ERC FUNDED PROJECTS

Advanced capitalist economies experience large and persistent movements in asset prices that are difficult to justify with economic fundamentals. The internet bubble of the 1990s and the real state market bubble of the 2000s are two recent examples. The predominant view is that these bubbles are a market failure, and are caused by some form of individual irrationality on the part of market participants. This project is based instead on the view that market participants are individually rational, although this does not preclude sometimes collectively sub-optimal outcomes. Bubbles are thus not a source of market failure by themselves but instead arise as a result of a pre-existing market failure, namely, the existence of pockets of dynamically inefficient investments. Under some conditions, bubbles partly solve this problem, increasing market efficiency and welfare. It is also possible however that bubbles do not solve the underlying problem and, in addition, create negative side-effects. The main objective of this project is to develop this view of asset bubbles, and produce an empirically-relevant macroeconomic framework that allows us to address the following questions: (i) What is the relationship between bubbles and financial market frictions? Special emphasis is given to how the globalization of financial markets and the development of new financial products affect the size and effects of bubbles. (ii) What is the relationship between bubbles, economic growth and unemployment? The theory suggests the presence of virtuous and vicious cycles, as economic growth creates the conditions for bubbles to pop up, while bubbles create incentives for economic growth to happen. (iii) What is the optimal policy to manage bubbles? We need to develop the tools that allow policy makers to sustain those bubbles that have positive effects and burst those that have negative effects.

1 000 000 €

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

The biomembrane is a prerequisite of life. It enables the cell to maintain a controlled environment and to establish electrochemical gradients as rapidly accessible energy stores. Biomembranes also provide scaffold for organisation and spatial definition of signal transmission in the cell. Crystal structures of membrane proteins are determined with an increasing pace. Along with functional studies integral studies of individual membrane proteins are now widely implemented. The BIOMEMOS proposal goes a step further and approaches the function of the biomembrane at the higher level of membrane protein complexes. Through a combination of X-ray crystallography, electrophysiology, general biochemistry, biophysics and bioinformatics and including also the application of single-particle cryo-EM and small-angle X-ray scattering, the structure and function of membrane protein complexes of key importance in life will be investigated. The specific targets for investigation in this proposal include: 1) higher-order complexes of P-type ATPase pumps such as signalling complexes of Na+,K+-ATPase, and 2) development of methods for structural studies of membrane protein complexes Based on my unique track record in structural studies of large, difficult structures (ribosomes and membrane proteins) in the setting of a thriving research community in structural biology and biomembrane research in Aarhus provides a critical momentum for a long-term activity. The activity will take advantage of the new possibilities offered by synchrotron sources in Europe. Furthermore, a single-particle cryo-EM research group formed on my initiative in Aarhus, and a well-established small-angle X-ray scattering community provides for an optimal setting through multiple cues in structural biology and functional studies

2 444 180 €

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

My lab is interested in the development of the tissue that gives rise to vertebrae and skeletal muscles called the paraxial mesoderm. A striking feature of this tissue is its segmental organization and we have made major contributions to the understanding of the molecular control of the segmentation process. We identified a molecular oscillator associated to the rhythmic production of somites and proposed a model for vertebrate segmentation based on the integration of a rhythmic signaling pulse gated spatially by a system of traveling FGF and Wnt signaling gradients. We are also studying the differentiation of paraxial mesoderm precursors into the muscle, cartilage and dermis lineages. Our work identified the Wnt, FGF and Notch pathways as playing a prominent role in the patterning and differentiation of paraxial mesoderm. In this application, we largely focus on the molecular control of paraxial mesoderm development. Using microarray and high throughput sequencing-based approaches and bioinformatics, we will characterize the transcriptional network acting downstream of Wnt, FGF and Notch in the presomitic mesoderm (PSM). We will also use genetic and pharmacological approaches utilizing real-time imaging reporters to characterize the pacemaker of the segmentation clock in vivo, and also in vitro using differentiated embryonic stem cells. We further propose to characterize in detail a novel RA-dependent pathway that we identified and which controls the somite left-right symmetry. Our work is expected to have a strong impact in the field of congenital spine anomalies, currently an understudied biomedical problem, and will be of utility in elucidating the etiology and eventual prevention of these disorders. This work is also expected to further our understanding of the Notch, Wnt, FGF and RA signalling pathways which are involved in segmentation and in the establishment of the vertebrate body plan, and which play important roles in a wide array of human diseases.

2 500 000 €

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

Eukaryotic cells inherit much of their genomic information in the form of chromosomes during cell division. Centimetre-long DNA molecules are packed into micrometer-sized chromosomes to enable this process. How DNA is organised within mitotic chromosomes is still largely unknown. A key structural protein component of mitotic chromosomes, implicated in their compaction, is the condensin complex. In this proposal, we aim to elucidate the molecular architecture of mitotic chromosomes, taking advantage of new genomic techniques and the relatively simple genome organisation of yeast model systems. We will place particular emphasis on elucidating the contribution of the condensin complex, and the cell cycle regulation of its activities, in promoting chromosome condensation. Our previous work has provided genome-wide maps of condensin binding to budding and fission yeast chromosomes. We will continue to decipher the molecular determinants for condensin binding. To investigate how condensin mediates DNA compaction, we propose to generate chromosome-wide DNA/DNA proximity maps. Our approach will be an extension of the chromosome conformation capture (3C) technique. High throughput sequencing of interaction points has provided a first glimpse of the interactions that govern chromosome condensation. The role that condensin plays in promoting these interactions will be investigated. The contribution of condensin s ATP-dependent activities, and cell cycle-dependent post-translational modifications, will be studied. This will be complemented by mathematical modelling of the condensation process. In addition to chromosome condensation, condensin is required for resolution of sister chromatids in anaphase. We will develop an assay to study the catenation status of sister chromatids and how condensin may contribute to their topological resolution.

2 076 126 €

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

Cellular clearance is a fundamental process required by all cells in all species. Important physiological processes, such as aging, and pathological mechanisms, such as neurodegeneration, are strictly dependent on cellular clearance. In eukaryotes, most of the cellular clearing processes occur in a specialized organelle, the lysosome. This project is based on a recent discovery, made in our laboratory, of a gene network, which we have named CLEAR, that controls lysosomal biogenesis and function and regulates cellular clearance. The specific goals of the project are: 1) the comprehensive characterization of the mechanisms underlying the CLEAR network, 2) the thorough understanding of CLEAR physiological function at the cellular and organism levels, 3) the development of strategies and tools to modulate cellular clearance, and 4) the implementation of proof-of-principle therapeutic studies based on the activation of the CLEAR network in murine models of human lysosomal storage disorders and of neurodegenerative diseases, such as Alzheimers s and Huntington s diseases. A combination of genomics, bioinformatics, systems biology, chemical genomics, cell biology, and mouse genetics approaches will be used to achieve these goals. Our goal is to develop tools to modulate cellular clearance and to use such tools to develop therapies to cure human disease. The potential medical relevance of this project is very high, particularly in the field of neurodegenerative disease. Therapies that prevent, ameliorate or delay neurodegeneration in these diseases would have a huge impact on human health.

2 100 000 €

Start date: 2010-03-01, End date: 2015-02-28

How do we understand the actions and intentions of others? Hereby we intend to address this issue by using a multidisciplinary approach. Our project is subdivided into four parts. In the first part we investigate the neural organization of monkey area F5, an area deeply involved in motor act understanding. By using a new set of electrodes we will describe the columnar organization of the area F5, establish the temporal relationships between the activity of F5 mirror and motor neurons, and correlate the activity of mirror neurons coding the observed motor acts in peripersonal and extrapersonal space with the activity of motor neurons in the same cortical column. In the second part we will assess the neural mechanism underlying the understanding of the intention of complex actions , i.e. actions formed by a sequence of two (or more) individual actions. The focus will be on the neurons located in ventrolateral prefrontal cortex, an area involved in the organization of high-order motor behavior. The rational of the experiment is that, while the organization of single actions and the understanding of intention behind them is function of parietal neurons, that of complex actions relies on the activity of the prefrontal lobe. In the third and fourth parts of the project we will delimit the cortical areas involved in understanding the goal (the what) and the intention (the why) of the observed actions in individuals with typical development (TD) and in children with autism and will establish the time relation between these two processes. Our hypothesis is that the chained organization of intentional motor acts is impaired in children with autism and this impairment prevents them from organizing normally their actions and from understanding others intentions.

