ERC FUNDED PROJECTS

Our aim is to provide a theoretical framework for studies of dynamical aspects of magnetic materials and magnetisation reversal, which has potential for applications for magnetic data storage and magnetic memory devices. The project focuses on developing and using an atomistic spin dynamics simulation method. Our goal is to identify novel materials and device geometries with improved performance. The scientific questions which will be addressed concern the understanding of the fundamental temporal limit of magnetisation switching and reversal, and the mechanisms which govern this limit. The methodological developments concern the ability to, from first principles theory, calculate the interatomic exchange parameters of materials in general, in particular for correlated electron materials, via the use of dynamical mean-field theory. The theoretical development also involves an atomistic spin dynamics simulation method, which once it has been established, will be released as a public software package. The proposed theoretical research will be intimately connected to world-leading experimental efforts, especially in Europe where a leading activity in experimental studies of magnetisation dynamics has been established. The ambition with this project is to become world-leading in the theory of simulating spin-dynamics phenomena, and to promote education and training of young researchers. To achieve our goals we will build up an open and lively environment, where the advances in the theoretical knowledge of spin-dynamics phenomena will be used to address important questions in information technology. In this environment the next generation research leaders will be fostered and trained, thus ensuring that the society of tomorrow is equipped with the scientific competence to tackle the challenges of our future.

2 130 000 €

Start date: 2010-01-01, End date: 2014-12-31

Telomeres are heterochromatic nucleoprotein complexes located at the end of linear eukaryotic chromosomes. Contrarily to a longstanding dogma, we have recently demonstrated that mammalian telomeres are transcribed into TElomeric Repeat containing RNA (TERRA) molecules. TERRA transcripts contain telomeric RNA repeats and are produced at least in part by DNA-dependent RNA polymerase II-mediated transcription of telomeric DNA. TERRA molecules form discrete nuclear foci that co-localize with telomeric heterochromatin in both interphase and transcriptionally inactive metaphase cells. This indicates that TERRA is an integral component of telomeres and suggests that TERRA might participate in maintaining proper telomere heterochromatin. We will use a variety of biochemistry, cell biology, molecular biology and microscopy based approaches applied to cultured mammalian cells and to the yeast Schizosaccharomyces pombe, to achieve four distinct major goals: i) We will over-express or deplete TERRA in mammalian cells in order to characterize the molecular details of putative TERRA-associated functions in maintaining normal telomere structure and function; ii) We will locate TERRA promoter regions on different human chromosome ends; iii) We will generate mammalian cellular systems in which to study artificially seeded telomeres that can be transcribed in an inducible fashion; iv) We will identify physiological regulators of TERRA by analyzing it in mammalian cultured cells where the functions of candidate factors are compromised. In parallel, taking advantage of the recent discovery of TERRA also in fission yeast, we will systematically analyze TERRA levels in fission yeast mutants derived from a complete gene knockout collection. The study of TERRA regulation and function at chromosome ends will strongly contribute to our understanding of how telomeres are maintained and will help to clarify the general functions of mammalian non-coding RNAs.

1 602 600 €

Start date: 2009-10-01, End date: 2014-09-30

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

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 role of children's behavior and temperament is increasingly acknowledged in family research. Gene-environment Correlation (rGE) processes may account for some child effects, as parents react to children s behavior which is in part genetically influenced (evocative rGE). In addition, passive rGE, in which parenting and children s behavior are correlated through overlapping genetic influences on family members behavior may account in part for the parenting-child behavior relationships. The proposed project will be the first one to directly address these issues with DNA information on family members and quality observational data on parent and child behaviors, following children through early development. Two separate longitudinal studies will investigate the paths from children s genes to their behavior, to the way parents react and modify their parenting towards the child, affecting child development: Study 1 will follow first-time parents from pregnancy through children s early childhood, decoupling parent effect and child effects. Study 2 will follow dizygotic twins and their parents through middle childhood, capitalizing on genetic differences between twins reared by the same parents. We will test the hypothesis that parents' characteristics, such as parenting style and parental attitudes, are associated with children's genetic tendencies. Both parenting and child behaviors will be monitored consecutively, to investigate the co-development of parents and children in an evocative rGE process. Child and parent candidate genes relevant to social behavior, notably those from the dompaminergic and serotonergic systems, will be linked to parents behaviors. Pilot results show children s genes predict parenting, and an important task for the study will be to identify mediators of this effect, such as children s temperament. We will lay the ground for further research into the complexity of gene-environment correlations as children and parents co-develop.

