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Project acronym ANALYTICAL SOCIOLOGY
Project Analytical Sociology: Theoretical Developments and Empirical Research
Researcher (PI) Mats Peter Hedström
Summary This proposal outlines a highly ambitious and path-breaking research program. Through a tightly integrated package of basic theoretical work, strategic empirical research projects, international workshops, and a large number of publications in leading journals, the research program seeks to move sociology in a more analytical direction. One part of the research program focuses on the epistemological and methodological foundations of analytical sociology, an approach to sociological theory and research that currently receives considerable attention in the international scholarly community. This work will be organized around two core themes: (1) the principles of mechanism-based explanations and (2) the micro-macro link. The empirical research analyzes in great detail the ethnic, gender, and socio-economic segregation of key interaction domains in Sweden using the approach of analytical sociology. The interaction domains focused upon are schools, workplaces and neighborhoods; domains where people spend a considerable part of their time, where much of the social interaction between people takes place, where identities are formed, and where important resources are distributed. Large-scale longitudinal micro data on the entire Swedish population, unique longitudinal data on social networks within school classes, and various agent-based simulation techniques, are used to better understand the processes through which schools, workplaces and neighborhoods become segregated along various dimensions, how the domains interact with one another, and how the structure and extent of segregation affects diverse social and economic outcomes.
This proposal outlines a highly ambitious and path-breaking research program. Through a tightly integrated package of basic theoretical work, strategic empirical research projects, international workshops, and a large number of publications in leading journals, the research program seeks to move sociology in a more analytical direction. One part of the research program focuses on the epistemological and methodological foundations of analytical sociology, an approach to sociological theory and research that currently receives considerable attention in the international scholarly community. This work will be organized around two core themes: (1) the principles of mechanism-based explanations and (2) the micro-macro link. The empirical research analyzes in great detail the ethnic, gender, and socio-economic segregation of key interaction domains in Sweden using the approach of analytical sociology. The interaction domains focused upon are schools, workplaces and neighborhoods; domains where people spend a considerable part of their time, where much of the social interaction between people takes place, where identities are formed, and where important resources are distributed. Large-scale longitudinal micro data on the entire Swedish population, unique longitudinal data on social networks within school classes, and various agent-based simulation techniques, are used to better understand the processes through which schools, workplaces and neighborhoods become segregated along various dimensions, how the domains interact with one another, and how the structure and extent of segregation affects diverse social and economic outcomes.
Project acronym BIOFINDER
Project New biomarkers for Alzheimer's & Parkinson's diseases - key tools for early diagnosis and drug development
Researcher (PI) Oskar Hansson
Summary Alzheimer's disease (AD) and Parkinson's disease (PD) are common in elderly and the prevalence of these is increasing. AD and PD have distinct pathogenesis, which precede the overt clinical symptoms by 10-15 years, opening a window for early diagnosis and treatment. New disease-modifying therapies are likely to be most efficient if initiated before the patients exhibit overt symptoms, making biomarkers for early diagnosis crucial for future clinical trials. Validated biomarkers would speed up initiation of treatment, avoid unnecessary investigations, and reduce patient insecurity. AIMS: (1) identify and validate accurate and cost-effective blood-based biomarkers for early identification of those at high risk to develop AD and PD, (2) develop algorithms using advanced imaging and cerebrospinal fluid biomarkers for earlier more accurate diagnoses, and (3) better understand the underlying pathology and early progression of AD and PD, aiming at finding new relevant drug targets. We will assess well-characterized and clinically relevant populations of patients and healthy elderly. We will use population- and clinic-based cohorts and follow them prospectively for 4 year. Participants will undergo neurocognitive evaluation, provide blood and cerebrospinal fluid, and have brain imaging using advanced MRI protocols and a newly developed PET-tracer visualizing brain amyloid. Sample will be analyzed with quantitative mass spectrometry and high sensitivity immunoassays. New biomarkers and brain imaging techniques will aid early diagnosis and facilitate the development of disease-modifying therapies, since treatment can start earlier in the disease process. New methods to quantify relevant drug targets, such as oligomers of β-amyloid and α-synuclein, will be vital when selecting drug candidates for large-scale clinical trials. By improving both diagnosis and therapies the social and economic burden of dementia might be reduced by expanding the period of healthy and active aging
Alzheimer's disease (AD) and Parkinson's disease (PD) are common in elderly and the prevalence of these is increasing. AD and PD have distinct pathogenesis, which precede the overt clinical symptoms by 10-15 years, opening a window for early diagnosis and treatment. New disease-modifying therapies are likely to be most efficient if initiated before the patients exhibit overt symptoms, making biomarkers for early diagnosis crucial for future clinical trials. Validated biomarkers would speed up initiation of treatment, avoid unnecessary investigations, and reduce patient insecurity. AIMS: (1) identify and validate accurate and cost-effective blood-based biomarkers for early identification of those at high risk to develop AD and PD, (2) develop algorithms using advanced imaging and cerebrospinal fluid biomarkers for earlier more accurate diagnoses, and (3) better understand the underlying pathology and early progression of AD and PD, aiming at finding new relevant drug targets. We will assess well-characterized and clinically relevant populations of patients and healthy elderly. We will use population- and clinic-based cohorts and follow them prospectively for 4 year. Participants will undergo neurocognitive evaluation, provide blood and cerebrospinal fluid, and have brain imaging using advanced MRI protocols and a newly developed PET-tracer visualizing brain amyloid. Sample will be analyzed with quantitative mass spectrometry and high sensitivity immunoassays. New biomarkers and brain imaging techniques will aid early diagnosis and facilitate the development of disease-modifying therapies, since treatment can start earlier in the disease process. New methods to quantify relevant drug targets, such as oligomers of β-amyloid and α-synuclein, will be vital when selecting drug candidates for large-scale clinical trials. By improving both diagnosis and therapies the social and economic burden of dementia might be reduced by expanding the period of healthy and active aging
Project acronym CACTUS
Project developmental social Cognition and ACTion UnderStanding
Researcher (PI) Kjell Gustaf Gredebäck
Summary Humans are social creatures throughout life. This proposal aims to advance our knowledge of the mechanisms that mediate understanding of others' actions from a developmental perspective. A special emphasis will be devoted to mirror neuron and teleological frameworks. The former framework focuses on reciprocal motor activation during action execution and observation whereas the later framework emphasizes the application of abstract principles to observed events. The mechanisms that guide both processes will be investigated in isolation, but special attention will also be devoted to understanding how these diverse forms of action understanding jointly contribute to action understanding. The project encompasses three essential research objectives, illustrated by three research questions. How do mirror neuron and teleological processes influence action understanding? How does action understanding enable social action evaluation (empathy and pro-social preferences)? How is action understanding expressed during real-life social interactions? These questions will be addressed by presenting infants and toddlers with social events of varying complexity (from simple actions and animated sequences to complex everyday social events), relating empirical findings to predictions derived from the teleological and motor cognitive frameworks. The overarching aim is to provide a computational model of early emerging social cognitive capabilities, with a focus on action understanding and action evaluation, while passively observing others and while partaking in social interactions with others.
Humans are social creatures throughout life. This proposal aims to advance our knowledge of the mechanisms that mediate understanding of others' actions from a developmental perspective. A special emphasis will be devoted to mirror neuron and teleological frameworks. The former framework focuses on reciprocal motor activation during action execution and observation whereas the later framework emphasizes the application of abstract principles to observed events. The mechanisms that guide both processes will be investigated in isolation, but special attention will also be devoted to understanding how these diverse forms of action understanding jointly contribute to action understanding. The project encompasses three essential research objectives, illustrated by three research questions. How do mirror neuron and teleological processes influence action understanding? How does action understanding enable social action evaluation (empathy and pro-social preferences)? How is action understanding expressed during real-life social interactions? These questions will be addressed by presenting infants and toddlers with social events of varying complexity (from simple actions and animated sequences to complex everyday social events), relating empirical findings to predictions derived from the teleological and motor cognitive frameworks. The overarching aim is to provide a computational model of early emerging social cognitive capabilities, with a focus on action understanding and action evaluation, while passively observing others and while partaking in social interactions with others.