1 992 000 €

Start date: 2010-05-01, End date: 2015-04-30

This project is directed towards development of new laser diagnostic techniques and a deepened physical understanding of more established techniques, aiming at new insights in phenomena related to combustion processes. These non-intrusive techniques with high resolution in space and time, will be used for measurements of key parameters, species concentrations and temperatures. The techniques to be used are; Non-linear optical techniques, mainly Polarization spectroscopy, PS. PS will mainly be developed for sensitive detection with high spatial resolution of "new" species in the IR region, e.g. individual hydrocarbons, toxic species as well as alkali metal compounds. Multiplex measurements of these species and temperature will be developed as well as 2D visualization. Quantitative measurements with high precision and accuracy; Laser induced fluorescence and Rayleigh/Raman scattering will be developed for quantitative measurements of species concentration and 2D temperatures. Also a new technique will be developed for single ended experiments based on picosecond LIDAR. Advanced imaging techniques; New high speed (10-100 kHz) visualization techniques as well as 3D and even 4D visualization will be developed. In order to properly visualize dense sprays we will develop Ballistic Imaging as well as a new technique based on structured illumination of the area of interest for suppression of multiple scattering which normally cause blurring effects. All techniques developed above will be used for key studies of phenomena related to various combustion phenomena; turbulent combustion, multiphase conversion processes, e.g. spray combustion and gasification/pyrolysis of solid bio fuels. The techniques will also be applied for development and physical understanding of how combustion could be influenced by plasma/electrical assistance. Finally, the techniques will be prepared for applications in industrial combustion apparatus, e.g. furnaces, gasturbines and IC engines

2 466 000 €

Start date: 2010-02-01, End date: 2015-01-31

What is the fundamental unit of computation in the brain? Answering this question is crucial not only for understanding how the brain works, but also for building accurate models of brain function, which require abstraction based on identification of the essential elements for carrying out computations relevant to behaviour. We will directly test the possibility that single dendritic branches may act as individual computational units during behaviour, challenging the classical view that the neuron is the fundamental unit of computation. We will address this question using a combination of electrophysiological, anatomical, imaging, molecular, and modeling approaches to probe dendritic integration in pyramidal cells and Purkinje cells in mouse cortex and cerebellum. We will define the computational rules for integration of synaptic input in dendrites by examining the responses to different spatiotemporal patterns of excitatory and inhibitory inputs. We will use computational modeling to extract simple rules describing dendritic integration that captures the essence of the computation. Next, we will determine how these rules are engaged by patterns of sensory stimulation in vivo, by using various strategies to map the spatiotemporal patterns of synaptic inputs to dendrites. To understand how physiological patterns of activity in the circuit engage these dendritic computations, we will use anatomical approaches to map the wiring diagram of synaptic inputs to individual dendrites. Finally, we will manipulate dendritic function using molecular tools, in order to provide causal links between specific dendritic computations and sensory processing. These experiments will provide us with deeper insights into how single neurons act as computing devices, and how fundamental computations that drive behaviour are implemented on the level of single cells and neural circuits.

2 416 078 €

Start date: 2010-06-01, End date: 2016-05-31

Chronic pain syndromes are to a large extent due to maladaptive plastic changes in the CNS. A CNS area particularly relevant for such changes is the spinal dorsal horn, where inputs from nociceptive and non-nociceptive fibers undergo their first synaptic integration. This area harbors a sophisticated network of interneurons, which function as a gate-control unit for incoming sensory signals. Several different types of interneurons can be distinguished based e.g. on their neurotransmitter and neuropeptide content. Despite more than 40 years of research, our knowledge about the integration of these neurons in dorsal horn circuits and their contribution to sensory processing is still very limited. This proposal aims at a comprehensive characterization of the dorsal horn neuronal network under normal conditions and in chronic pain states with a focus on inhibitory interneurons. A genome-wide analysis of the gene expression profile shall be made from defined dorsal horn interneurons genetically tagged with fluorescent markers and isolated by fluorescence activated cell sorting. A functional characterization of the connectivity of these neurons in spinal cord slices and of their role in in vivo sensory processing shall be achieved with optogenetic tools (channelrhodopsin-2), which permit activation of these neurons with light. Finally, behavioral analyses shall be made in mice after diphteria toxin-mediated ablation of defined interneuron types. All three approaches shall be applied to naïve mice and to mice with inflammatory or neuropathic pain. The results from these studies will improve our understanding of the malfunctioning of sensory processing in chronic pain states and will provide the basis for novel approaches to the prevention or reversal of chronic pain states.

2 467 000 €

Start date: 2010-05-01, End date: 2016-04-30

We plan to construct a theoretical bridge between classical dynamic allocation models used in Operations Research/Management Science, and between the modern theory of mechanism design. Our theoretical results will generate insights for the construction of applied pricing schemes and testable implications about the pattern of observed prices. The Economics literature has focused on information and incentive issues in static models, whereas the Operations Research/Management Science literature has looked at dynamic models that were often lacking strategic/ informational aspects. There is an increased recent interest in combining these bodies of knowledge, spurred by studies of yield management, and of decentralized platforms for interaction/ communication among agents. A general mechanism design analysis starts with the characterization of all dynamically implementable allocation policies. Variational arguments can be used then to characterize optimal policies. The research will focus on models with multidimensional incomplete information, such as: 1) Add incomplete information to the dynamic & stochastic knapsack problem; 2) Allow for strategic purchase time in dynamic pricing models; 3)Allow for competing mechanism designers. The ensuing control problems are often not standard and require special tools. An additional attack line will be devoted to models that combine design with learning about the environment. The information revealed by an agent affects then both the value of the current allocation, and the option value of future allocations. We plan to: 1) Derive the properties of learning processes that allow efficient, dynamic implementation; 2) Characterize second-best mechanism in cases where adaptive learning and efficiency are not compatible with each other.

1 123 200 €

Start date: 2010-05-01, End date: 2016-04-30

Our genetic material is continually subjected to damage, either from endogenous sources such as reactive oxygen species produced as by-products of oxidative metabolism, from the breakdown of replication forks during cell growth, or by agents in the environment such as ionising radiation or carcinogenic chemicals. To cope with DNA damage, cells employ elaborate and effective repair processes that specifically recognise a wide variety of lesions in DNA. These repair systems are essential for the maintenance of genome integrity. Unfortunately, some individuals are genetically predisposed to crippling diseases or cancers that are the direct result of mutations in genes involved in the DNA damage response. For several years our work has been at the forefront of basic biological research in the area of DNA repair, and in particular we have made significant contributions to the understanding of inheritable diseases such as breast cancer, Fanconi anemia, and the neurodegenerative disease Ataxia with Oculomotor Apraxia-1 (AOA-1). The focus of this ERC proposal is: (i) to define the phenotypic interplay between three inheritable cancer predisposition syndromes, Fanconi anemia, Bloom s syndrome and breast cancers caused by mutation of BRCA2, (ii) to determine the biological role of the newly discovered GEN1 Holliday junction resolvase in homologous recombination and repair, and (iii) to understand the actions of Aprataxin and Senataxin in relation to the inheritable neurodegenerative diseases AOA-1 and AOA-2, respectively. Our studies will provide an improved understanding of basic mechanisms of DNA repair and thereby underpin future therapeutic developments that will help individuals afflicted with these diseases.

2 449 091 €

Start date: 2010-06-01, End date: 2015-05-31

Studies concerning the mechanism of DNA replication have advanced our understanding of genetic transmission through multiple cell cycles. Recent work has shed light on possible means to ensure the stable transmission of information beyond just DNA and the concept of epigenetic inheritance has emerged. Considering chromatin-based information, key candidates have arisen as epigenetic marks including DNA and histone modifications, histone variants, non-histone chromatin proteins, nuclear RNA as well as higher-order chromatin organization. Thus, understanding the dynamics and stability of these marks following disruptive events during replication and repair and throughout the cell cycle becomes of critical importance for the maintenance of any given chromatin state. To approach these issues, we propose to study the maintenance of heterochromatin at centromeres, key chromosomal regions for the proper chromosome segregation. Our current goal is to access to the sophisticated mechanisms that have evolved in order to facilitate inheritance of epigenetic marks not only at the replication fork, but also at other stages of the cell cycle, during repair and development. Beyond inheritance of DNA methylation, understanding how inheritance of histone variants and their modifications can be controlled either coupled or not coupled to DNA replication will be a major focus of this project. Our studies will build on the expertise and tools developed over the years in a strategy that integrates molecular, cellular, and biochemical approaches. This will be combined with the use of new technologies to monitor cell cycle (Fucci), protein dynamics (SNAP-Tagging) together with single molecule analysis involving DNA and chromatin combing. We wish to define a possible framework for an understanding of both the stability and reversibility of epigenetic marks and their dynamics at centromeres. These lessons may teach us general principles of inheritance of epigenetic states.

