and thereby unravel fundamental processes in chemistry and biology. We apply a fully coherent attosecond X-ray source based on coherent inverse Compton scattering off a free-electron crystal, developed in this project, to outrun radiation damage effects due to the necessary high X-ray irradiance required to acquire diffraction signals [A. Cho, ""Breakthrough of the year"", Science 388, 1530 (2012)]. Our synergistic project will optimize the entire instrumentation towards fundamental measurements of the mechanism of light absorption and excitation energy transfer. The multidisciplinary team optimizes X-ray pulse parameters, in tandem with sample delivery, crystal size, and advanced X-ray detectors. We will apply our new capabilities to one of the most important problems in structural biology, which is to elucidate the dynamics of light reactions, electron transfer and protein structure in photosynthesis. Also, the attosecond source can provide a coherent seed and will help to overcome peak flux limitations of X-ray FELs by introducing chirped pulse amplification to FEL technology."

13 884 200 €

Start date: 2014-08-01, End date: 2020-07-31

Membranes of eukaryotic cells organize signal transduction proteins into microdomains or lipid rafts whose integrity is essential for numerous cellular processes. Lipid rafts has been considered a fundamental step to define the cellular complexity of eukaryotes, assuming that bacteria do not require such a sophisticated organization of their signaling networks. However, I have discovered that bacteria organize many signaling pathways in membrane microdomains similar to the eukaryotic lipid rafts. Perturbation of bacterial lipid rafts leads to a potent and simultaneous impairment of all raft-harbored signaling pathways. Consequently, the disassembly of lipid rafts in pathogens like Staphylococcus aureus generates a simultaneous inhibition of numerous infection-related processes that can be further explored to control bacterial infections. This unexpected sophistication in membrane organization is unprecedented in bacteria and hence, this proposal will explore the molecular basis of the assembly of bacterial lipid rafts and their role in the infection-related processes. These questions will be addressed in three main goals: First, I will elucidate the molecular components and the mechanism of assembly of bacterial lipid rafts using S. aureus as model organism. Second, I will dissect the molecular basis that links the functionality of the infection-related processes to the integrity of bacterial lipid rafts. Third, my collection of anti-raft small molecules that are able to disrupt lipid rafts will be tested as antimicrobial agents to prevent hospital-acquired infections, abrogate pre-existing infections and develop bacteria-free materials that can be used in clinical settings. I will use a number of molecular approaches in combination with cutting-edge techniques in flow cytometry, cell-imaging and transcriptomics to clarify the architecture and functionality of lipid rafts and demonstrate the feasibility of targeting lipid a new strategy for anti-microbial therapy.

1 493 126 €

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

"The main objective of this application is to study the molecular basis of cellular infection by bacterial ABC-type toxins (Tc). Tc complexes are important virulence factors of a range of bacteria, including Photorhabdus luminescens and Yersinia pseudotuberculosis that infect insects and humans. Belonging to the class of pore-forming toxins, tripartite Tc complexes perforate the host membrane by forming channels that translocate toxic enzymes into the host. In our previous cryo-EM work on the P. luminescens Tc complex we discovered that Tcs use a special syringe-like device for cell entry. Building on these results, we now intend to unravel the molecular mechanism through which this unusual and complicated injection system allows membrane permeation and protein translocation. We will use a hybrid approach, including biochemical reconstitution, structural analysis by cryo-EM and X-ray crystallography, fluorescence-based assays and site-directed mutagenesis to provide a comprehensive description of the molecular mechanism of infection at an unprecedented level of molecular detail. Our results will be paradigmatic for understanding the mechanism of action of ABC-type toxins and will shed new light on the interactions of bacterial pathogens with their hosts."