1 443 687 €

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

Few systems in nature are entirely in equilibrium. Out of equilibrium, there are heat currents, and different degrees of freedom or parts of studied systems may be described by entirely different temperatures if the concept of temperature is at all well defined. In this project we will study the emergence of the subsystem temperatures in different types of small electronic systems, and the physical phenomena associated with those temperatures. Our emphasis is on the mesoscopic effects, residing between the microscopic world of individual atoms and electrons, and the macroscopic everyday world. In particular, we will research thermometry methods, different types of relaxation, magnitudes of fluctuations and effects at high frequencies. We will explore these effects in a wide variety of systems: normal metals and superconductors, carbon nanostructures, nanoelectromechanical and spintronic systems. Besides contributing to the understanding of the fundamental properties of electronic systems, our studies are directly relevant for the development of thermal sensors and electron refrigerators. The improved understanding of the thermal phenomena will also benefit the study of almost any type of a nonlinear phenomenon in electronics, for example the research of solid-state realizations of quantum computing or the race towards quantum limited mass and force detection.

1 322 371 €

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

One of the key challenges in scientific research is to link together our understanding of different levels of biological organisation. This challenge is fundamental to the scientific endeavour: from understand how genes interact to drive the cell, to how cells interact to form organisms, up to how organisms interact to form groups and societies. My own and the research of others has addressed this question in the context of the collective behaviour of animals. Mathematical models of complex systems have been used to successfully predict experimental outcome. Most previous studies are however limited in one important aspect: individuals are treated as identical units. The aim of the proposed research proposed is to investigate features which produce differences within the units. The model systems of our study will be sticklebacks, homing pigeons and house sparrows. Individuals can differ from each other on a range of time scales, from information acquired within the last few minutes, through socially learnt information, to genetically inherited differences. Through a series of experiments on each of the study species, the development of mathematical models which incorporate between individual differences, and novel forms of data analysis, we will begin to understand the role played by individual differences within groups. We will look at the rules of motion for fish and birds; the role of personality in decision-making and how short term information differences improve decision-making accuracy. Achieving the project objectives will greatly enhance our understanding of the relationship between individual animals and the groups they live in, as well as impacting on our understanding of individual differences in other areas of biology.

977 768 €

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

The aim of this project is to try to understand the complex molecular mechanisms involved in DNA editing, repair and recombination during immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). We have developed a series of PCR-based assays to study in vivo generated CSR junctions and the pattern of mutations introduced in the immunoglobulin variable region genes in human B cells, allowing us to characterize CSR and SHM in patients with immunodeficiency due to defect(s) in DNA repair/recombination. Novel in vitro CSR assays, based on GFP expression, allowing quantitative measurement of substrate recombination, are also being developed. In addition, we have initiated an evolutionary analysis of the function and structure of activation-induced deaminase, an essential molecule involved both in CSR and SHM, aiming to identify CSR specific-cofactor(s). Combining these approaches, we will be able to define the DNA repair pathways involved in CSR and SHM. The suggested project requires access to patients with various defects in the DNA repair pathways. Many of these diseases are exceedingly rare. However, through worldwide collaboration, we have obtained samples from a majority of the diagnosed patients. We are also refining the existing screening methods and developing novel methods, that will allow identification of additional patients both with recognized and new diseases caused by mutations in DNA repair pathways. Finally, we hope to be able to address the question whether illegitimate CSR events are associated with predisposition to lymphomagenesis in patients with immunodeficiency/DNA repair defect(s), by analyzing the CSR induced chromosomal breaks and translocations in these patients. A large-scale sequencing project is also planned to characterize the CSRnome in B-cell lymphoma samples.

1 888 166 €

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

The objective of this project is to use rich Swedish registry data to learn about mechanisms behind intergenerational correlations. Typically, considerably effort has been spent on estimating correlations between outcome variables, such as education and income, for parents and children. However, the estimated correlations are driven by the causal effect of the parental variable of interest as well as unobservable factors such as other family background related variables and a part that is due to genetic transmission between parent and child. Disentangling these parts is very difficult and only recently has researchers made serious attempts to disentangling these different parts. However, findings vary widely across methods and this literature is still in its infancy. Among questions we ask are: How much of the association between outcome variables for the child and a parent is due to a causal effect from the parental variable, and how much is transmitted through unobservable family factors and genetic transmission? What are the intergenerational transmission and channels for life expectancy and health? What is the importance of genes-environmental interaction? Has the importance of genes, environment and its interactions for the intergenerational associations changed during the growth of the Scandinavian welfare state? How many generations does it take for ancestors placement in the income distribution to not longer matter for life success? These questions are directly relevant for policy, and relate to classical social science issues such as inequality of opportunity and level-of-living in general. The innovativeness of this project is based on using the uniqueness of Swedish registry data (ideal to answer these questions), with which one can match biological and adoptive parents, children and siblings, and hence can identify whether children are reared by their biological or adoptive parents, for the population of Swedes.