2 490 483 €

Start date: 2010-06-01, End date: 2015-12-31

X-chromosome inactivation (XCI) represents a classic example of epigenetics in mammals. In this process, one of the two X chromosomes in females is converted from an active into a clonally heritable, inactive, state during early embryonic development, to ensure dosage compensation between the sexes. This process is also remarkable in that an entire chromosome is silenced while its homologue, present in the same nucleus, remains active. Thus, in addition to being an epigenetics paradigm, XCI also represents a powerful model for monoallelic gene expression and could provide important insights into the mechanisms underlying other examples of random, monoallelic regulation. The key locus underlying the initiation of XCI is the X-inactivation centre (Xic). The Xic ensures the induction and monoallelic expression of a non-coding RNA (Xist) that is responsible for triggering chromosomal silencing in cis during development. We would like to understand the mechanisms underlying the Xic's functions and define whether other, Xic-like loci exist in the genome. Once XCI is established, the inactive state is initially reversible but becomes progressively locked in as development proceeds due to numerous epigenetic marks such as DNA methylation and histone modifications, as well as nuclear compartmentalization and asynchronous replication. In the proposed program, we will exploit our expertise in XCI to develop new lines of research and use novel technologies to investigate monoallelic gene expression, nuclear organization and epigenetics during development. Our main objectives are (1) to understand how monoallelic expression states are established and maintained during early development and (2) to assess how chromosome dynamics and nuclear architecture can impact on these states.

2 860 000 €

Start date: 2010-05-01, End date: 2015-10-31

The ribosome is a large cellular organelle that plays a central role in the process of protein synthesis in all organisms. Currently, structural information at atomic resolution exists only for bacterial ribosomes and some of their functional complexes. Eukaryotic ribosomes are larger and significantly more complex than their bacterial counterparts. They consist of two unequal subunits with a combined molecular weight of approximately 4 million Daltons and contain 70-80 different protein molecules and four different RNAs. Currently the only structural information on eukaryotic ribosomes is available from cryo electron microscopic reconstructions in the nanometer resolution range, which is insufficient to derive information about the function of the eukaryotic ribosome at the atomic level. The aim of this proposal is to use X-ray crystallography to obtain structural and functional information on the eukaryotic ribosome and its functional complexes at high resolution. The key targets of the structural work will be: i) the structure of the small ribosomal subunit, ii) the structure of the large ribosomal subunit, and iii) structures of complexes involved in the initiation of protein synthesis. Besides the obvious fundamental importance of this research for understanding protein synthesis in eukaryotes the proposed studies will also be the prerequisite for understanding the structural basis of the regulation of protein synthesis in normal cells and how it is perturbed in various diseases. Finally, comparing the structures of bacterial and eukaryotic ribosomes is important for understanding the specificity of various clinically used antibiotics for the bacterial ribosome.

2 446 725 €

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

The evolution of the first rooting systems approximately 470 million years ago was a critical event in the history of life on Earth because it allowed the growth of complex multicellular eukaryotic photosynthetic organisms – plants - on the surface of the land. Rooting systems are important because they facilitate the uptake of every chemical element in the plant body with the exception of carbon. The root systems of the first land plants (liverworts) comprised a mass of unicellular tip-growing filaments (rhizoids) that grew from the plant surface into the soil. All root systems that evolved since then similarly comprise a system of tipgrowing filamentous cells located at the interface between the plant and the soil, indicating that the differentiation of filamentous root cells has been critical for root function for the past 470 million years. This proposal aims to characterize the origin and evolution of this essential cellular differentiation process. The proposed research is in three parts: First we propose to define the mechanism that controlled the development of the first land plant root system by identifying genes that control liverwort rooting system (rhizoids) development and characterizing their regulatory interactions. Second we propose to determine if the mechanism that controlled the development of the first land plant root system was inherited from algal ancestors. Third we propose to characterize the mechanism that controls filamentous root hair growth in Arabidopsis in response to environmental factors, and determine if it is conserved among land plants. In combination, these experiments will define the genetic mechanisms underpinning the development and evolution of one of the fundamental developmental processes in land plants.

2 463 835 €

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

Nanotechnology research has been directed mostly to the design and synthesis of (a) materials with passive nanostructures (e.g. coatings, nanoparticles of organics, metals and ceramics) and (b) active devices with nanostructured materials (e.g. transistors, amplifiers, sensors, actuators etc). Little is known, however, about how well the unique properties of nanostructured materials are reproduced during their large scale synthesis, and how such manufacturing can be designed and carried out. A key goal here is to fundamentally understand synthesis of surface-functionalized, nanostructured, multicomponent particles by flame aerosol reactors (a proven scalable technology for simple ceramic oxide nanopowders). That way technology for making such sophisticated materials would be developed systematically for their efficient manufacture so that active devices containing them can be made economically. Our focus is on understanding aerosol formation of layered solid or fractal-like nanostructures by developing quantitative process models and systematic comparison to experimental data. This understanding will be used to guide synthesis of challenging nanoparticle compositions and process scale-up with close attention to safe product handling and health effects. The ultimate goal of this research is to address the next frontier of this field, namely the assembling of high performance active devices made with such functionalized or layered nanoparticles. Here these devices include but not limited to (a) actuators containing layered single superparamagnetic nanoparticles and (b) ultraselective and highly sensitive sensors made with highly conductive but disperse nanoelectrode layers for detection of trace organic vapors in the human breath for early diagnosis of serious illnesses.

2 500 000 €

Start date: 2010-05-01, End date: 2015-04-30

The prefrontal cortex (PFC) subserves decision-making and executive control, i.e. the ability to make decisions and to regulate behavior according to external events, mental models of situations, internal drives and subjective preferences. Our overall aim is to understand the functional architecture of the human PFC and computational mechanisms of PFC function. The PFC function is known to operate along three major dimensions, namely the affective, motivational and cognitive control of action subserved by the orbital, medial and lateral sectors of the PFC, respectively. In this project, our specific objectives are to solve the following three open issues of critical theoretical significance: (1) the functional organization of motivational control in the medial prefrontal cortex; (2) the mechanisms that enables the PFC to control the learning of representational sets required for cognitive control; (3) the functional interactions between the medial and lateral prefrontal cortex, i.e. the integration of motivational and cognitive control into a unitary decision-making and control system. We will address these theoretically and methodologically challenging issues by elaborating computational models that integrate learning and control mechanisms, and in relation to these models, by conducting functional magnetic resonance imaging experiments in healthy humans. The project is expected to significantly improve our knowledge of the human PFC function. This basic project has potential major implications especially in medicine, because alterations of the prefrontal function is observed in aging and most neuropsychiatric diseases, as well as in technology for developing artificial and robotics intelligence with human-like adaptive reasoning and decision-making abilities.

2 500 000 €

Start date: 2010-05-01, End date: 2016-04-30

DNA sequence and epigenetic chromatin maps are important in understanding how genomes are regulated. However, these maps are linear and do not account for the three-dimensional context within which the genome functions in the cell. The spatial organisation of the genome in the nucleus is not random and is conserved in evolution, implying that it is under functional selection. This proposal aims to determine the functional significance of positioning specific genome regions at the edge of the nucleus in mammalian cells. The nuclear periphery has conventionally been considered as a zone of inactive chromatin and transcriptional repression. Several regulatory gene loci move away from the nuclear periphery as they are activated during differentiation. Novel approaches, developed by ourselves and others, that allow genomic regions to be relocated from the centre of the nucleus to the periphery, have directly shown that proximity to the nuclear edge can down-regulate human gene expression. We propose to dissect the pathways that mediate this spatially-defined transcriptional regulation, to determine what features make certain genes susceptible to it, to establish the functional consequences of preventing gene repositioning during differentiation, and to examine defects of the periphery found in premature ageing. A neglected hypothesis is that positioning of inactive chromatin against the nuclear periphery is a mechanism to minimize DNA damage on sequences in the nuclear centre. We will determine whether mutation rate is altered when loci are repositioned towards the nuclear periphery. By experimentally remodelling the spatial organisation of the genome, this proposal goes beyond the current descriptive phase of 3D nuclear organisation, into an understanding of its functional consequences on multiple aspects of genome function. It will also aid in understanding human diseases characterised by alterations of the nuclear periphery.