1 999 992 €

Start date: 2014-07-01, End date: 2019-06-30

The discovery of deep-sea hydrothermal vents in 1977 was one of the most profound findings of the 20th century, revolutionizing our perception of energy sources fueling primary productivity on Earth. These ecosystems are based on chemosynthesis, that is the fixation of carbon dioxide into organic compounds as in photosynthesis, but using inorganic compounds such as sulfide, methane or hydrogen, as energy sources instead of sunlight. Hydrothermal vents support tremendous biomass and productivity of which the majority is generated through symbiotic microbe-animal associations. Bathymodiolus mussels are able to build extraordinarily large and productive communities at hydrothermal vents because they harbor symbiotic bacteria that use inorganic energy sources from the vent fluids to feed their hosts via carbon fixation. In addition to their beneficial symbionts, the mussels are infected by a novel bacterial parasite that exclusively invades and multiplies in their nuclei. In the work proposed here, I will use a wide array of tools that range from deep-sea in situ instruments to sophisticated molecular, 'omic' and imaging analyses to study the microbiome associated with Bathymodiolus mussels. The proposed research bridges biogeochemistry, ecological and evolutionary biology, and molecular microbiology to develop a systematic understanding of the symbiotic interactions between microbes, their hosts, and their environment in one of the most extreme and fascinating habitats on Earth, hydrothermal vents.

2 499 122 €

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

Next generation sequencing (NGS) is revolutionizing all fields of biological research but it fails to extract the full range of information associated with genetic material and is lacking in its ability to resolve variations between genomes. The high degree of genome variation exhibited both on the population level as well as between genetically “identical” cells (even in the same organ) makes genetic and epigenetic analysis on the single cell and single genome level a necessity. Chromosomes may be conceptually represented as a linear one-dimensional barcode. However, in contrast to a traditional binary barcode approach that considers only two possible bits of information (1 & 0), I will use colour and molecular structure to expand the variety of information represented in the barcode. Like colourful beads threaded on a string, where each bead represents a distinct type of observable, I will label each type of genomic information with a different chemical moiety thus expanding the repertoire of information that can be simultaneously measured. A major effort in this proposal is invested in the development of unique chemistries to enable this labelling. I specifically address three types of genomic variation: Variations in genomic layout (including DNA repeats, structural and copy number variations), variations in the patterns of chemical DNA modifications (such as methylation of cytosine bases) and variations in the chromatin composition (including nucleosome and transcription factor distributions). I will use physical extension of long DNA molecules on surfaces and in nanofluidic channels to reveal this information visually in the form of a linear, fluorescent “barcode” that is read-out by advanced imaging techniques. Similarly, DNA molecules will be threaded through a nanopore where the sequential position of “bulky” molecular groups attached to the DNA may be inferred from temporal modulation of an ionic current measured across the pore.

1 627 600 €

Start date: 2013-10-01, End date: 2018-09-30

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

The challenge in cell physiology/pathology today is to translate in vitro findings to the living organism. We have developed a unique approach where signal-transduction can be investigated in vivo non-invasively, longitudinally at single cell resolution, using the anterior chamber of the eye as a natural body window for imaging. We will use this approach to understand how the universally important and highly complex signal Ca2+ is regulated in the pancreatic beta-cell, while localized in the vascularized and innervated islet of Langerhans, and how that affects the insulin secretory machinery in vivo. Engrafted islets in the eye take on identical innervation- and vascularization patterns as those in the pancreas and are proficient in regulating glucose homeostasis in the animal. Since the pancreatic islet constitutes a micro-organ, this imaging approach offers a seminal model system to understand Ca2+ signaling in individual cells at the organ level in real life. We will test the hypothesis that the Ca2+-signal has a key role in pancreatic beta-cell function and survival in vivo and that perturbation in the Ca2+-signal serves as a common denominator for beta-cell pathology associated with impaired glucose homeostasis and diabetes. Of special interest is how innervation impacts on Ca2+-dynamics and the integration of autocrine, paracrine and endocrine signals in fine-tuning the Ca2+-signal with regard to beta-cell function and survival. We aim to define key defects in the machinery regulating Ca2+-dynamics in association with the autoimmune reaction, inflammation and obesity eventually resulting in diabetes. Our imaging platform will be applied to clarify in vivo regulation of Ca2+-dynamics in both healthy and diabetic human beta-cells. To define novel drugable targets for treatment of diabetes, it is crucial to identify similarities and differences in the molecular machinery regulating the in vivo Ca2+-signal in the human and in the rodent beta-cell.