631 600 €

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

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

If we are ever to unravel the mysteries of brain function at its most fundamental level, we will need a precise understanding of how its component neurons connect to each other. Furthermore, given the many recent advances in genetic engineering, viral targeting, and immunohistochemical labeling of specific cellular structures, there is a growing need for automated quantitative assessment of neuron morphology and connectivity. Electron microscopes can now provide the nanometer resolution that is needed to image synapses, and therefore connections, while Light Microscopes see at the micrometer resolution required to model the 3D structure of the dendritic network. Since both the arborescence and the connections are integral parts of the brain's wiring diagram, combining these two modalities is critically important. In fact, these microscopes now routinely produce high-resolution imagery in such large quantities that the bottleneck becomes automated processing and interpretation, which is needed for such data to be exploited to its full potential. We will therefore use our Computer Vision expertise to provide not only the necessary tools to process images acquired using a specific modality but also those required to create an integrated representation using all available modalities. This is a radical departure from earlier approaches to applying Computer Vision techniques in this field, which have tended to focus on narrow problems. State-of-the-art methods have not reached the level of reliability and integration that would allow automated processing and interpretation of the massive amounts of data that are required for a true leap of our understanding of how the brain works. In other words, we cannot yet exploit the full potential of our imaging technology and that is what we intend to change.

2 495 982 €

Start date: 2010-04-01, End date: 2016-03-31

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

At a low temperature, nearly macroscopic quantum states can be sustained in superconducting (SC) Josephson junctions. Recently, these superconducting qubits have been coupled to electromagnetic resonators, in a manner analogous to cavity Quantum Electro Dynamics (QED) which describes the interaction between atoms and quantized oscillation modes in the quantum limit. On the other hand, there is yet no experimental evidence of a mode of a mechanical oscillator, such as that of a miniaturized vibrating string, to be chilled down to its quantum ground state. The main part of the proposal involves the use the coupling of Nanomechanical Resonators (NR) to SC qubits employed as artificial atoms in order to address the quantum-classical interface in mechanical motion. Similarly as the SC qubit can exchange quanta with electrical oscillators, it can, in principle, communicate with mechanical modes. The research will begin with demonstrating this kind of electromechanical interaction. In order to tackle experimental surprises, I plan on launching two parallel paths, one with a charge qubit, the other using a phase qubit. The formidable main goal is to experimentally reach the quantum ground state of a mechanical mode. I will investigate the following routes: Make a 1 GHz frequency NR, corresponding to 50 mK, which will reach the ground state at accessible temperatures. On the other hand, I propose to side-band cool a lower-frequency NR via the attached SC qubit. Near the quantum limit, I will start taking advantage of the NR as a building block of electromechanical quantum information. I also propose to push the QED setup of SC qubits coupled to electrical cavities towards more and more complicated states in order to test quantum mechanics in the nearly classical limit.

1 373 000 €

Start date: 2010-01-01, End date: 2014-12-31

There is an immediate need to increase our understanding of the genetic basis for fitness differences in natural populations (Ellegren and Sheldon Nature 452:169-175, 2008). Fortunately, technological developments within genome research, notably the recent ability to retrieve massive amounts of DNA sequence data based on next generation sequencing , will make possible completely novel investigations of the link between genotypes and phenotypes in non-model organisms. With our background as major players in molecular ecology and evolutionary genomics of non-models for the last 15-20 years, we are excellently placed to take on a leading role in this process, developing a Next Generation Molecular Ecology . This research program will combine studies of candidate genes with large-scale gene expression analysis, several mapping approaches and comparative genomics to study the genetic basis of trait evolution in wild bird populations. First, we will search for and analyse loci involved with reproductive isolation and adaptive population divergence in a well-known system for speciation research the pied flycatcher and the collared flycatcher. A milestone of this program will be genome sequencing of the two flycatcher species. Second, we will track the genetic basis of behaviour using a unique breeding population of zebra finches and benefitting from the recently obtained genome sequence of this species. Third, we will identify the targets for adaptive evolution during avian evolution using comparative genomics. Overall, the program will be able to reveal the molecular genetic architecture behind phenotypic variation. The potential for scientific break-through in this interdisciplinary program should be significant.