1 701 090 €

Start date: 2010-03-01, End date: 2016-02-29

The general framework is that of game theory, with multiple participants ( players ) that interact repeatedly over time. The players may be people, corporations, nations, computers even genes. While many of the standard concepts of game theory are static by their very nature (for example, strategic equilibria and cooperative solutions), it is of utmost importance theoretically as well as in applications to study dynamic processes, and relate them to appropriate static solutions. This is a fundamental issue. On the one hand, the significance of a solution depends in particular on how easy it is to reach it. On the other hand, natural dynamics, that is, processes that to a certain degree reflect observed behaviors and actual institutions, are important to study and understand in their own right. We propose to work on three main areas. First, adaptive dynamics: the goal is to characterize those classes of dynamics for which convergence to Nash or correlated equilibria can be obtained, and those for which it cannot, and to find and study natural dynamics that are related to actual behavior and yield useful insights. Second, evolutionary dynamics: the goal is to investigate evolutionary and similar dynamics, with a particular emphasis on understanding the role that large populations may play, and on characterizing which equilibria are evolutionarily stable and which are not. Third, bargaining and cooperation: the goal is to develop a general research program that studies natural bargaining procedures that lead to cooperation and are based directly on the strategic form; some particular aims are to establish connections between the bargaining institutions and the resulting cooperative solutions, and to analyze relevant economic models.

1 361 000 €

Start date: 2010-01-01, End date: 2015-12-31

Global energy consumption is continuously increasing, leading to an increased world wide demand for new power generation installations in the near future. In order to protect the earth s climate, energy conversion efficiency and the use of sustainable resources have to be improved significantly to reduce the emission of the greenhouse gas CO2. To maintain our high standard of living and to enhance it for developing countries, the improved technologies have to be cost-neutral. Gas turbines play today a major role in energy generation. In the future, gas turbines will become even more important, when old coal-fired steam cycle power plants are replaced by integrated gasification plants. However, current gas turbine technology experiences a flattening technology curve and further increase in total efficiency at low NOx emissions is only achieved in incremental small steps. Additionally, current technology is not prepared to operate on hydrogen-rich fuels from biological resources or coal gasification. A new approach was developed that promises a significant improvement in efficiency and emissions and provides the ability to burn hydrogen-rich fuels. For operation on carbon-containing fuels, it enables CO2 capture at low cost. The concept is based on a high pressure air-steam gas turbine cycle using extremely high amounts of steam. The goal of the proposed project is to investigate the fundamentals of ultra wet combustion to develop the technology for a prototype combustor which is capable of burning natural gas, hydrogen and fuels from coal or biowaste gasification at low NOx emissions. Research will include the combustion process, the aerodynamic design, acoustics and control, combining the main disciplines of the Chair of Experimental Fluid Dynamics.

3 137 648 €

Start date: 2010-07-01, End date: 2016-06-30

Spinelectronics merges magnetism and electronics (Nobel Prize 2007). Besides its fundamental interest, it has found applications in hard disk drives (1998) and in non-volatile standalone memories (MRAM, on market since 2006). MRAMs integrate CMOS components with magnetic tunnel junctions (MTJ). The PI and his team are convinced that besides MRAMs, this hybrid CMOS/MTJ technology can yield a totally new approach in the way electronic devices are designed. Most CMOS devices such as microprocessors are based on Von Neumann architecture in which logic and memories are separate components. The unique set of characteristics combined within MTJs: cyclability, switching speed, scalability, makes it possible to conceive novel electronic systems in which logic and memory are intimately combined in non-volatile logic components (non-volatile CPU). Such systems would have outstanding advantages in terms of energy savings, logic-memory communication speed, ultrafast reprogrammability, compactness, design simplicity. The objective of this project is to lay the fundation of this novel approach, which requires addressing both fundamental and more applied issues. The basic issues concern the improvement and reliability of spintronic materials, mastering the speed and coherence of magnetization switching, developing tools for the quantitative interpretation of MTJ properties and for designing hybrid CMOS/MTJ devices. The applied goals are the conception, building and testing of a few illustrative devices demonstrating the outstanding advantages of this technology. A further one is to establish an internationally recognized roadmap for this non-volatile logic. If successful, its impact on European microelectronics and magnetism industry could be huge.

2 500 000 €

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

We propose to study the determinants of the accumulation of productive assets among poor households in developing countries with a special, but not exclusive focus, on human capital. We plan to study how preferences, beliefs, information, expectations and available resources affect investment decisions, how these investment decisions are transformed in assets and how these assets can affect the material well being of poor households. We will also study how the availability (or lack thereof) of credit and insurance markets affects the accumulation of productive assets of poor households. An important part of our research is the construction, validation and use of innovative measurement tools. We plan to construct and use quantitative measures of beliefs, expectations, attitudes and preferences. We will be able to embed these measures in surveys being collected for the evaluation of a variety of policies and government programs in developing countries. The use of data from the evaluation of development policies has the additional advantage of capturing variation in resources and incentives that is introduced in an exogenous and controlled fashion. This allows the empirical identification of rich and credible structural models. The specific projects that make our research agenda will focus on three types of determinants: (i) preferences, perceptions, information and expectations; (ii) technology (how various inputs- investments- are converted into assets); (iii) resources and markets to access them. Estimation of these models will allow us to go beyond the simple estimation of the impacts of given policies, and shed light on the mechanisms and causal path that from individual perceptions, beliefs and expectations lead to investment choices and, eventually, to outcomes.

1 636 185 €

Start date: 2010-07-01, End date: 2013-12-31

Immunological memory confers long term protection against pathogens and is the basis of successful vaccination. Following antigenic stimulation long lived plasma cells and memory B cells are maintained for a lifetime, conferring immediate protection and enhanced responsiveness to the eliciting antigen. However, in the case of variable pathogens such as influenza virus, B cell memory is only partially effective, depending on the extent of similarity between the preceding and the new viruses. The B cell response is dominated by serotype-specific antibodies and heterosubtypic antibodies capable of neutralizing several serotypes appear to be extremely rare. Understanding the basis of broadly neutralizing antibody responses is a critical aspect for the development of more effective vaccines. In this project we will explore the specificity and dynamics of human antibody responses to influenza virus by using newly developed technological platforms to culture human B cells and plasma cells and to analyze the repertoire of human naïve and memory T cells. High throughput functional screenings, structural analysis and testing in animal models will provide a thorough characterization of the human immune response. The B cell and T cell analysis aims at understanding fundamental aspects of the immune response such as: the selection and diversification of memory B cells; the individual variability of the antibody response, the mechanisms of T-B cooperation and the consequences of the original antigenic sin and of aging on the immune response. This analysis will be complemented by a translational approach whereby broadly neutralizing human monoclonal antibodies will be developed and used: i) for passive vaccination against highly variable viruses; ii) for vaccine design through the identification and production of recombinant antigens to be used as effective vaccines; and iii) for active vaccination in order to facilitate T cell priming and jump start the immune responses.

1 979 200 €

Start date: 2010-09-01, End date: 2015-08-31

Terrestrial subsurface geomicrobiology is a matter of growing interest on many level. From a fundamental point of view, it seeks to determine wheter life can be sustained in the absence of radiation. From an astrobiological point of view, it is an interesting model for early life on Earth, as well as a representation of life as it could occur in other planetary bodies. Río Tinto is an unusual extreme acidic environment, it rises in the core of the Iberian Pyritic Belt (IPB), one of the biggest sulfidic ore deposits in the world. Today it is clear that the extreme characteristics of Ró Tinto are not due to mining activity, but to the chemolithotrophic microorganisms thriving in the high concentration of metal sulfides of the IPB. To explore the hypothesis that a continuous underground reactor of chemolithotrophic microorganisms thriving in the rich sulfidic minerals of the IPB is responsible for the extreme conditions found in the river, we propose a drilling project to detect the subsurface microbial activity, the potential resources to support these microbial communities, and to follow the in situ geomicrobiological evolution in real time. In this project, we propose to explore the Río Tinto at deep-basement regions (200-1000 m) by means of new approaches comprising: i) detection of life and estimation of the microbial diversity at the drilling sites providing an instant picture of the subsurface habitat, and ii) real time monitoring, inside the borehole, of physico-chemical parameters and biological activity generating essential information to recognize matter and energy fluxes. All these procesess are associated to long-term changes in the underground habitats and are not fully understood based on seasonal discontinuous subsurface analysis. To achieve these goals we will analize cores and fluids in the field site using new and poweful tools.