2 499 590 €

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

Alzheimer disease (AD) is the most common form of age-related dementia affecting millions of patients worldwide. Disturbingly, disorders of lipid and glucose metabolism emerge as major risk factors for onset and progression of neurodegeneration in the human population. Thus, an increasing life expectance combined with an observable rise in metabolic disturbances is expected to turn AD into one of the most serious health problems for future generations. Still, the molecular mechanisms whereby dysregulation of glucose and lipid homeostasis elicits noxious insults to the brain remain poorly understood. We characterized a novel class of intracellular sorting receptors, termed VPS10P domain receptors with dual roles in regulation of neuronal viability and function, but also in modulation of glucose and lipid homeostasis. Our proposal aims at elucidating an important yet poorly understood link between metabolism and neurodegeneration that converges on these receptors. Our approach is unique and novel in several ways. Thematically, our studies focus on a novel class of receptors previously not considered. Based on the receptors’ ability to act as sorting proteins, we propose faulty protein trafficking as a major unifying concept underlying neurodegenerative and metabolic disorders. Conceptually, our approach relies on the interdisciplinary effort of neuroscientists and metabolism researchers working jointly on pathophysiological pathways converging on these receptors. Through this effort, we are confident to gain important insights into the crosstalk between brain and peripheral tissues, and to elucidate pathways common to metabolic disturbances and dementia, two prevailing degenerative disorders inflicting our societies.

2 415 229 €

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

Cavitation is the formation of vapor cavities inside a liquid due to low pressure. Cavitation is an ubiquitous and destructive phenomenon common to most engineering applications that deal with flowing water. At the same time, the extreme conditions realized in cavitation are increasingly exploited in medicine, chemistry, and biology. What makes cavitation unpredictable is its multiscale nature: nucleation of vapor bubbles heavily depends on micro- and nanoscale details; mesoscale phenomena, as bubble collapse, determine relevant macroscopic effects, e.g., cavitation damage. In addition, macroscopic flow conditions, such as turbulence, have a major impact on it. The objective of the BIC project is to develop the lacking multiscale description of cavitation, by proposing new integrated numerical methods capable to perform quantitative predictions. The detailed and physically sound understanding of the multifaceted phenomena involved in cavitation (nucleation, bubble growth, transport, and collapse in turbulent flows) fostered by BIC project will result in new methods for designing fluid machinery, but also therapies in ultrasound medicine and chemical reactors. The BIC project builds upon the exceptionally broad experience of the PI and of his research group in numerical simulations of flows at different scales that include advanced atomistic simulations of nanoscale wetting phenomena, mesoscale models for multiphase flows, and particle-laden turbulent flows. The envisaged numerical methodologies (free-energy atomistic simulations, phase-field models, and Direct Numerical Simulation of bubble-laden flows) will be supported by targeted experimental activities, designed to validate models and characterize realistic conditions.