2 500 000 €

Start date: 2010-04-01, End date: 2015-09-30

Our goal is to develop fundamentally new architectures for wireless networks that offer the convenience of wireless communication while achieving the performance, predictability and security of wired networks. The wireless channel is inherently a shared medium characterized by limited resources and complex signal interactions between transmitted signals. The question we address is how do we transmit information over wireless and how do we exploit the wireless channel properties to share its resources. Ours is a fundamentally different approach to existing strategies, that builds on new physical and packet layer sharing and cooperation paradigms that we have been working on, to extract the optimal throughput and reliability performance from the wireless medium. These are recent breakthroughs in (i) network coding and (ii) wireless cooperation. Network coding is a new area bringing a novel paradigm for network information flow that enables cooperation at a packet level to optimally share the network resources. Deployment of the first network coding ideas in wireless have already indicated benefits as large as a factor of ten in terms of throughput. Complex signal interactions caused by the inherent broadcast nature of wireless channels, is traditionally viewed as an impediment to be mitigated. Recently it has been demonstrated that one can utilize interference to develop cooperation at the wireless signal level (physical layer) for arbitrary wireless networks. This can give significant capacity advantages over techniques that mitigate interference. Both these ideas can radically affect the way information is communicated, stored and collected, and can revolutionize the design of future wireless networks. In this project we plan to addess several fundamental questions that develop on these themes. We take a complete view of these ideas by not only developing the underlying theory but also through validation on wireless testbeds.

1 771 520 €

Start date: 2009-09-01, End date: 2014-08-31

Cellular responses to external signals begin at the plasma membrane, where the dynamic assembly of receptors can regulate cellular activity. Membrane-enveloped viruses, including the human immunodeficiency virus (HIV) also assemble at the plasma membrane, exploiting mechanisms evolved for cellular trafficking. However, our physical paradigm for how proteins form mesoscale assemblies is far from complete. While the organization and dynamics of membrane proteins are heterogeneous, commonly used fluorescence-based measurements lack information at the molecular scale. In contrast, single molecule measurements limited to looking at only a few molecules in a given cell lack ensemble information. Thus, the study of protein assembly has been limited by a lack of spatially resolved, dynamic information on ensembles of molecules. We will use super-resolution fluorescence imaging techniques combined with live cell imaging and single molecule tracking to determine how the dynamics of protein assembly are coordinated. The long-term goal of my research is to use quantitative fluorescence methods to identify the physical mechanisms for protein transport and organization in cells. The objective of this proposal is to establish quantitative models of protein assembly in two specific biological systems which were selected for the distinct characteristics of their assembly, and their relevance to human health. This will test the central hypothesis that molecular assembly is enhanced by the organization of the plasma membrane in the form of cytoskeletal elements and protein-lipid platforms. This interdisciplinary research will provide an experimental foundation for a statistical description of the cell, whose behaviour is embedded in protein organization and dynamics.

1 542 518 €

Start date: 2009-12-01, End date: 2015-11-30

Each year 1.1 million new cases of breast cancer will occur among women worldwide and 400,000 women will die from this disease. Although progress has been made in understanding breast tumor biology, most of the relevant molecules and pathways remain undefined. Their delineation is critical to a rational approach to breast cancer therapy. This proposal focuses on the role of the under-explored family of protein-tyrosine phosphatases (PTPs) in the normal and neoplastic breast. Virtually all cell signaling pathways are modulated by reversible protein tyrosine phosphorylation, which is regulated by two classes of enzymes: protein-tyrosine kinases (PTKs) and PTPs. Not surprisingly, tyrosine phosphorylation has an important role in breast development and cancer. Whereas the role of specific PTKs, like the HER2 receptor, in breast cancer is well studied, almost nothing is known about the function of specific PTPs in this disease. Our preliminary data suggest that PTP1B has an important role in breast differentiation and that both PTP1B and SHP2 play positive roles in breast cancer. The two predominant goals of this proposal are: First, to delineate the role of PTP1B and other PTPs in normal breast development and differentiation; second, to address the roles of PTP1B and other PTPs in the maintenance of breast cancer and metastasis and to assess their merits as drug targets. These studies not only use state-of-the-art ex vivo and in vivo models for studying breast pathophysiology, but also cross the boundaries between the developmental and cancer research fields and between basic science and clinical applications. Our research should ultimately lead to the rational design of targeted therapies that will improve the clinical management of patients with breast cancer.