Project acronym COMPENZYMEEVOLUTION
Project Harnessing Proto-Enzymes for Novel Catalytic Functions
Researcher (PI) Shina Caroline Lynn Kamerlin
Summary Enzymes are Nature's catalysts, reducing the timescales of the chemical reactions that drive life from millions of years to seconds. There is also great scope for enzymes as biocatalysts outside the cell, from therapeutic and synthetic applications, to bioremediation and even for the generation of novel biofuels. Recent years have seen several impressive breakthroughs in the design of artificial enzymes, particularly through experimental studies that iteratively introduce random mutations to refine existing systems until a property of interest is observed (directed evolution), as well as examples of de novo enzyme design using combined in silico / in vitro approaches. However, the tremendous catalytic proficiencies of naturally occurring enzymes are, as yet, unmatched by any man made system, in no small part due the vastness of the sequence space that needs navigating and the almost surgical precision by which enzymatic catalysis is regulated. The proposed work aims to combine state of the art computational approaches capable of consistently reproducing the catalytic activities of both wild-type and mutant enzymes with novel screening approaches for predicting mutation hotspots, in order to redesign selected showcase systems. Specifically, we aim to (1) map catalytic promiscuity in the alkaline phosphatase superfamily, using the existing multifunctionality of these enzymes as a training set for the introduction of novel functionality, and (2) computationally design enantioselective enzymes, a problem which is of particular importance to the pharmaceutical industry due to the role of chirality in drug efficacy. The resulting theoretical constructs will be subjected to rigorous testing by our collaborators, providing a feedback loop for further design effort and methodology development. In this way, we plan to push existing theoretical tools to the limit in order to bridge the gap that exists between the catalytic proficiencies of biological and man-made catalysts.
Enzymes are Nature's catalysts, reducing the timescales of the chemical reactions that drive life from millions of years to seconds. There is also great scope for enzymes as biocatalysts outside the cell, from therapeutic and synthetic applications, to bioremediation and even for the generation of novel biofuels. Recent years have seen several impressive breakthroughs in the design of artificial enzymes, particularly through experimental studies that iteratively introduce random mutations to refine existing systems until a property of interest is observed (directed evolution), as well as examples of de novo enzyme design using combined in silico / in vitro approaches. However, the tremendous catalytic proficiencies of naturally occurring enzymes are, as yet, unmatched by any man made system, in no small part due the vastness of the sequence space that needs navigating and the almost surgical precision by which enzymatic catalysis is regulated. The proposed work aims to combine state of the art computational approaches capable of consistently reproducing the catalytic activities of both wild-type and mutant enzymes with novel screening approaches for predicting mutation hotspots, in order to redesign selected showcase systems. Specifically, we aim to (1) map catalytic promiscuity in the alkaline phosphatase superfamily, using the existing multifunctionality of these enzymes as a training set for the introduction of novel functionality, and (2) computationally design enantioselective enzymes, a problem which is of particular importance to the pharmaceutical industry due to the role of chirality in drug efficacy. The resulting theoretical constructs will be subjected to rigorous testing by our collaborators, providing a feedback loop for further design effort and methodology development. In this way, we plan to push existing theoretical tools to the limit in order to bridge the gap that exists between the catalytic proficiencies of biological and man-made catalysts.
Project acronym DD-PD
Project A novel mechanism to regulate gene expression in the brain
Researcher (PI) Deniz KIRIK
Summary "Development of advanced therapeutics based on non-small molecule drugs for brain diseases is an area of intense research. Experimental work using viral vector-mediated in vivo gene therapy showed great potential as a competitive therapeutic strategy for clinical use in neurodegenerative diseases. AAV vectors are now in early clinical trials stage for treatment of Parkinson's disease. Although it is deemed very important to have controlled expression in the brain, none of the currently tested strategies have implemented an approach that can be exogenously controlled. Regulation of the therapeutic intervention is important not only for safety reasons but has important implications for tuning the delivery of the therapeutic molecule to the individual needs of the patients, i.e., personalizing their treatment. The core of this proof-of-concept application is to develop a novel gene regulation system as a product for clinical use in patients with Parkinson's disease. The applicant has assembled a strong team of experts that can take this exciting idea that has spun out of his ERC-funded research to an early business strategy and bridge to commercialization. The work will include filing of new IP, a proactive use of novelty search, formation of a dedicated start-up company for handling the new IPR as well as in-licensing of related IP, and sketching a path towards commercialization via obtaining regulatory authorization, investigation of strategies for large-scale production of the product."
"Development of advanced therapeutics based on non-small molecule drugs for brain diseases is an area of intense research. Experimental work using viral vector-mediated in vivo gene therapy showed great potential as a competitive therapeutic strategy for clinical use in neurodegenerative diseases. AAV vectors are now in early clinical trials stage for treatment of Parkinson's disease. Although it is deemed very important to have controlled expression in the brain, none of the currently tested strategies have implemented an approach that can be exogenously controlled. Regulation of the therapeutic intervention is important not only for safety reasons but has important implications for tuning the delivery of the therapeutic molecule to the individual needs of the patients, i.e., personalizing their treatment. The core of this proof-of-concept application is to develop a novel gene regulation system as a product for clinical use in patients with Parkinson's disease. The applicant has assembled a strong team of experts that can take this exciting idea that has spun out of his ERC-funded research to an early business strategy and bridge to commercialization. The work will include filing of new IP, a proactive use of novelty search, formation of a dedicated start-up company for handling the new IPR as well as in-licensing of related IP, and sketching a path towards commercialization via obtaining regulatory authorization, investigation of strategies for large-scale production of the product."
Project acronym DM
Project Dirac Materials
Researcher (PI) Alexander Balatsky
Host Institution (HI) KUNGLIGA TEKNISKA HOEGSKOLAN
Summary "The elegant Dirac equation, describing the linear dispersion (energy/momentum) relation of electrons at relativistic speeds, has profound consequences such as the prediction of antiparticles, reflection less tunneling (Klein paradox) and others. Recent discovery of graphene and topological insulators (TI) highlights the scientific importance and technological promise of materials with "relativistic Dirac dispersion"" of electrons for functional materials and device applications with novel functionalities. One might use term 'Dirac materials' to encompass a subset of (materials) systems in which the low energy phase space for fermion excitations is reduced compared to conventional band structure predictions (i.e. point or lines of nodes vs. full Fermi Surface). Dirac materials are characterized by universal low energy properties due to presence of the nodal excitations. It is this reduction of phase space due to additional symmetries that can be turned on and off that opens a new door to functionality of Dirac materials. We propose to use the sensitivity of nodes in the electron spectrum of Dirac materials to induce controlled modifications of the Dirac points/lines via band structure engineering in artificial structures and via inelastic scattering processes with controlled doping. Proposed research will expand our theoretical understanding and guide design of materials and engineered geometries that allow tunable energy profiles of Dirac carriers."