2 491 200 €

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

High precision radiotherapy (RT) allows extremely flexible tumour treatments achieving highly conformal radiation doses while sparing surrounding organs at risk. Nevertheless, failure rates of up to 50% are reported for head and neck cancer (HNC) due to radiation resistance induced by pathophysiologic factors such as hypoxia and other clinical factors as HPV-status, stage and tumour volume. This project aims at developing a multi-parametric model for individualized RT (iRT) dose prescriptions in HNC based on biological markers and functional PET/MR imaging. This project goes far beyond current research standards and clinical practice as it aims for establishing hypoxia PET and f-MRI as well as biological markers in HNC as a role model for a novel concept from anatomy-based to biologically iRT. During this project, a multi-parametric model will be developed on a preclinical basis that combines biological markers such as different oncogenes and hypoxia gene classifier with functional PET/MR imaging, such as FMISO PET in combination with different f-MRI techniques, like DW-, DCE- and BOLD-MRI in addition to MR spectroscopy. The ultimate goal of this project is a multi-parametric model to predict therapy outcome and guide iRT. In a second part, a clinical study will be carried out to validate the preclinical model in patients. Based on the most informative radiobiological and imaging parameters as identified during the pre-clinical phase, biological markers and advanced PET/MR imaging will be evaluated in terms of their potential for iRT dose prescription. Successful development of a model for biologically iRT prescription on the basis of multi-parametric molecular profiling would provide a unique basis for personalized cancer treatment. A validated multi-parametric model for RT outcome would represent a paradigm shift from anatomy-based to biologically iRT concepts with the ultimate goal of improving cancer cure rates.

1 370 799 €

Start date: 2014-01-01, End date: 2018-12-31

Personalized medicine is a medical model that proposes the customization of healthcare, with decisions and practices being tailored to the individual patient by use of patient-specific information and/or application of patient-specific cell-based therapies. BioBlood aims to deliver personalised healthcare through a “step change” in the clinical field of haemato-oncology. BioBlood represents an engineered bio-inspired integrated experimental/modelling platform for normal and abnormal haematopoiesis that receives disease & patient input (patient primary cells & patient/disease-specific data) and will produce cellular (red blood cell product) and drug (optimal drug treatment) therapies as its output. Blood supply to meet demand is the primary challenge for Blood Banks and requires significant resources to avoid shortages and ensure safety. An alternative, practical and cost-effective solution to conventional donated blood is essential to reduce patient morbidity and mortality, stabilise and guarantee the donor supply, limit multiple donor exposures, reduce risk of infection of known or as yet unidentified pathogens, and ensure a robust and safe turn-around for blood supply management. BioBlood aims to meet this challenge by developing a novel in vitro platform for the mass production of RBCs for clinical use. More than £32b/year is spent to develop and bring new drugs to market, which takes 14 years. Most patients diagnosed with leukaemias are unable to tolerate treatment and would benefit from novel agents. There is a need to optimise current treatment schedules for cancers such as AML to limit toxicities and improve clinical trial pathways for new drugs to enable personalised healthcare. BioBlood’s in vitro & in silico platform would be a powerful tool to tailor treatments in a patient- and leukaemia-specific chemotherapy schedule by considering the level of toxicity to the specific individual and treatment efficiency for the specific leukaemia a priori.

2 498 903 €

Start date: 2014-01-01, End date: 2018-12-31

"In the course of biomineralization, organisms produce a large variety of functional biogenic crystals that exhibit fascinating mechanical, optical, magnetic and other characteristics. More specifically, when living organisms grow crystals they can effectively control polymorph selection as well as the crystal morphology, shape, and even atomic structure. Materials existing in nature have extraordinary and specific functions, yet the materials employed in nature are quite different from those engineers would select. I propose to emulate specific strategies used by organisms in forming structural biogenic crystals, and to apply these strategies biomimetically so as to form new structural materials with new properties and characteristics. This bio-inspired approach will involve the adoption of three specific biological strategies. We believe that this procedure will open up new ways to control the structure and properties of smart materials. The three bio-inspired strategies that we will utilize are: (i) to control the short-range order of amorphous materials, making it possible to predetermine the polymorph obtained when they transform from the amorphous to the succeeding crystalline phase; (ii) to control the morphology of single crystals of various functional materials so that they can have intricate and curved surfaces and yet maintain their single-crystal nature; (iii) to entrap organic molecules into single crystals of functional materials so as to tailor and manipulate their electronic structure. The proposed research has significant potential for opening up new routes for the formation of novel functional materials. Specifically, it will make it possible for us (1) to produce single, intricately shaped crystals without the need to etch, drill or polish; (2) to control the short-range order of amorphous materials and hence the polymorph of the successive crystalline phase; (3) to tune the band gap of semiconductors via incorporation of tailored bio-molecules."