3 246 000 €

Start date: 2010-06-01, End date: 2015-05-31

Ubiquitin (Ub) is a small modifier that labels proteins in a highly specific manner. Like phosphorylation, modification of proteins by Ub is prevalent in the majority of cellular processes. An increasing number of distinct functions have been assigned to different types of ubiquitin modifications (monoUb and different Lys-linked chains). Moreover, aberrations in the ubiquitin system underlie many disease states, including cancer, inflammatory, immune and metabolic disorders as well as neurodegeneration. The most recently described physiological ubiquitin modification is the linear ubiquitin chain, in which ubiquitin monomers are conjugated via Met-Gly linkages. We have found that linear ubiquitin chains bind specifically to the NEMO adaptor molecule, an event critical for the proper regulation of NF-ºB signaling (Rahighi, 2009). Here we propose to use a multidisciplinary strategy to study the role of linear ubiquitination in the NF-ºB pathway, autophagy, apoptosis and DNA repair and how these changes can impact on disease states such as inflammation and cancer development. Scientific objectives are: " Characterize the components of linear ubiquitination: E3 ligases, specific substrates and domains recognizing linear ubiquitin chains " Elucidate the in vivo role of linear ubiquitination in the regulation of the NF-ºB pathway, apoptosis and DNA repair. " Reveal the molecular basis for the connections between linear ubiquitination and selective autophagy " Identify elements in the linear ubiquitin network as potential drug targets " Generate transgenic mouse models of inflammatory diseases and cancer " Develop system and computational biology approaches to assess the global role of linear ubiquitination in cellular proteome

2 440 560 €

Start date: 2010-06-01, End date: 2015-05-31

Overall objective and Specific Aims. The overall objective of this proposal is to elucidate the pathogenesis of HBV infection with the ultimate hope that this knowledge will lead to the development of new therapeutic strategies to terminate persistent infection and its attendant costs and complications. Our approach is to dissect poorly understood cellular and molecular pathways responsible for both liver disease and viral clearance taking advantage of technological advances in the field of live imaging and unique mouse models of HBV infection. Three specific aims will be pursued: 1. Visualize and characterize where and how naïve and effector CTL of different specificities adhere to vessels and recognize/kill HBV-expressing hepatocytes within the “normal”, fibrotic/cirrhotic or cancerous liver. 2. Characterize the role of platelets in HBV pathogenesis. 3. Characterize the role of Kupffer cells in HBV pathogenesis.

2 046 200 €

Start date: 2010-09-01, End date: 2016-03-31

The general theme is to explore the connections between reasoning and computations in mathematics. There are two main research directions. The first research direction is a refomulation of Hilbert's program, using ideas from formal, or pointfree topology. We have shown, with multiple examples, that this allows a partial realization of this program in commutative algebra, and a new way to formulate constructive mathematics. The second research direction explores the computational content using type theory and the Curry-Howard correspondence between proofs and programs. Type theory allows us to represent constructive mathematics in a formal way, and provides key insight for the design of proof systems helping in the analysis of the logical structure of mathematical proofs. The interest of this program is well illustrated by the recent work of G. Gonthier on the formalization of the 4 color theorem.

1 912 288 €

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

Over the last decade epigenetic gene regulation has become a major focus of scientific research as it was shown to play an important role in normal plant and animal development, but also in the ontogeny of human disease. A role of epigenetic processes in evolution, however, has found little general support to date. The goal of this project is to understand the complex interplay of epigenetic mechanisms in plant development and evolution. Many of the approaches we use rely on the recent advances in sequencing technologies, which allow the analysis of molecular characters at an unprecedented level and speed. To achieve our goal, we will focus on two epigenetic paradigms. In Program A, we will focus on dissecting the mechanisms of genomic imprinting at the MEDEA (MEA) locus in Arabidopsis, which we will investigate using genetic, molecular, and innovative biochemical approaches to gain a comprehensive picture of the complex interplay of various epigenetic pathways. In program B, we will analyze the role of epigenetic change in adaptation and evolution using (i) an experimental selection approach in Arabidopsis, where genome-wide analyses of epigenetic modifications have become possible, and (ii) a stable, heritable, epigenetic change occurring in Mimulus populations. In this system, an epigenetic switch of the pollinator syndrome leads to reproductive isolation and, therefore, has an effect on population structure and thus the evolutionary trajectory. These experimental systems each offer unique opportunities to shed light onto the underlying mechanisms controlling epigenetic states. In combination with the new methodologies used, these analyses promise to provide step change in our understanding of epigenetic processes at the level of genes, organisms, and populations.

2 496 641 €

Start date: 2010-04-01, End date: 2015-12-31

MHC class II molecules are crucial for specific immune responses. In a complicated series of cell biological events, they catch a peptide in the endosomal route for presentation at the plasma membrane to the immune system. At present some 20 factors have been identified as involved in the process of MHC class II antigen presentation that are potential targets for manipulating these responses as MHC class II molecules are involved in most auto-immune diseases. Defining further targets for manipulating MHC class II responses would have implications for various disease states when these can be inhibited by chemical compounds or biologicals. We have performed a genome-wide FACS-based siRNA screen for molecules affecting MHC class II expression and peptide loading. After 100.000 individual 2-color FACS analyses, we identified 276 proteins that can be functionally sub-clustered for expression and for cell biological effects. We now propose to study the cell biology of these 276 hits to elucidate the molecular and cell biological mechanisms of MHC class II antigen presentation (the MHC class II-ome). As a first step, the 276 hits are sub-clustered for effects on MHC class II transcription or cell biology. These sub-clusters may correspond to networks. We propose to validate and extend these networks by experiments by a team of scientists concentrating on the various aspects of the cell biology of MHC class II antigen presentation. A parallel chemical compound screen will be performed to identify compounds affecting MHC class II antigen presentation. By cross-correlating the biological phenotypes of compounds with those of siRNA silencing, novel target-lead combinations will be defined by reciprocal chemical genetics. Our experiments should result in a global understanding of MHC class II antigen presentation. In addition, it should reveal target-lead combinations for manipulation of MHC class II antigen presentation in infection, auto-immune disease and transplantation.

2 112 300 €

Start date: 2010-09-01, End date: 2015-08-31

The primary objective of the proposed project is to develop robot mediated human interface technologies to manually explore, manipulate and assemble progressively smaller objects ranging from micro- to nano-meter scales and a secondary objective is to demonstrate the power of the interface system in the investigation of the fundamental mechanics and neural mechanisms of touch. The proposed system will consist of a master-slave robotic teleoperation (TO) subsystem and a virtual reality (VR) subsystem. The master robot will enable the user to touch, feel and manipulate (1) real micro/nano structures through the slave robot or (2) computer models of micro/nano structures in the virtual reality environment. Specific aims of this effort are as follows: (1) design and develop a custom master system to enable the user to have real-time visual, auditory, and bimanual haptic interactions; (2) design and develop a slave system consisting of microscopes and manipulators progressively augmented to enable micro to nano-precision movements and forces; (3) develop modular software architecture with device abstraction to support multiple master and slave devices; (4) integrate virtual reality software to enable the user to have real-time visual, auditory, and bimanual interactions with virtual models at micro- to nano-meter scales based on empirical data or to test hypotheses; (5) use the system to perform biomechanics and neurophysiology experiments at progressively micro- to nano-precision movements and forces; (6) develop mathematical models of mechanotransduction for quantitative understanding of touch mechanisms at multiple scales.

3 264 188 €

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

The mechanisms powering the transition from one cell state to another are the central engine of embryonic development. Genetic analysis over the last twenty years has provided us with a catalogue of genes and proteins that can be linked in linear and time dependent manners to specific states and transitions in this process. However this picture, characterized by complex charts of univocal relationships between different genes, is static and rigid and contrasts with the plasticity displayed by cells in many processes, in particular during repair and regeneration. The early mammalian embryo and the closely related ES cells provide extreme examples of this in the form of toti- and pluri-potency i.e. the maintenance of an open uncommitted state from which all cell types emerge. Understanding the molecular basis of these uncommitted states and the way they are established and regulated will not only provide a deeper insight into the operation of biological systems but will also new targets for regulation and therapies. This project revolves around the hypothesis that the plasticity displayed by cells in developmental and regulative processes is associated with dynamical cellular heterogeneities generated by transcriptional noise: phenotypic variability in genetically identical cells that arises from stochastic fluctuations during transcription and translation. Specifically I propose to provide measurements and analysis of gene expression noise in mammalian cells, its origin, regulation and use using ES cells and early mouse embryos as experimental systems.