"The elegant Dirac equation, describing the linear dispersion (energy/momentum) relation of electrons at relativistic speeds, has profound consequences such as the prediction of antiparticles, reflection less tunneling (Klein paradox) and others. Recent discovery of graphene and topological insulators (TI) highlights the scientific importance and technological promise of materials with "relativistic Dirac dispersion"" of electrons for functional materials and device applications with novel functionalities. One might use term 'Dirac materials' to encompass a subset of (materials) systems in which the low energy phase space for fermion excitations is reduced compared to conventional band structure predictions (i.e. point or lines of nodes vs. full Fermi Surface). Dirac materials are characterized by universal low energy properties due to presence of the nodal excitations. It is this reduction of phase space due to additional symmetries that can be turned on and off that opens a new door to functionality of Dirac materials. We propose to use the sensitivity of nodes in the electron spectrum of Dirac materials to induce controlled modifications of the Dirac points/lines via band structure engineering in artificial structures and via inelastic scattering processes with controlled doping. Proposed research will expand our theoretical understanding and guide design of materials and engineered geometries that allow tunable energy profiles of Dirac carriers."
Project acronym ESUX
Project Electron Spectroscopy using Ultra Brilliant X-rays - a program for the advancement of state-of-the-art instrumentation and science
Researcher (PI) Nils Ove Tor Mårtensson
Summary The progress of materials science depends critically on the access to advanced characterization methods. During the last decades there has been an almost revolutionary development of modern X-ray based tools. We are today at a turning point in the development of synchrotron radiation based electron spectroscopy, where the program of the PI has maintained a leading position since 20 years. New techniques are evolving parallel to the development of a new generation of ultra-brilliant synchrotron radiation (SR) facilities. Electron spectroscopy is one of the most important techniques for the advancement of materials science and is one of the corner stones for the research at SR facilities. It is of highest priority to introduce new types of instruments to push the spectroscopy into new domains of time, spatial, energy and angular resolution. We have recently accomplished a break-through in this field with a new type of electron analyzer, the ArTOF instrument, capable of increasing the energy resolution down to the micro-eV range with a simultaneous increase of the transmission of almost three orders of magnitude, compared to the earlier instruments. In addition the emission angles of all electrons are determined, with high precision and within a wide cone. This allows us to obtain three dimensional electronic structure information in real time. The present ERC proposal defines an ambitious program to fully exploit the new possibilities in urgent fields of research: In situ time resolved electronic band structure of organic crystals for electronic applications, time resolved studies of 3D band structure of solids and new 2D materials (graphene, topological insulators), electron structure and dynamics of materials for solar cell applications, and in other important research fields. The research program will also adapt the new technique to take advantage of new opportunities opened by emerging ultra-brilliant X-ray sources.
The progress of materials science depends critically on the access to advanced characterization methods. During the last decades there has been an almost revolutionary development of modern X-ray based tools. We are today at a turning point in the development of synchrotron radiation based electron spectroscopy, where the program of the PI has maintained a leading position since 20 years. New techniques are evolving parallel to the development of a new generation of ultra-brilliant synchrotron radiation (SR) facilities. Electron spectroscopy is one of the most important techniques for the advancement of materials science and is one of the corner stones for the research at SR facilities. It is of highest priority to introduce new types of instruments to push the spectroscopy into new domains of time, spatial, energy and angular resolution. We have recently accomplished a break-through in this field with a new type of electron analyzer, the ArTOF instrument, capable of increasing the energy resolution down to the micro-eV range with a simultaneous increase of the transmission of almost three orders of magnitude, compared to the earlier instruments. In addition the emission angles of all electrons are determined, with high precision and within a wide cone. This allows us to obtain three dimensional electronic structure information in real time. The present ERC proposal defines an ambitious program to fully exploit the new possibilities in urgent fields of research: In situ time resolved electronic band structure of organic crystals for electronic applications, time resolved studies of 3D band structure of solids and new 2D materials (graphene, topological insulators), electron structure and dynamics of materials for solar cell applications, and in other important research fields. The research program will also adapt the new technique to take advantage of new opportunities opened by emerging ultra-brilliant X-ray sources.
Project acronym F12
Project Factor XII and the contact system: cross-talk between thrombosis and inflammation
Researcher (PI) Hans Thomas Renné
Summary Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. Factor XII (FXII, Hageman factor) is a plasma protease that initiates the contact system. This system starts a cascade of procoagulant and proinflammatory reactions via the intrinsic pathway of coagulation, and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood, however its in vivo functions are just beginning to emerge. We have previously demonstrated that FXII is essential for thrombus formation while being dispensable for hemostatic processes that terminate blood loss. Challenging the dogma of a coagulation balance, targeting factor XII protected from cerebral ischemia without interfering with hemostasis. In contrast, excess FXII activity is associated with a life threatening inflammatory disorder, Hereditary angioedema. We recently have identified platelet polyphosphate (an inorganic polymer) and mast cell heparin as in vivo FXII activators with implications on the initiation of thrombosis and edema. The current investigations will explore roles of the FXII-driven contact system at the intersection of procoagulant and proinflammatory pathways using genetically altered murine models. We aim to understand activation, regulation and functions of the system for ischemic heart disease, vascular leakage in Hereditary angioedema, allergic airway inflammation as well as procoagulant reactions driven by bacterial infections in skin and lung. A key aspect of this proposal will be analysis of common principles, interactions and cross-talk between coagulation and inflammation, to identify novel therapeutic targets. Elucidating the FXII-driven contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory diseases.
Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. Factor XII (FXII, Hageman factor) is a plasma protease that initiates the contact system. This system starts a cascade of procoagulant and proinflammatory reactions via the intrinsic pathway of coagulation, and the bradykinin-producing kallikrein-kinin system, respectively. The biochemistry of the contact system in vitro is well understood, however its in vivo functions are just beginning to emerge. We have previously demonstrated that FXII is essential for thrombus formation while being dispensable for hemostatic processes that terminate blood loss. Challenging the dogma of a coagulation balance, targeting factor XII protected from cerebral ischemia without interfering with hemostasis. In contrast, excess FXII activity is associated with a life threatening inflammatory disorder, Hereditary angioedema. We recently have identified platelet polyphosphate (an inorganic polymer) and mast cell heparin as in vivo FXII activators with implications on the initiation of thrombosis and edema. The current investigations will explore roles of the FXII-driven contact system at the intersection of procoagulant and proinflammatory pathways using genetically altered murine models. We aim to understand activation, regulation and functions of the system for ischemic heart disease, vascular leakage in Hereditary angioedema, allergic airway inflammation as well as procoagulant reactions driven by bacterial infections in skin and lung. A key aspect of this proposal will be analysis of common principles, interactions and cross-talk between coagulation and inflammation, to identify novel therapeutic targets. Elucidating the FXII-driven contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory diseases.
Project acronym FLOWGENE
Project Following the Genomic Footprints of Early Europeans
Researcher (PI) Bo Mattias Jakobsson
Summary Two of greatest challenges of the post-genomic era are to (i) develop a detailed understanding of the heritable variation in the human genome, and to (ii) determine which key events in human evolutionary history that are responsible for patterns of genomic variation. The recent genomic revolution will be instrumental in these quests and we will very soon have access to several thousand complete genomes from diverse populations. Extracting genetic information from ancient material has for long been hampered by numerous difficulties after its first steps some two decades ago, but in the last few years, many of these problems have been solved and the use of ancient DNA is now beginning to show its full potential. The use of ancient DNA has been announced among the top-ten 'insights of the decade' by Science, and promises to transform our views on human origins and prehistory. The demographic history of Europeans attracts great interest in archaeology, anthropology, and human genetics, and it has drawn extensive research focus for more than a century. The recent genomic revolution has opened up the time dimension for genomic analyses, however, to harness the full potential of genomic data from modern and ancient material, we need new population genetic theory and modern statistical analysis tools. I propose to conduct 3 Ancient Genome Projects to generate complete genomes for multiple individuals from 3 time epochs in the European prehistory; the Cro-Magnon-, the Mesolithic-, and the Neolithic-Genome project. These Genome Projects will proceed in concert with development a) new population genetic theory and novel tools for demographic inference, b) a novel, temporal based, framework for characterizing selection and local adaptation, and c) explore the evolutionary history of gene-variants associated with traits and diseases. Genomic data from temporal samples has the potential to revolutionize our understanding of human evolution and the demographic history of Europe.