1 500 000 €

Start date: 2013-09-01, End date: 2018-08-31

Water is the first molecule to come into contact with biomaterials in biological systems and thus essential to the processes of biodegradation, biocompatibility and biofouling. Despite this fact, little is currently known about how biomaterials interact with water. This knowledge is crucial for the development and optimisation of novel functional biomaterials for human health (e.g. biosensing devices, erodible biomaterials, drug release carriers, wound dressings). BioWater will develop near and mid infrared chemical imaging (NIR-MIR-CI) techniques to investigate the fundamental interaction between biomaterials and water in order to understand the key processes of biodegradation, biocompatibility and biofouling. This ambitious yet achievable project will focus on two major categories of biomaterials relevant to human health: extracellular collagens and synthetic biopolymers. Initially, interactions between these biomaterials and water will be investigated; subsequently interactions with more complicated matrices (e.g. protein solutions and cellular systems) will be studied. CI data will be correlated with standard surface characterization, biocompatibility and biodegradation measurements. Molecular dynamic simulations will complement this work to identify the most probable molecular structures of water at different biomaterial interfaces. Advanced understanding of the role of water in biocompatibility, biofouling and biodegradation processes will facilitate the optimization of biomaterials tailored to specific cellular environments with a broad range of therapeutic applications (e.g. drug eluting stents, tissue engineering, wound healing). The new NIR-MIR-CI/chemometric methodologies developed in BioWater will allow for the rapid characterization and monitoring of novel biomaterials at pre-clinical stages, improving process control by overcoming the laborious and time consuming large-scale sampling methods currently required in biomaterials development.

1 487 682 €

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

"Transcriptional regulation of protein coding genes in eukaryotic cells requires a complex interplay of sequence-specific DNA-binding factors, co-activators, general transcription factors (GTFs), RNA polymerase II and the epigenetic status of target sequences. Nuclear transcription complexes function as large multiprotein assemblies and are often composed of functional modules. The regulated decision-making that exists in cells governing the assembly and the allocation of factors to different transcription complexes to regulate distinct gene expression pathways is not yet understood. To tackle this fundamental question, we will systematically analyse the regulated biogenesis of transcription complexes from their sites of translation in the cytoplasm, through their assembly intermediates and nuclear import, to their site of action in the nucleus. The project will have four main Aims to decipher the biogenesis of transcription complexes: I) Investigate their co-translation-driven assembly II) Determine their cytoplasmic intermediates and factors required for their assembly pathways III) Uncover their nuclear import IV) Understand at the single molecule level their nuclear assembly, dynamics and action at target genes To carry out these aims we propose a combination of multidisciplinary and cutting edge approaches, out of which some of them will be high-risk taking, while others will utilize methods routinely run by the group. The project builds on several complementary expertise and knowledge either already existing in the group or that will be implemented during the project. At the end of the proposed project we will obtain novel results extensively describing the different steps of the regulatory mechanisms that control the assembly and the consequent gene regulatory function of transcription complexes. Thus, we anticipate that the results of our research will have a major impact on the field and will lead to a new paradigm for contemporary metazoan transcription."