2 299 367 €

Start date: 2010-05-01, End date: 2016-04-30

How does the assembly of neuronal circuits contribute to the emergence of function controlling dedicated animal behaviors? Finding answers to this question requires a deep understanding of the connectivity map of neuronal circuits controlling a behavior as well as the mechanisms involved in the generation of these specific circuit maps. In the project outlined here, I propose the analysis of the neuronal circuits involved in the generation of motor output, a behavior representing the ultimate output of nearly all nervous system activity. Studying the mouse motor output system will allow the analysis of neuronal circuit connectivity at an exquisite degree of specificity. Owing to the anatomical arrangement of motor neuron pools innervating individual muscles, this system offers the possibility to combine genetic, anatomical and physiological analysis of synaptic specificity with a direct link to a behavioral output. Generation of coordinated motor behavior is functionally linked to the high degree of specificity in presynaptic connections controlling the activation of individual motor neuron pools, yet knowledge on the specificity map of premotor circuits is currently missing. The aim of this research project is to acquire information on the general principles guiding the acquisition, maintenance and developmental plasticity of neuronal connectivity between premotor neurons and functionally defined subpopulations of motor neurons. This project is now possible due to the unique combination of our detailed know-how of the motor system in mice including a variety of genetic animal models, and the application of novel viral circuit tracing technology revealing monosynaptically connected premotor neurons, which we have recently applied successfully to the motor system in mice in vivo. Together, our project will elucidate the anatomical connectome of the motor output system as well as the principles governing the specificity with which motor circuits assemble.

2 499 354 €

Start date: 2010-03-01, End date: 2016-02-29

In recent years it has been recognized that small metal nanoparticles hold the promise that their catalytic properties may be completely different from those of their bulk analogs or their monometallic complexes. Entirely new chemical conversions may be expected because of their shape and thermodynamic properties. So far, this promise has not led to important breakthroughs, as most findings can be categorized, mostly, as typical of homogeneous catalysis, or mimics of heterogeneous catalysts, especially hydrogenation. Nanoparticles need stabilizating reagents; polymers, dendrimers, ionic liquids, detergents, solid surfaces, and small ligands, have been discovered and used by trial and error. In this project we propose the use of concave, large organic molecules that will be developed and used to stabilize small nanoparticles by covering part of the vertices and apices, thereby controlling the size and the shape, leaving edges next to the molecular wings and uncovered surface available for interactions leading to catalysis. The controlling wings contain two or three strongly binding phosphines to prevent dissociation of the controlling agent and to modify, simultaneously the electronic properties of part of the metal atoms. The organic platforms have the advantage that additional groups can be connected to them which can serve as chiral modifiers, as recognition sites for larger molecules, as additional organic catalysts, or as ligands to hold a homogeneous co-catalyst. Three high-risk reactions will be investigated, (enantio)selective hydrogenation of aromatics, conversion of glycerol to high added value products and the selective conversion of syn gas by using devices derived from homogeneous and supramolecular catalysis.

3 495 000 €

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

We aim to find the limits of subliminal information processing and clarify the function and brain architecture underlying conscious processing in adults, infants, patients and non-human primates. (1) We will design experimental tests applicable to non-verbal organisms that can reveal behavioral and cerebral signatures of conscious processing. Those tests, respectively called rule extraction and central collision , each comprise an automatic sensory component and a central component thought to require conscious access. (2) Using these tests, we will identify brain signatures of non-conscious and conscious processing using neuroimaging techniques (ERPs, MEG, fMRI, intracranial recordings) in normal human adults. To validate our approach, we will manipulate stimulus perceptibility (masking), attention (distraction by another task) and vigilance (sleep and anesthesia). (3) We will then extend the approach to brain-damaged adults with coma, persistent vegetative state or minimal consciousness, in order to detect residual processing and to obtain predictors of recovery. We will design computer systems to extract signatures of conscious processing in real time. (4) We will also examine when these signatures first appear in human infancy. (5) Finally, we will measure fMRI activation in monkeys during the same tests, thus allowing for a direct comparison of monkey and human signatures of conscious processing. We will study the effects of anesthesia on the loss of these signatures, and the potential beneficial impact of thalamic stimulation on their restoration. This research will clarify the brain mechanisms of conscious processing, illuminate their ontogeny and phylogeny, and pave the way to clinical intervention studies in patients with impaired consciousness.

2 486 640 €

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

The aim of this proposal is to understand how self-renewal is controlled in neural stem cell lineages and how defects in this process can lead to the formation of brain tumors in model organisms. The system we use are Drosophila neuroblasts, stem cell like progenitors in the developing fly brain that undergo repeated rounds of asymmetric cell division. During each division, protein determinants called Numb, Prospero and Brat are segregated into one of the daughter cells where they stop self-renewal and ultimately trigger neuronal differentiation. Mutations in those proteins or their segregation machinery lead to the formation of tumor neuroblasts, which proliferate indefinitely leading to the formation of a deadly brain tumor. The approach we take is to determine the transcriptional network that acts in neuroblasts to control self-renewal. We will use time-resolved transcriptional profiling to determine, how this network changes in the differentiating daughter cell and develop tools for medium-throughput functional analysis of the key network players. We will develop methodology for tissue-specific chromatin immunoprecipitation to determine, how the asymmetrically segregating determinants feed into this network. Using this data set, we will determine the pathological state of the network in the tumorigenic situation. We will determine, how wild type neural stem cells limit their proliferation capacity and how those control mechanisms are affected in the tumor situation. Ultimately, we will expand this analysis to other stem cell systems inside and outside the fly nervous system to determine how modifications of stem cell systems like transit amplifying pools or perpetual adult proliferation are reflected in network architecture.

2 499 875 €

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

The performance of engineering structures is continuously increasing, enabled by the accurate simulation and subsequent optimization of these systems. The ACARE Vision 2020 document set the ambitious goal of a 50% reduction in aircraft emissions that can only be achieved through a step change in aircraft technology. Adaptive structures and morphing aircraft are novel technologies that can provide this step change, and this proposal provides an efficient method to model, optimize and realize these structures. Morphing aircraft have the ability to alter the shape of their wings to improve fuel efficiency or to increase control effectiveness. The Wright brothers employed wing warping for roll control, but as aircraft speeds increased compliant structures were replaced with small, rigid control surfaces. Bird flight motivates the search for more efficient solutions, where a compliant structure is continuously optimized in flight using distributed sensors and actuators. From the structural perspective the objective is to produce fully integrated, hierarchical structures with compliance control. However the requirements are conflicting: the structure must be stiff to withstand the external loads, but must be flexible to enable shape changes. The solution to this conflict is to design the structure to decouple the two actions, through components with significant anisotropy and integrated actuation. The components may be modelled at the micro scale, but these models are too large for system optimization studies. This proposal provides a step change to existing methods by developing a framework where multi-scale and multi-physics modelling may be achieved efficiently, though significant improvements in the way in which the different models of varying fidelity communicate.

2 481 462 €

Start date: 2010-05-01, End date: 2015-04-30

Traditional models of transport networks ignore the existence and strategic behaviour of large actors who are often active in transport markets. Examples of such large actors are private infrastructure or service operators, insurance companies, or vehicle manufacturers. Both for positive and normative analyses, this omission can lead to substantial errors, and therefore to seriously biased policy evaluations and recommendations. The reason is that such actors will have their own objectives to pursue, while their market power gives them ample opportunity to influence market outcomes through strategic behaviour. Ignoring their behavioural responses to policy changes therefore leads to a wrong prediction of the policy s optimal design as well as its impacts. An important reason why they are nevertheless usually ignored is the analytical and numerical complexity of transport network models in which large actors, with strategic behaviour, are active. This project seeks to develop such models. Specific applications will include models of road transport networks allowing for private road operators, vehicle manufacturers, and insurance companies; models of urban taxi markets; and networks models for public transport and aviation. Although applying to different cases, these models will have important methodological characteristics in common, particularly in that they apply multilevel optimization techniques for (transport) network models that account for strategic behaviour of and interactions between large actors. We will investigate how this behaviour affects the formation of network equilibria in transport markets, as well as the impacts and (second-best) optimal design of transport policies.