Two of greatest challenges of the post-genomic era are to (i) develop a detailed understanding of the heritable variation in the human genome, and to (ii) determine which key events in human evolutionary history that are responsible for patterns of genomic variation. The recent genomic revolution will be instrumental in these quests and we will very soon have access to several thousand complete genomes from diverse populations. Extracting genetic information from ancient material has for long been hampered by numerous difficulties after its first steps some two decades ago, but in the last few years, many of these problems have been solved and the use of ancient DNA is now beginning to show its full potential. The use of ancient DNA has been announced among the top-ten 'insights of the decade' by Science, and promises to transform our views on human origins and prehistory. The demographic history of Europeans attracts great interest in archaeology, anthropology, and human genetics, and it has drawn extensive research focus for more than a century. The recent genomic revolution has opened up the time dimension for genomic analyses, however, to harness the full potential of genomic data from modern and ancient material, we need new population genetic theory and modern statistical analysis tools. I propose to conduct 3 Ancient Genome Projects to generate complete genomes for multiple individuals from 3 time epochs in the European prehistory; the Cro-Magnon-, the Mesolithic-, and the Neolithic-Genome project. These Genome Projects will proceed in concert with development a) new population genetic theory and novel tools for demographic inference, b) a novel, temporal based, framework for characterizing selection and local adaptation, and c) explore the evolutionary history of gene-variants associated with traits and diseases. Genomic data from temporal samples has the potential to revolutionize our understanding of human evolution and the demographic history of Europe.
Project acronym FSA
Project Fluid Spectrum Acess
Researcher (PI) Alexandre Proutiere
Summary Spectrum is a key and scarce resource in wireless communication networks, and it remains tightly controlled by regulation authorities. Most of the frequency bands are exclusively allocated to a single system licensed to use it everywhere and for long periods of time. This rigid spectrum management model inevitably leads to significant inefficiencies in spectrum use. The explosion of demand for broadband wireless services also calls for more flexible models where much larger spectrum parts could be dynamically shared among users in a fluid manner. In such models, Dynamic Spectrum Access (DSA) techniques will play a major role. These techniques make it possible for radio devices to become frequency-agile, i.e. able to rapidly and dynamically access bands of a wide spectrum part. The success and spread of dynamic spectrum access strongly rely on the ability for many frequency-agile devices (or systems) to coexist peacefully and efficiently. With multiple interacting devices, the research agenda shifts from spectrum access problems to spectrum sharing problems, which raises original and challenging questions. There may be limited or no communication between the different devices or systems sharing spectrum. We further expect systems to be heterogeneous in their transmission capabilities, but also in the type of service they support. In that context, the design of spectrum access strategies resulting in an efficient and fair spectrum resource use constitutes a challenging puzzle. The broad objective of the proposed research is to develop original analytical and simulation tools to tackle dynamic spectrum sharing issues. The project leverages and marries techniques from distributed optimization and machine learning to design decentralized, efficient, and fair spectrum sharing algorithms. We believe that such algorithms are critical for the birth and rapid expansion of DSA technologies and hence for the development of future wireless broadband systems.
Spectrum is a key and scarce resource in wireless communication networks, and it remains tightly controlled by regulation authorities. Most of the frequency bands are exclusively allocated to a single system licensed to use it everywhere and for long periods of time. This rigid spectrum management model inevitably leads to significant inefficiencies in spectrum use. The explosion of demand for broadband wireless services also calls for more flexible models where much larger spectrum parts could be dynamically shared among users in a fluid manner. In such models, Dynamic Spectrum Access (DSA) techniques will play a major role. These techniques make it possible for radio devices to become frequency-agile, i.e. able to rapidly and dynamically access bands of a wide spectrum part. The success and spread of dynamic spectrum access strongly rely on the ability for many frequency-agile devices (or systems) to coexist peacefully and efficiently. With multiple interacting devices, the research agenda shifts from spectrum access problems to spectrum sharing problems, which raises original and challenging questions. There may be limited or no communication between the different devices or systems sharing spectrum. We further expect systems to be heterogeneous in their transmission capabilities, but also in the type of service they support. In that context, the design of spectrum access strategies resulting in an efficient and fair spectrum resource use constitutes a challenging puzzle. The broad objective of the proposed research is to develop original analytical and simulation tools to tackle dynamic spectrum sharing issues. The project leverages and marries techniques from distributed optimization and machine learning to design decentralized, efficient, and fair spectrum sharing algorithms. We believe that such algorithms are critical for the birth and rapid expansion of DSA technologies and hence for the development of future wireless broadband systems.
Project acronym GAPWAVE ICS
Project Waveguide-type semiconductor integrated circuits (ICs) in gaps between conducting surfaces with texture – architecture, electromagnetic modeling and micromachining
Researcher (PI) Per-Simon Kildal
Host Institution (HI) CHALMERS TEKNISKA HOEGSKOLA AB
Summary In order to explore and exploit the frequency range from 30 GHz up to THz, new types of transmission lines and semiconductor architectures are needed. Conventional microwave technologies that are commonly used below 30 GHz become either too lossy or are too expensive to manufacture, and technologies used in the optical regime are not usable either. The intermediate frequency band is therefore often referred to as the THz gap, indicating the lack of commercialize-able technologies there. Professor Kildal has invented a fundamentally new regime of transmission line, referred to as gap waveguides. The basis is newly discovered local waves appearing in the gap between two conducting surfaces, controlled by a texture in one or both of the surfaces. The gap waveguide has been verified below 20 GHz, but it will be more advantageous in the THz gap. The texture will for THz applications be of submillimeter or micrometer scale, realizable by micromachining or etching. Also, there is no need for a dielectric substrate, and there is no need for conductive contact between the two surfaces. Therefore, such gap waveguides and circuits for the THz gap can be manufactured with low cost. The vision is that the topology of this new regime of gap waveguides will facilitate integration of semiconductor devices, and may lay the foundation for new architectures of transistors and other integrated circuits, being located inside the gap encapsulated by the conductive surfaces themselves. In order to reach this vision new and efficient numerical electromagnetic methods and modeling tools need to be developed, taking advantage of the particular gap waveguide geometry, and being able to connect to or replace the charge transport models for the transistors in the doped semiconductors themselves. The gap waveguide technology can get a tremendous impact on exploring higher frequencies in radio astronomy, communications, and imaging for medical as well as security applications.
In order to explore and exploit the frequency range from 30 GHz up to THz, new types of transmission lines and semiconductor architectures are needed. Conventional microwave technologies that are commonly used below 30 GHz become either too lossy or are too expensive to manufacture, and technologies used in the optical regime are not usable either. The intermediate frequency band is therefore often referred to as the THz gap, indicating the lack of commercialize-able technologies there. Professor Kildal has invented a fundamentally new regime of transmission line, referred to as gap waveguides. The basis is newly discovered local waves appearing in the gap between two conducting surfaces, controlled by a texture in one or both of the surfaces. The gap waveguide has been verified below 20 GHz, but it will be more advantageous in the THz gap. The texture will for THz applications be of submillimeter or micrometer scale, realizable by micromachining or etching. Also, there is no need for a dielectric substrate, and there is no need for conductive contact between the two surfaces. Therefore, such gap waveguides and circuits for the THz gap can be manufactured with low cost. The vision is that the topology of this new regime of gap waveguides will facilitate integration of semiconductor devices, and may lay the foundation for new architectures of transistors and other integrated circuits, being located inside the gap encapsulated by the conductive surfaces themselves. In order to reach this vision new and efficient numerical electromagnetic methods and modeling tools need to be developed, taking advantage of the particular gap waveguide geometry, and being able to connect to or replace the charge transport models for the transistors in the doped semiconductors themselves. The gap waveguide technology can get a tremendous impact on exploring higher frequencies in radio astronomy, communications, and imaging for medical as well as security applications.