1 571 365 €

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

The current financial crisis testifies that the sophisticated risk management models used by large financial institutions are inadequate. The main objective of this research project is to analyze the sources of this failure and to develop sound conceptual principles for founding new risk management methods for financial institutions. In spite of the wide use of sophisticated risk management models by the majority of large firms, the conceptual foundations for them are weak. Most of them rely on the assumption that financial markets always function well. The few theoretical models that incorporate endogenous financial frictions use contract theoretic tools but they are static or two period models. Such models cannot generate really testable implications, or provide quantitatively reasonable policy recommendations. Another strand of the theoretical literature has developed diffusion models for modelling the financial behaviour of corporations in continuous time. However this literature is mathematically oriented and makes very strong assumptions, without clear justifications. Our objective is to combine these two approaches and construct testable dynamic models with endogenous financial frictions. These models are to be simple enough that they can provide reasonable policy recommendations, with a particular attention to banks and insurance companies. By adapting the general model of corporate risk management in a dynamic set-up to the specificities of financial intermediaries, we will develop a model of risk management for the financial sector. Implications will be derived for prudential regulation of financial intermediaries and the organisation of supervision, with a particular attention to the prevention and management of future financial crises.

1 440 000 €

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

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 envisages a research program in the field of systems and signals that will lead to innovative and agile mathematical modeling as well as model-based signal processing and control tools for applications in biology and medicine. The project's goal is to bridge the gap between systems biology, on one hand, and medical signal processing and control engineering, on the other. Mathematical models of systems biology will be used to devise algorithms for biological data processing and computerized medical interventions. Experimental biological and clinical data will be utilized to estimate and characterize the parameters of mathematical models derived for biological phenomena and mechanisms. An extensive collaboration network of medical researchers from Sweden and abroad will provide the project team with necessary experimental data as well as with access to medical competence. The envisaged tools are expected to be applicable more generally but their efficacy will be demonstrated in two main application areas. These areas are endocrinology and neurology for which the use of formal control engineering and signal processing methods is currently deemed to be most promising. The proposed program will result in novel systems and signals tools for medical research and health care enabling multi-input multi-output modeling and analysis of endocrine regulations and providing model-based algorithms for individualized drug dose titration.

2 379 000 €

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

One of the central mysteries of immunology is self-tolerance. How does the human body select ~10e12 T lymphocytes, that are reactive to foreign pathogens but tolerant to normal cellular constituents of the host? Over the last few years, my laboratory identified 2 fundamental mechanisms used by thymocytes to establish T cell tolerance. We demonstrated that the affinity threshold for negative selection is a constant for all thymocytes expressing MHC I restricted TCRs. This binding affinity threshold (KD H 6 ¼M; estimated T1/2 H 2 sec) is the fundamental biophysical parameter used by TCRs to delete autoimmune T cells. We also established how the TCR generates distinct signals for positive and negative selection. At the selection threshold, a small increase in ligand affinity for the T-cell antigen receptor leads to a marked change in the activation and subcellular localization of Ras and mitogen-activated protein kinase (MAPK) signaling intermediates. The ability to compartmentalize signaling molecules differentially within the cell endows the thymocyte with the ability to convert a small change in analogue input (affinity) into a digital output (positive versus negative selection) and provides the molecular basis for central tolerance. In the present application, we plan to fully understand 1-how the biophysical events during antigen binding to the TCR initiate an intracellular signal; 2-how these signals program an unambiguous cell fate and 3-how the system fails, when an autoimmune T cell is generated and activated. We will use a combination of transgenic and knockout mice, biochemistry and molecular imaging to fully define how the TCR functions as a molecular switch.

1 930 000 €

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

The overall effectiveness at which the underlying talent resources in an economy are utilized is an important determinant of long-run economic growth and well-being. Recent work has shown that the processes through which talent is discovered and revealed in the economy are likely to suffer from market imperfections that are analogous to problems that have been for long been understood in the context of private provision of job training and education, resulting in not just reduced economic efficiency but also contributing to income inequality. The first basic question is what is the role of talent rents in explaining income inequality? In a static world where all information about talent is known, such talent rents would merely be compensation to a scarce factor of production. However, when the discovery of talent is subject to market imperfections then income differences that ostensibly look like talent rents are partly due to inefficient information rents. This raises the second and novel question, about whether and to what extent observed income differences are due to inefficient rents to information about talent that masquerade as talent rents. I also plan to investigate how technological change has impacted the distribution of talent rents via its effect on the discovery/revelation process of talent. The larger goal of the project is to help understand the economy-wide implications of institutions and policies that govern the discovery and allocation of talent in the economy. Better understanding could also point the way towards improved policy interventions.

1 003 440 €

Start date: 2009-10-01, End date: 2015-03-31