2 493 318 €

Start date: 2010-05-01, End date: 2015-04-30

A new generation of polymeric materials is needed promptly that does not behave like traditional commodity plastics in terms of environmental interaction, degradation pattern, fragmentation tendency, and biological persistency. I herein propose a new paradigm in the design of polymeric materials; the design of polymeric materials through a retro-structural approach where the macroscopic performance is translated to every scale level of structural order so that appropriate molecular recognitions are identified and subsequently synthetically generated in a bottom-up procedure. Inspiration on how to design such materials is best drawn from Nature which is unsurpassed in its ability to combine molecular building blocks into perfectly designed versatile super- and supramolecular structures with well-defined properties, disassembly patterns, and biological functions. A closer look into the structural build-up of biological materials gives important clues on how to design synthetic functional materials with desirable environmental interaction. In addition to advanced synthesis, surface modification and processing, the materials and their degradation behavior will be thoroughly characterized by using traditional characterization techniques in combination with latest spectroscopic and imaging techniques. I have chosen to focus on two areas that stand out as highly prioritized in maintaining or even raising our quality of life; sustainable materials for commodity applications and tissue engineering systems in biomaterials science. This is a bold high risk proposal which if successful will have a ground-breaking influence on how we design polymeric materials.

2 500 000 €

Start date: 2010-03-01, End date: 2016-02-29

The study of primary immunodeficiency diseases has provided significant insights into how the immune system works. This notably includes in vivo immune responses to microorganisms, pathogens or opportunistic agents and in vivo control of reactivity to self, in relation to the identification of specific gene mutations. Hence, some of the key factors of the immune system have been unraveled. In this respect, studies in human conditions are essential because (i) they provide truly natural models of the immune system at work and (ii) because there are many known differences between the human and murine immune systems. Detailed investigations of newly described phenotypes and further delineation of known phenotypes which lack associated gene mutations represent as many new models for studying multiple facets of the human immune system. Appropriate in vitro and in vivo experimental models will be designed in order to gain a detailed understanding of newly identified molecules. It is also expected that the elucidation of immune system pathways will have an impact on therapeutic research. This proposal has been generated by a group of scientists with expertise in both fundamental and clinical research and aims at tackling some of these multifaceted questions. These studies will benefit from the well-characterized cohorts of patients with specific primary immunodeficiencies (PIDs) that have been constituted over the years. The project has 3 major subheadings: 1) Primary immunodeficiencies (PIDs) of DNA repair pathways, 2) PIDs of lymphocyte cytotoxicity/cell death pathways; 3) Therapeutics for primary immunodeficiencies. Scientists who take part in the project will address these various topics as a function of their respective fields of expertise. Also, as observed in the past, the unexpected observation of new phenotypes might significantly impact on research orientations, as a function of their potential interest and feasibility of their analysis.

1 719 600 €

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

Oligomers are toxic in an array of protein misfolding and aggregation (PMA) disorders. However, the chain of events from protein aggregation to dysfunction is poorly understood. Prion diseases are marked by accumulation of PrPSc, a misfolded variant of wild-type PrPC. PrPC mediates PrPSc neurotoxicity and counteracts toxic PrPC mutants, indicating that a subversion of normal PrPC function may underlie neurodegeneration, and this may not be limited to prion disease. Here, we propose to explore these newly discovered physiological functions of PrPC in three paradigms. We show that PrPC assembles into a multiprotein complex containing a protease; neurotoxic PrPC mutants generate a smaller complex that is uncleaved. We show that neuronal expression of PrPC is required in trans for long-term myelin maintenance in peripheral nerves. We will therefore investigate the hypothesis that a fragment of PrPC transmits signals crucial for axomyelinic integrity. We show that PrPC physically interacts with both amyloid b and islet amyloid polypeptide and attenuates functional impairment mediated by these peptides. We therefore propose to test whether subversion of normal PrPC function is involved in diverse PMA disorders. We developed an ex vivo model that accurately reproduces major features of prion infections, most notably neurodegeneration. We have identified several unexpected PrPSc-induced cellular stress pathways which may be common to other PMA disorders. Using this model system, we will clarify the role of PrPC in cell survival pathways and determine the requirement for PrPC in the pathology of other PMA disorders. This proposal capitalizes on provocative recent results and, if successful, will provide valuable insights into PMA toxicity that will go far beyond prion diseases.

2 500 000 €

Start date: 2010-05-01, End date: 2015-04-30

The simultaneous presence of several different fluids in external or internal flows is found in daily life, environment and numerous industrial processes. These types of flows are termed multi-fluid flows. Examples are gas-liquid transport, crude oil recovery, spray cans, sediment transport in rivers, pollutant transport in the atmosphere, cloud formation, fuel injection in engines, bubble column reactors and spray driers for food processing, to name only a few. Real time computational mechanics (RTCM) aims to developing computational systems to solve problems which must produce their results within short time intervals. Examples of real-time systems include flight control programs, patient monitoring; nuclear plants controls, industrial processing and prevention of risk. RTCM systems are having an ever increasing impact on the quality of human life. The objective of the project is to develop new formal approaches and computational methods based on innovative RTCM procedures for building accurate and robust quasi-real time computer codes applicable to solve multi-fluid engineering problems. In the project we will develop and validate new computational fluid dynamic techniques based on innovative particle methods, new time integration schemes allowing large time steps, reduction methods, GPUs and parallel processing to reach acceptable results for multi-fluid problems in quasi-real time. The main outcome of the REALTIME project will be a collection of methods and codes to predict and control in quasi-real time different problems involving natural and human induced hazards such as risky industrial processes, fire spread, critical atmospheric situations or patients monitoring situations in which the security or human life depends of a response in real time.

2 478 000 €

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

Biofilms represent a multicellular lifestyle of bacteria that causes serious biomedical and technological problems. Biofilm developmental involves an inhibition of motility and an induction of adhesins at the cell surface and culminates in complex structures, in which bacteria are embedded in an extracellular matrix, which renders them resistant against antibiotics and host immune systems. The overall objective of the proposed project is to clarify nature and nurture in bacterial biofilm formation, i.e. to reveal the underlying genetic control network and its integration with environmentally responsive pathways that influence biofilm composition and architecture. The major working hypothesis of this proposal is that the ubiquitously biofilm-stimulating second messenger c-di-GMP and the many proteins associated with its synthesis, degradation and action are mainly responsible for this integration (i) by providing the molecular switches that establish the metastable states characteristic for biofilm development, and (ii) by integrating many of the environmental signals that modulate biofilm composition and architecture. Even in single species, c-di-GMP is produced and degraded by multiple diguanylate cyclases (GGDEF domain proteins) and phosphodiesterases (EAL domain proteins), respectively. This project will elucidate the regulation, function, cooperation and targets of all 29 GGDEF/EAL domain proteins during the entire series of molecular events that generates a biofilm of the model organism Escherichia coli, which includes commensals as well as important pathogens. As c-di-GMP is used by virtually all bacteria, understanding its production and mode of action will open new and general perspectives for interference with bacterial biofilm formation.

1 998 000 €

Start date: 2010-06-01, End date: 2015-05-31

Human Immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, infects primarily cells of the immune system. The outcome of HIV-1 infection results from complex interactions between viral proteins and host cell factors (ref). In most cases, HIV-1 successfully hijacks cellular pathways and bypasses cellular restriction factors for optimal replication leading to continuous rounds of infection, replication and cell death (ref). Continuous viral replication causes the loss of CD4+T cells and progression to immunodeficiency in infected individuals. However, in certain situations virus replication can be successfully controlled. First, HAART (Highly Active AntiRetroviral Therapy) treatment revealed the existence of a pool of resting memory CD4+ T cells harbouring integrated but silent HIV-1 provirus. Although this situation occurs in a small number of cells, it suggests that intracellular defence mechanisms can be effective against HIV. This long lived viral reservoir is believed to be the major obstacle against HIV-1 eradication by HAART. Second, HIV-infected individuals who are able to control their virus to undetectable levels for many years in absence of any treatment have been identified and referred to as Elite HIV controllers EC . Again, this is a rare situation observed in 0.5% of infected patients. Still, it demonstrates that it is possible to naturally and effectively control HIV replication and disease progression. A common feature of these two situations is that virus replication is controlled at the gene expression level. A major challenge in the HIV field is to understand how these naturally occurring situations where intracellular defence and/or immune response win the battle against HIV. Our project aim at identifying the host factors and define the molecular mechanisms involved in the control of virus replication both in HAART-treated and in EC patients.