Project acronym GENEWELL
Project Genetics and epigenetics of animal welfare
Researcher (PI) Per Ole Stokmann Jensen
Call Details Advanced Grant (AdG), LS9, ERC-2012-ADG_20120314
Summary Animal welfare is a topic of highest societal and scientific priority. Here, I propose to use genomic and epigenetic tools to provide a new perspective on the biology of animal welfare. This will reveal mechanisms involved in modulating stress responses. Groundbreaking aspects include new insights into how environmental conditions shape the orchestration of the genome by means of epigenetic mechanisms, and how this in turn modulates coping patterns of animals. The flexible epigenome comprises the interface between the environment and the genome. It is involved in both short- and long-term, including transgenerational, adaptations of animals. Hence, populations may adapt to environmental conditions over generations, using epigenetic mechanisms. The project will primarily be based on chickens, but will also be extended to a novel species, the dog. We will generate congenic chicken strains, where interesting alleles and epialleles will be fixed against a common background of either RJF or domestic genotypes. In these, we will apply a broad phenotyping strategy, to characterize the effects on different welfare relevant behaviors. Furthermore, we will characterize how environmental stress affects the epigenome of birds, and tissue samples from more than 500 birds from an intercross between RJF and White Leghorn layers will be used to perform an extensive meth-QTL-analysis. This will reveal environmental and genetic mechanisms affecting gene-specific methylation. The dog is another highly interesting species in the context of behavior genetics, because of its high inter-breed variation in behavior, and its compact and sequenced genome. We will set up a large-scale F2-intercross experiment and phenotype about 400 dogs in standardized behavioral tests. All individuals will be genotyped on about 1000 genetic markers, and this will be used for performing an extensive QTL-analysis in order to find new loci and alleles associated with personalities and coping patterns.
Animal welfare is a topic of highest societal and scientific priority. Here, I propose to use genomic and epigenetic tools to provide a new perspective on the biology of animal welfare. This will reveal mechanisms involved in modulating stress responses. Groundbreaking aspects include new insights into how environmental conditions shape the orchestration of the genome by means of epigenetic mechanisms, and how this in turn modulates coping patterns of animals. The flexible epigenome comprises the interface between the environment and the genome. It is involved in both short- and long-term, including transgenerational, adaptations of animals. Hence, populations may adapt to environmental conditions over generations, using epigenetic mechanisms. The project will primarily be based on chickens, but will also be extended to a novel species, the dog. We will generate congenic chicken strains, where interesting alleles and epialleles will be fixed against a common background of either RJF or domestic genotypes. In these, we will apply a broad phenotyping strategy, to characterize the effects on different welfare relevant behaviors. Furthermore, we will characterize how environmental stress affects the epigenome of birds, and tissue samples from more than 500 birds from an intercross between RJF and White Leghorn layers will be used to perform an extensive meth-QTL-analysis. This will reveal environmental and genetic mechanisms affecting gene-specific methylation. The dog is another highly interesting species in the context of behavior genetics, because of its high inter-breed variation in behavior, and its compact and sequenced genome. We will set up a large-scale F2-intercross experiment and phenotype about 400 dogs in standardized behavioral tests. All individuals will be genotyped on about 1000 genetic markers, and this will be used for performing an extensive QTL-analysis in order to find new loci and alleles associated with personalities and coping patterns.
Project acronym HEART4FLOW
Project Improved Diagnosis and Management of Heart Disease by 4D Blood Flow Assessment
Researcher (PI) Antonius Hendrikus Gerardus Ebbers
Summary The primary purpose of the cardiovascular system is to drive, control and maintain blood flow to all parts of the body. Despite the primacy of flow, cardiac diagnostics still rely almost exclusively on tools focused on morphological assessment. The objective of the HEART4FLOW project is to develop the next generation of methods for the non-invasive quantitative assessment of cardiac diseases and therapies by focusing on blood flow dynamics, with the goals of earlier and more accurate detection and improved management of cardiac diseases. Recently, a novel moment framework for flow quantification using magnetic resonance imaging (MRI) has been presented which allows for simultaneous measurement of time-resolved, three-dimensional (time + 3D = 4D) blood flow velocity and turbulence intensity. In the HEART4FLOW project, this framework is extended and exploited for assessment of intracardiac blood flow dynamics. A user-friendly quantitative assessment approach is obtained for intracardiac blood flow energetics and wall interaction, as well as stenotic and regurgitant blood flow. Furthermore, the accuracy, measurement time, and robustness of 4D flow MRI acquisition are optimized, allowing its use in large clinical trails. Studying intracardiac blood flow dynamics in patients and healthy subjects at rest and under stress will improve our understanding of the roles of flow dynamics in both health and disease, leading to improved cardiac diagnostics, novel assessments of pharmaceutical, interventional, and surgical therapies, and promoting exploration of new avenues for management of cardiac disorders.
The primary purpose of the cardiovascular system is to drive, control and maintain blood flow to all parts of the body. Despite the primacy of flow, cardiac diagnostics still rely almost exclusively on tools focused on morphological assessment. The objective of the HEART4FLOW project is to develop the next generation of methods for the non-invasive quantitative assessment of cardiac diseases and therapies by focusing on blood flow dynamics, with the goals of earlier and more accurate detection and improved management of cardiac diseases. Recently, a novel moment framework for flow quantification using magnetic resonance imaging (MRI) has been presented which allows for simultaneous measurement of time-resolved, three-dimensional (time + 3D = 4D) blood flow velocity and turbulence intensity. In the HEART4FLOW project, this framework is extended and exploited for assessment of intracardiac blood flow dynamics. A user-friendly quantitative assessment approach is obtained for intracardiac blood flow energetics and wall interaction, as well as stenotic and regurgitant blood flow. Furthermore, the accuracy, measurement time, and robustness of 4D flow MRI acquisition are optimized, allowing its use in large clinical trails. Studying intracardiac blood flow dynamics in patients and healthy subjects at rest and under stress will improve our understanding of the roles of flow dynamics in both health and disease, leading to improved cardiac diagnostics, novel assessments of pharmaceutical, interventional, and surgical therapies, and promoting exploration of new avenues for management of cardiac disorders.