2 500 000 €

Start date: 2014-01-01, End date: 2018-12-31

"Atmospheric aerosol particles have been shown to impact the earth's climate because they scatter and absorb solar radiation (direct effect) and because they can modify the microphysical properties of clouds by acting as cloud condensation nuclei or ice nuclei (indirect effects). Radiative forcing by anthropogenic aerosols remains poorly quantified, thus leading to considerable uncertainty in our understanding of the earth’s climate response to the radiative forcing by greenhouse gases. Black carbon (BC), mostly emitted by anthropogenic combustion processes and biomass burning, is an important component of atmospheric aerosols. Estimates show that BC may be the second strongest contributor (after CO2) to global warming. Adverse health effects due to particulate air pollution have also been associated with traffic-related BC particles. These climate and health effects brought BC emission reductions into the political focus of possible mitigation strategies with immediate and multiple benefits for human well-being. Laboratory experiments aim at the physical and chemical characterisation of BC emissions from diesel engines and biomass burning under controlled conditions. A mobile laboratory equipped with state-of-the-art aerosol sensors will be used to determine the contribution of different BC sources to atmospheric BC loadings, and to investigate the evolution of the relevant BC properties with atmospheric aging during transport from sources to remote areas. The interactions of BC particles with clouds as a function of BC properties will be investigated with in-situ measurements by operating quantitative single particle instruments behind a novel sampling inlet, which makes selective sampling of interstitial, cloud droplet residual or ice crystal residual particles possible. Above experimental studies aim at improving our understanding of BC’s atmospheric life cycle and will be used in model simulations for quantitatively assessing the atmospheric impacts of BC."

1 992 015 €

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

The global performing arts community is requiring innovative systems to: a) document, transmit and preserve the knowledge contained in choreographic-dramaturgic practices; b) assist artists with tools to facilitate their compositional processes, preferably on a collaborative basis. The existing digital archives of performing arts mostly function as conventional e-libraries, not allowing higher degrees of interactivity or active user intervention. They rarely contemplate accessible video annotation tools or provide relational querying functionalities based on artist-driven conceptual principles or idiosyncratic ontologies. This proposal endeavours to fill that gap and create a new paradigm for the documentation of performance composition. It aims at the analysis of artists’ unique conceptual structures, by combining the empirical insights of contemporary creators with research theories from Multimodal Communication and Digital Media studies. The challenge is to design a model for a web-based collaborative platform enabling both a robust representation of performance composition methods and novel visualization technologies to support it. This can be done by analysing recurring body movement patterns and by fostering online contributions of users (a.o. performers and researchers) to the multimodal annotations stored in the platform. To accomplish this goal, two subjacent components must be developed: 1. the production of a video annotation-tool to allow artists in rehearsal periods to take notes over video in real-time and share them via the collaborative platform; 2. the linguistic analysis of a corpus of invited artists’ multimodal materials as source for the extraction of indicative conceptual structures, which will guide the architectural logics and interface design of the collaborative platform software.The outputs of these two components will generate critical case-studies to help understanding the human mind when engaged in cultural production processes.

1 378 200 €

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

Within BMP4EAC we aim to investigate the commercial feasibility of our newly discovered and highly specific antibodies against BMP4 and one of its receptors, BMPR1a, for imaging applications in oncology. BMP4 and BMPR1a are highly expressed in esophageal adenocarcinoma (EAC) and other tumors as well as their metastases. The specificity, strong binding capacity, rapid clearance, high tissue penetration level, and flexibility of our antibodies is unprecedented and makes them highly suitable for in vivo imaging applications. The opportunity: The current methods for evaluation of disease stage consist of diverse modalities, including, CT and PET-CT scans, and ultrasonography. These techniques have major limitations to accurately detect metastasis and are inadequate for monitoring disease response. In the clinical setting we foresee applications of our proprietary technology in the non-invasive diagnosis of tumors and metastases with high expression of BMP4 and/or BMPR1a (e.g. EAC), identification of patients with high chance to respond to BMP4 inhibitors, follow tumor progression during treatment, and facilitated localization of small metastases during surgical treatment. Furthermore, the labeled antibodies can be used to investigate the efficacy of novel therapeutic agents by following tumor progression in animal models in a research setting. The project and expected outcomes: Within the ERC PoC we will explore the commercial feasibility by in vivo validation experiments as well as by performing essential research for the formulation of a business proposition, strengthening our IP position, and developing a sound business plan. These activities will result in a proposition package that will be used to present the commercial potential to investors and other strategic partners to attract funding after completion of the ERC PoC and potentially even initiate licensing and partnership deals.

149 840 €

Start date: 2014-09-01, End date: 2016-02-29