2 019 500 €

Start date: 2010-05-01, End date: 2015-04-30

Incentive learning is a universal mechanism by which animals and humans learn rewarding behavioral responses. Its diversion towards the wrong targets is involved in human conditions ranging from drug addiction to pathological gambling and obesity. Incentive learning has been studied from a behavioral standpoint and only few of the underlying molecular mechanisms have been identified. We propose innovative approaches to characterize at the molecular and cellular level incentive memory traces , i.e. stable alterations in identified neuronal populations. We focus on the striatum, a brain region crucial for incentive learning, where dopamine encodes reward-related signals. Dopamine controls the flow of information through glutamatergic synapses and its long-lasting adaptations. It regulates the balance between striatal output pathways, which underlies action selection , i.e. behavioral choices in response to a given combination of internal state and external cues and context. We will address two important issues: What are the signaling mechanisms involved in the formation and reconsolidation of incentive memory traces induced by DA and glutamate? In which neuronal populations are these traces formed and what are their time-dependent modifications? The program uses a variety of approaches including novel mouse genetic models and approaches for visualizing striatal neurons in vivo. If successful, these methods have a strong potential for more general applicability. This basic research program will allow the identification of the molecular and cellular mechanisms of a simple learning mechanism with an unprecedented precision and will provide important information related to its alterations in neurological and psychiatric conditions, including addiction.

2 500 000 €

Start date: 2010-06-01, End date: 2016-05-31

The hallmark of social insect colonies is reproductive division of labour which is often associated with dramatic morphological and behavioural differences between queens, workers and males. The aim of this proposal is three-fold. First, we will use our recently developed fiducial identification system to investigate the general principles of social organisation and division of labour. The video tracking of workers labelled with markers derived from the augmented reality library ARTag allows us for the first time to distinguish up to 2000 individuals and precisely locate them every 500ms, hence allowing large-scale experiments addressing the question of how the behaviour of individual workers is influenced by the joint effects of environmental factors and social interactions. The second related aim is to investigate how the level of altruism within colonies and the reliability of communication systems are shaped by colony kin structure. Because it is not possible to conduct artificial evolution with social insects we will use a new experimental system consisting of colonies of small mobile robots with simple vision and communication abilities. This system permits to conduct hundreds of generations of experimental evolution in colonies with variable group composition to identify the factors affecting the evolution of altruism and communication. Finally, we will complement these studies with a genetic perspective using a remarkable genetic social polymorphism that we recently discovered in the fire ant Solenopsis invicta. The advent of new ultra high-throughput sequencing techniques will allow us to document the steps involved in the evolution of this genetic social polymorphism and test the suggestion that the chromosome involved in the social polymorphism has the properties of a sex chromosome. This project will be highly interdisciplinary, involving skills in evolutionary biology, the study of animal behaviour, bioinformatics, engineering and molecular biology

2 497 500 €

Start date: 2010-05-01, End date: 2016-04-30

The proposed research concerns two sets of issues. The first concerns the role of state building in the development process, and the role played by violent conflict whether internal or external to the state. In this research, we will build a sequence of theoretical models, taking a stepping stone in a basic framework where new infrastructure that expands the state s capacity to raise revenue and to support private markets is viewed as outcome of investments under uncertainty. Our objective in model building is to provide guidance for the collection of historical and contemporary data and for econometric testing, which will both be central to the project. The overall goal of this project is to bring the analysis of state capacity into the mainstream of economics, and thereby shed light on the complex interactions between state building, conflict and development. The second set of issues ultimately concerns the economics of climate change. A first subproject aims at estimating the historical effects of weather on infant mortality in Africa, using a variety of data sources: individual data based on retrospective DHS surveys, finely-gridded weather data based on so-called re-analyis with large-scale climate models, and spatial data on harvest times based on satellite data on plant growth. Exploiting the random component of historical weather fluctuation allows us to estimate causal effects on health outcomes via mechanisms like malnutrition and malaria. This initial research will serve as a pilot study, to develop a methodology for studying the weather impacts on any outcome of interest anywhere in the world. Eventually such estimates will serve to estimate the future costs of climate change.

1 489 744 €

Start date: 2010-02-01, End date: 2015-01-31

This proposal describes experiments aimed at defining the multiple roles of vesicular glutamate transporters (VGLUTs) in central synapses. Classically, VGLUTs transport glutamate from the cytoplasm into synaptic vesicles. Deletion of these genes disrupts synaptic glutamate release and their expression suffices to determine neurons as glutamatergic. We recently discovered that VGLUTs control additional key parameters such as quantal size and vesicular release probability, suggesting that they are fundamental regulators of synaptic strength and synaptic plasticity. To study these novel functions, we will first address whether the number of VGLUTs per vesicle (VGLUT content) can affect the amount of stored glutamate and in addition, the probability of vesicle release. We will subsequently explore the underlying mechanisms. Second, we will test the hypothesis that different VGLUT paralogs contribute to functional differences in discrete synapse populations, as implied by our preliminary data and the distribution pattern of the two main paralogs VGLUT1 and VGLUT2 in the brain. Subsequently, we will perform structure function studies on VGLUTs in native synapses to identify the underlying molecular interactions. Finally, the little understood VGLUT3 paralog is expressed mainly in subclasses of cholinergic, dopaminergic and GABAergic neurons, but no evidence exists that demonstrates VGLUT3 s role in glutamate release. We will address whether VGLUT3 is used to co-release glutamate with other neurotransmitters, and will test whether presence of glutamate in synaptic vesicles interferes with the storage or release of other neurotransmitters. Our studies will yield important insights into how these transporters operate, and how modulation of VGLUTs affects synaptic encoding and brain function. Because of observed profound regulation of VGLUTs in schizophrenia, depression and Parkinsons disease, these findings will also contribute to diagnosis and treatment of mental illness.

2 413 200 €

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

Telomeres have long been known to play crucial roles in protecting chromosome ends from attrition and fusion and thus safeguarding genome stability, but their complete functional repertoire has yet to be fully understood. Among the fundamental roles of telomeres is their role in meiosis, the process by which parental genomes are recombined and halved, allowing the generation of genetic diversity via sexual reproduction. As cells progress from mitotic to meiotic cycles, telomere functions change radically as all telomeres gather to a small region of the nuclear periphery near the centrosome to form the telomere bouquet . While this bouquet is widely conserved, the challenges of manipulating meiosis in most eukaryotes has made bouquet function a matter of speculation until recently. We utilize the fission yeast Schizosaccharomyces pombe as a model to study telomeres, as this organism provides a powerful combination of genetic manipulability and striking conservation of chromosomal structure/function with human. Recently, we made the unexpected discovery that the bouquet controls the behavior of meiotic centrosomes and spindles. Furthermore, we find that the bouquet is required not only for proper spindle formation, but also for attachment of meiotic chromosomes to the spindle via their centromeres. Using molecular genetics, quantitative live analysis and biochemistry, we propose to define the mechanisms by which the gathered telomeres control spindle behavior. We will also investigate what aspect of the telomere confers proper centromere-spindle attachment and what goes wrong at centromeres in cells lacking the bouquet. These studies will illuminate mechanisms of communication between chromosomes and the spindle apparatus that should be widely conserved among eukaryotes.

1 451 943 €

Start date: 2010-06-01, End date: 2015-05-31

The main objective of this interdisciplinary research project is to elucidate regulatory mechanisms through which the circadian timing system coordinates temporal physiology. This system has a hierarchical architecture, in that a master clock in the brain s suprachiasmatic nucleus synchronizes subsidiary oscillators in nearly all body cells. The establishment of phase coherence is obviously of utmost importance in the coordination of circadian physiology. While recent studies have identified feeding cycles, hormone rhythms, and body temperature oscillations as timing cues for peripheral clocks, the molecular makeup of the involved signalling mechanisms is largely unknown. Using liver and cultured cells as model systems, we will employ two innovative strategies for the elucidation of relevant signalling pathways. (1) STAR-Prom (Synthetic TAndem Repeat-PROmoter display), a technique developed in our laboratory, will hopefully identify most if not all immediate early transcription factors activated in cultured cells by rhythmic blood-borne and temperature-dependent signals. (2) A transgenic mouse model with conditionally active liver clocks will be explored in the genome-wide identification of coding and non-coding transcripts whose rhythmic accumulation is system-driven. The in vivo significance of the components emerging from these approaches will be assessed via RNA interference. Thus, relevant siRNAs will be injected into the tail vein of mice, and their effect on the phase of circadian liver gene expression will be monitored in freely moving mice by using whole body fluorescence imaging. Physiologically important components will serve as entry points for the identification of upstream and downstream constituents in the corresponding signal transduction cascades.

2 360 136 €

Start date: 2010-04-01, End date: 2015-12-31