Project acronym IN-BRAIN
Project IN VIVO REPROGRAMMING: A NOVEL ROUTE TO BRAIN REPAIR
Researcher (PI) Malin Parmar
Summary Recent progress on direct re-programming into functional neurons provides a new approach towards cell-based therapy for neurodegenerative disorders. The induced neurons (iNs) are a novel type of cell resulting from rapid and remarkable conversion of somatic cells into subtype-specific functional neurons. Importantly they are non-proliferating which make them interesting alternatives to induced pluripotent (iPS) cells as sources of patient specific neurons for exogenous cell replacement therapy and disease modeling. Another major advantage with direct conversion over iPS cells is that the reprogramming could be performed in vivo. While direct conversion has been successful in organs such as the pancreas, where exocrine cells can be directly converted into insulin producing cells by viral injections in vivo (Zhou et al., Nature, 2008), the method is yet to be explored in the brain. Once direct conversion of non-neuronal cells into subtype specific neurons directly in the brain is established, it provides a new strategy for cell based brain repair that do not depend on exogenous cells. The overall goal of this project is to provide proof-of-principle that induced neurogenesis is achievable in the adult brain through guided transcription factor reprogramming of non-neuronal cells, to determine which cells are best suited as cellular substrate for in vivo neural conversion, and to compare this approach with transplantation of converted fibroblasts. The ability to directly reprogram cell fate using defined combinations of transcription factors have already turned basic studies of stem cell differentiation and cell therapy into a new direction. Establishing this technique in vivo would be another paradigm-shifting finding that opens up for novel strategies for brain repair
Recent progress on direct re-programming into functional neurons provides a new approach towards cell-based therapy for neurodegenerative disorders. The induced neurons (iNs) are a novel type of cell resulting from rapid and remarkable conversion of somatic cells into subtype-specific functional neurons. Importantly they are non-proliferating which make them interesting alternatives to induced pluripotent (iPS) cells as sources of patient specific neurons for exogenous cell replacement therapy and disease modeling. Another major advantage with direct conversion over iPS cells is that the reprogramming could be performed in vivo. While direct conversion has been successful in organs such as the pancreas, where exocrine cells can be directly converted into insulin producing cells by viral injections in vivo (Zhou et al., Nature, 2008), the method is yet to be explored in the brain. Once direct conversion of non-neuronal cells into subtype specific neurons directly in the brain is established, it provides a new strategy for cell based brain repair that do not depend on exogenous cells. The overall goal of this project is to provide proof-of-principle that induced neurogenesis is achievable in the adult brain through guided transcription factor reprogramming of non-neuronal cells, to determine which cells are best suited as cellular substrate for in vivo neural conversion, and to compare this approach with transplantation of converted fibroblasts. The ability to directly reprogram cell fate using defined combinations of transcription factors have already turned basic studies of stem cell differentiation and cell therapy into a new direction. Establishing this technique in vivo would be another paradigm-shifting finding that opens up for novel strategies for brain repair
Project acronym K9GENES
Project Mapping canine genes and pathways to leverage personalized treatment options
Researcher (PI) Kerstin Lindblad-Toh
Summary The domestic dog encompasses hundreds of genetically isolated breeds, many of which show an increased risk for certain diseases. With the canine genome sequence, an understanding of the haplotype structure and availability of disease gene mapping tools, we are now in a unique position to map canine disease genes to inform human biology and medicine. So far we have mapped monogenic traits as well as >40 loci for >10 complex traits. We now propose to map genes for key diseases using many breeds to dissect a larger number of genes underlying the specific disease. We further plan to evaluate the functional consequences of mutations and pilot personalized treatment strategies based on genetic risk. The specific aims are: 1.Characterization of disease phenotypes, breed predisposition and sample acquisition. We are currently collecting samples from >20 diseases and will expand our phenotypic classification and sample collection to a larger number of breeds for some key diseases such as osteosarcoma, breast cancer, behavior and atopy or lymphocytic thyroiditis. 2.Identification and functional characterization of canine disease genes and pathways. We will perform genomewide association mapping followed by targeted resequencing for mutation detection. Pathway analysis will be performed to understand the disease mechanisms mostly contributing to the disease. For select mutations, we will use state of the art molecular biology to provide detailed functional characterization of selected genes revealed by our gene discovery platform. 3.Piloting canine personalized treatment strategies based on inherited risk factors. For a few diseases we will pilot personalized treatment strategies based on inherited risk factors, utilizing the genetic information gathered in aim 2. Available or novel drugs acting on the identified pathways will be tested in dogs with specific risk factors using a veterinary network for clinical trials. Knowledge gained should inform human personalized medicine.
The domestic dog encompasses hundreds of genetically isolated breeds, many of which show an increased risk for certain diseases. With the canine genome sequence, an understanding of the haplotype structure and availability of disease gene mapping tools, we are now in a unique position to map canine disease genes to inform human biology and medicine. So far we have mapped monogenic traits as well as >40 loci for >10 complex traits. We now propose to map genes for key diseases using many breeds to dissect a larger number of genes underlying the specific disease. We further plan to evaluate the functional consequences of mutations and pilot personalized treatment strategies based on genetic risk. The specific aims are: 1.Characterization of disease phenotypes, breed predisposition and sample acquisition. We are currently collecting samples from >20 diseases and will expand our phenotypic classification and sample collection to a larger number of breeds for some key diseases such as osteosarcoma, breast cancer, behavior and atopy or lymphocytic thyroiditis. 2.Identification and functional characterization of canine disease genes and pathways. We will perform genomewide association mapping followed by targeted resequencing for mutation detection. Pathway analysis will be performed to understand the disease mechanisms mostly contributing to the disease. For select mutations, we will use state of the art molecular biology to provide detailed functional characterization of selected genes revealed by our gene discovery platform. 3.Piloting canine personalized treatment strategies based on inherited risk factors. For a few diseases we will pilot personalized treatment strategies based on inherited risk factors, utilizing the genetic information gathered in aim 2. Available or novel drugs acting on the identified pathways will be tested in dogs with specific risk factors using a veterinary network for clinical trials. Knowledge gained should inform human personalized medicine.
Project acronym M&M'S+
Project 3D Printer for Silicon MEMS & NEMS
Researcher (PI) Frank NIKLAUS
Summary "Additive manufacturing technologies such as 3D printing of polymers and metals have a large impact in many sectors. In this project we propose to explore ways to develop and commercially exploit a new type of 3D printing tool for manufacturing of silicon nanostructures. These 3D printers will make it possible to design and implement silicon micro- and nano-electromechanical system (MEMS&NEMS) sensors and photonic components in low volumes at affordable costs. As a result, resource-intensive semiconductor clean-room infrastructure will no longer be required to design and implement MEMS, NEMS and photonics components. A 3D printer for silicon nanostructures is made possible by employing a novel additive layer-by-layer manufacturing process that has been developed within the ERC Starting Grant project M&M´s (No.277879) lead by the PI. This process is based on alternating steps of chemical vapour deposition (CVD) of silicon and local implantation of gallium ions by focused ion beam (FIB) writing. In a final step, the defined 3D structures are formed by etching the silicon in potassium hydroxide (KOH), where the ion implantation provides the etching selectivity. The feasibility of the technology has been demonstrated within the ERC-M&M´s project by forming 3D silicon structures with layer thicknesses of 40 nm and lateral dimensions as small as 30 nm. To implement a 3D printer that can manufacture 3D silicon nanostructures from computer-generated 3D graphics, the steps of focused ion beam (FIB) writing and silicon deposition have to be combined as a fully automated switched process in a single tool."
"Additive manufacturing technologies such as 3D printing of polymers and metals have a large impact in many sectors. In this project we propose to explore ways to develop and commercially exploit a new type of 3D printing tool for manufacturing of silicon nanostructures. These 3D printers will make it possible to design and implement silicon micro- and nano-electromechanical system (MEMS&NEMS) sensors and photonic components in low volumes at affordable costs. As a result, resource-intensive semiconductor clean-room infrastructure will no longer be required to design and implement MEMS, NEMS and photonics components. A 3D printer for silicon nanostructures is made possible by employing a novel additive layer-by-layer manufacturing process that has been developed within the ERC Starting Grant project M&M´s (No.277879) lead by the PI. This process is based on alternating steps of chemical vapour deposition (CVD) of silicon and local implantation of gallium ions by focused ion beam (FIB) writing. In a final step, the defined 3D structures are formed by etching the silicon in potassium hydroxide (KOH), where the ion implantation provides the etching selectivity. The feasibility of the technology has been demonstrated within the ERC-M&M´s project by forming 3D silicon structures with layer thicknesses of 40 nm and lateral dimensions as small as 30 nm. To implement a 3D printer that can manufacture 3D silicon nanostructures from computer-generated 3D graphics, the steps of focused ion beam (FIB) writing and silicon deposition have to be combined as a fully automated switched process in a single tool."
Project acronym MEMORYSTICK
Project Plasticity and formation of lasting memories in health and disease. Genetic modeling of key regulators in adult and aging mammals and in neurodegenerative disease
Researcher (PI) Lars Olson
Summary When an adult mammal acquires new skills and new knowledge, the degree to which transition will occur from temporary to permanent memories of such events is governed by factors such as emotional weight and importance of the experiences for survival. To execute the necessary structural synaptic reorganisations needed to permanently embed novel memories in the brain, a complex and precisely orchestrated molecular machinery is activated. We have found that rapid down-regulation of Nogo receptor 1 (NgR1) is one key element needed to allow permanent memories to form. Thus, our MemoFlex mice, with inducible overexpression of NgR1 in forebrain neurons, are severely impaired with respect to the ability to form lasting memories. When transgenic NgR1 is turned off in these mice, the ability to form lasting memories is restored. Several other genes are also involved in the process of consolidation of memories, including prompt activity-driven upregulation of BDNF. Very recently, we have discovered that Lotus, a newly identified negative regulator of NgR1, is also upregulated by activity, thus providing additional efficacy to the process of causing nerve endings to become temporarily insensitive to Nogo when plasticity is needed. Based on our experience with neurotrophic factors and the Nogo signaling system, and using additional transgenic mouse models, including the mtDNA Mutator mouse with premature, yet typical aging, NgR1 KO mice and mice modeling neurodegenerative diseases (such as APPSwePSEN mice and our MitoPark mice to model aspects of Alzheimer's and Parkinson's disease, respectively) we will examine the formation of lasting normal and pathological (addiction, posttraumatic stress disorder) memories in adult and aging individuals with and without additional neurodegenerative genotypes known to include cognitive impariment. This research will further the understanding of mechanisms behind memory dysfunction and help the design of memory-improving stratetegies.
When an adult mammal acquires new skills and new knowledge, the degree to which transition will occur from temporary to permanent memories of such events is governed by factors such as emotional weight and importance of the experiences for survival. To execute the necessary structural synaptic reorganisations needed to permanently embed novel memories in the brain, a complex and precisely orchestrated molecular machinery is activated. We have found that rapid down-regulation of Nogo receptor 1 (NgR1) is one key element needed to allow permanent memories to form. Thus, our MemoFlex mice, with inducible overexpression of NgR1 in forebrain neurons, are severely impaired with respect to the ability to form lasting memories. When transgenic NgR1 is turned off in these mice, the ability to form lasting memories is restored. Several other genes are also involved in the process of consolidation of memories, including prompt activity-driven upregulation of BDNF. Very recently, we have discovered that Lotus, a newly identified negative regulator of NgR1, is also upregulated by activity, thus providing additional efficacy to the process of causing nerve endings to become temporarily insensitive to Nogo when plasticity is needed. Based on our experience with neurotrophic factors and the Nogo signaling system, and using additional transgenic mouse models, including the mtDNA Mutator mouse with premature, yet typical aging, NgR1 KO mice and mice modeling neurodegenerative diseases (such as APPSwePSEN mice and our MitoPark mice to model aspects of Alzheimer's and Parkinson's disease, respectively) we will examine the formation of lasting normal and pathological (addiction, posttraumatic stress disorder) memories in adult and aging individuals with and without additional neurodegenerative genotypes known to include cognitive impariment. This research will further the understanding of mechanisms behind memory dysfunction and help the design of memory-improving stratetegies.
Project acronym MUSTANG
Project Magnonics Using Spin Torque, spin caloritronics, And Nanoplasmonic engineerinG
Researcher (PI) Johan Åkerman
Host Institution (HI) GOETEBORGS UNIVERSITET
Summary My overall aim is to develop a Magnonic technology platform where Spintronic, Spin-Caloritronic and Nano-plasmonic devices and structures combine to create ground-breaking functionality from novel interactions between charge, spin, heat and light. With traditional Magnonic studies typically geared towards the low GHz range, and nanoplasmonic phenomena primarily focusing on visible light, my proposed platform will also attempt to bridge the so-called "THz gap" and create ultra-broadband and rapidly tuneable spin wave (SW) based signal generators, manipulators, detectors, and even spectrometers, in the 10–200 GHz frequency range. I will reach this goal by transferring my documented nano-contact spin torque oscillator (NC-STO) expertise into the magnonics world of both metal and insulator based SW propagation, add recently discovered spin hall (SHE) and inverse spin hall effect (ISHE) SW manipulation/detection, and combine it with my recently acquired know-how in nanoplasmonics. My specific aims are: 1. SW generation and manipulation using metal and YIG based NC-STOs 2. SW-light/heat interaction using nanoplasmonic structures and Spin-Caloritronics 3. ISHE/SHE detection and control of propagating SWs in metals and YIG
My overall aim is to develop a Magnonic technology platform where Spintronic, Spin-Caloritronic and Nano-plasmonic devices and structures combine to create ground-breaking functionality from novel interactions between charge, spin, heat and light. With traditional Magnonic studies typically geared towards the low GHz range, and nanoplasmonic phenomena primarily focusing on visible light, my proposed platform will also attempt to bridge the so-called "THz gap" and create ultra-broadband and rapidly tuneable spin wave (SW) based signal generators, manipulators, detectors, and even spectrometers, in the 10–200 GHz frequency range. I will reach this goal by transferring my documented nano-contact spin torque oscillator (NC-STO) expertise into the magnonics world of both metal and insulator based SW propagation, add recently discovered spin hall (SHE) and inverse spin hall effect (ISHE) SW manipulation/detection, and combine it with my recently acquired know-how in nanoplasmonics. My specific aims are: 1. SW generation and manipulation using metal and YIG based NC-STOs 2. SW-light/heat interaction using nanoplasmonic structures and Spin-Caloritronics 3. ISHE/SHE detection and control of propagating SWs in metals and YIG
Project acronym NAQUOP
Project Nanodevices for Quantum Optics
Researcher (PI) Valery Zwiller
Summary We propose developing a nanodevice toolbox for single photon quantum optics. A scalable scheme to generate indistinguishable single photons, an interface to couple single photon polarization to a single electron spin and high efficiency single photon detectors represent the core of the scientific problems to be addressed in this project. We set the following research objectives: 1- Understand to what extent quantum dots can be made indistinguishable. 2- Interface coherently single photons to single electron spins via strain engineering in quantum dots. 3- Gain a better understanding of the limits to time resolution and detection efficiency of ultrafast superconducting single photon detectors. The proposed research effort will yield novel experiments: the realization of scalable indistinguishable quantum dot sources by frequency locking single quantum dots to atomic transitions, the demonstration of new selection rules in semiconductor nanostructures to couple photon polarization to the electron spin only, the development of ultrafast and high efficiency single photon and single plasmon detectors and their implementation in two photon interference and quantum plasmonics experiments. To carry out the work, multidisciplinary efforts where nanofabrication, quantum optics, semiconductor and superconductor physics will be merged to demonstrate the scalability of quantum dots for quantum information processing, providing crucial new knowledge in single photon optics at the nanoscale. The impact of the project will be important and far reaching as it will address fundamental questions related to the scalability of quantum indistinguishability of remote nanostructures.
We propose developing a nanodevice toolbox for single photon quantum optics. A scalable scheme to generate indistinguishable single photons, an interface to couple single photon polarization to a single electron spin and high efficiency single photon detectors represent the core of the scientific problems to be addressed in this project. We set the following research objectives: 1- Understand to what extent quantum dots can be made indistinguishable. 2- Interface coherently single photons to single electron spins via strain engineering in quantum dots. 3- Gain a better understanding of the limits to time resolution and detection efficiency of ultrafast superconducting single photon detectors. The proposed research effort will yield novel experiments: the realization of scalable indistinguishable quantum dot sources by frequency locking single quantum dots to atomic transitions, the demonstration of new selection rules in semiconductor nanostructures to couple photon polarization to the electron spin only, the development of ultrafast and high efficiency single photon and single plasmon detectors and their implementation in two photon interference and quantum plasmonics experiments. To carry out the work, multidisciplinary efforts where nanofabrication, quantum optics, semiconductor and superconductor physics will be merged to demonstrate the scalability of quantum dots for quantum information processing, providing crucial new knowledge in single photon optics at the nanoscale. The impact of the project will be important and far reaching as it will address fundamental questions related to the scalability of quantum indistinguishability of remote nanostructures.
Project acronym NEOTROPICS
Project The Past, Present and Future of Neotropical Biodiversity
Researcher (PI) Alexandre Marcos Antonelli
Summary The American tropics – the Neotropics – comprise more species than any other region on Earth, including thousands of species used as crops, medicines and crafts. Understanding the evolution of this biodiversity and predicting the effects of climate and habitat changes on species losses constitute a major scientific challenge. This project will: 1) Estimate the rates of historical migration, speciation and extinction among and within all major Neotropical biomes and regions, thereby identifying key areas for 'evolutionary' conservation (i.e., those necessary for biotic interchange and vegetation shifts, and those that may function as 'species pumps' to the rest of the continent). 2) Test competing hypotheses of speciation (soil specialisation, temperature increases, polyploidy, habitat shifts, range expansion) for the two main centres of Neotropical biodiversity: the tropical Andes and Amazonia. 3) Produce new estimates on species losses due to on-going climate and habitat changes based on our new findings in 1) and 2) above. To achieve these goals we will develop novel bioinformatics pipelines that will greatly improve our use of biological databases. We will analyse DNA sequences, georeferences and biotic traits for tens of thousands of plant and animal species. Our tools will enable continuously up-to-date inferences and allow the easy integration of new data by students and researchers interested in the evolution of particular species groups or biomes. This is a multi-disciplinary project that requires a wide range of skills in molecular phylogenetics, bioinformatics, field botany, ecology and palaeontology. It will greatly profit from the well-established scientific network I have built up in my career, the vast collections of Neotropical species deposited at European natural history collections, and the excellent laboratory and cultivation facilities available in Gothenburg, Sweden.
The American tropics – the Neotropics – comprise more species than any other region on Earth, including thousands of species used as crops, medicines and crafts. Understanding the evolution of this biodiversity and predicting the effects of climate and habitat changes on species losses constitute a major scientific challenge. This project will: 1) Estimate the rates of historical migration, speciation and extinction among and within all major Neotropical biomes and regions, thereby identifying key areas for 'evolutionary' conservation (i.e., those necessary for biotic interchange and vegetation shifts, and those that may function as 'species pumps' to the rest of the continent). 2) Test competing hypotheses of speciation (soil specialisation, temperature increases, polyploidy, habitat shifts, range expansion) for the two main centres of Neotropical biodiversity: the tropical Andes and Amazonia. 3) Produce new estimates on species losses due to on-going climate and habitat changes based on our new findings in 1) and 2) above. To achieve these goals we will develop novel bioinformatics pipelines that will greatly improve our use of biological databases. We will analyse DNA sequences, georeferences and biotic traits for tens of thousands of plant and animal species. Our tools will enable continuously up-to-date inferences and allow the easy integration of new data by students and researchers interested in the evolution of particular species groups or biomes. This is a multi-disciplinary project that requires a wide range of skills in molecular phylogenetics, bioinformatics, field botany, ecology and palaeontology. It will greatly profit from the well-established scientific network I have built up in my career, the vast collections of Neotropical species deposited at European natural history collections, and the excellent laboratory and cultivation facilities available in Gothenburg, Sweden.
Project acronym NOVEL_MYOKINE
Project Irisin - a novel myokine protective against metabolic disease
Researcher (PI) Pontus Almer Boström
Summary Cardiovascular disease and diabetes constitute the major disease burden in the western world with growing morbidity. Exercise is known to ameliorate many of the key processes in the pathogenesis of these diseases, but the underlying mechanism is not clear. Especially little is known about how exercise affects non-muscle tissues such as the heart, fat and liver. Knowledge of such pathways could lead to new therapeutic possibilities for diabetes and cardiovascular diseases. I have recently discovered a new hormone, named Irisin. Irisin is regulated by PGC1α, secreted from muscle to plasma after exercise and promotes the formation of brown fat via an unknown receptor. Furthermore, irisin is 100% conserved between mice and humans at the amino acid level (89% identity between zebfrafish and human). Nanomolar levels of this protein increase uncoupling protein 1 (UCP1) in cultures of primary white fat cells by 50 fold or more, resulting in very large increases in uncoupled respiration. Perhaps more remarkable, in vivo delivery of irisin stimulates a robust increase in UCP1, increased energy expenditure and reversal of type II diabetes in high fat fed mice. It is thus likely that irisin is responsible for at least some of the beneficial effects of exercise on the browning of adipose tissues and increases in energy expenditure. The therapeutic potential of irisin is obvious; it is a conserved endogenous polypeptide, induced with exercise and with powerful anti-diabetic properties. Irisin could, for example, be administered exogenously, or the secretion of irisin could be enhanced. These approaches, however, require additional studies, and my aim in this project is to advance the knowledge around irisin for future therapeutic testing. Given success of the ERC grant application, I will move from Harvard/Boston 2012 and start my lab at the department of Cell- and Molecular Biology, Karolinska Institute, Sweden. As seen in my list of publication, Im well prepared for this task
Cardiovascular disease and diabetes constitute the major disease burden in the western world with growing morbidity. Exercise is known to ameliorate many of the key processes in the pathogenesis of these diseases, but the underlying mechanism is not clear. Especially little is known about how exercise affects non-muscle tissues such as the heart, fat and liver. Knowledge of such pathways could lead to new therapeutic possibilities for diabetes and cardiovascular diseases. I have recently discovered a new hormone, named Irisin. Irisin is regulated by PGC1α, secreted from muscle to plasma after exercise and promotes the formation of brown fat via an unknown receptor. Furthermore, irisin is 100% conserved between mice and humans at the amino acid level (89% identity between zebfrafish and human). Nanomolar levels of this protein increase uncoupling protein 1 (UCP1) in cultures of primary white fat cells by 50 fold or more, resulting in very large increases in uncoupled respiration. Perhaps more remarkable, in vivo delivery of irisin stimulates a robust increase in UCP1, increased energy expenditure and reversal of type II diabetes in high fat fed mice. It is thus likely that irisin is responsible for at least some of the beneficial effects of exercise on the browning of adipose tissues and increases in energy expenditure. The therapeutic potential of irisin is obvious; it is a conserved endogenous polypeptide, induced with exercise and with powerful anti-diabetic properties. Irisin could, for example, be administered exogenously, or the secretion of irisin could be enhanced. These approaches, however, require additional studies, and my aim in this project is to advance the knowledge around irisin for future therapeutic testing. Given success of the ERC grant application, I will move from Harvard/Boston 2012 and start my lab at the department of Cell- and Molecular Biology, Karolinska Institute, Sweden. As seen in my list of publication, Im well prepared for this task
Project acronym OTEGS
Project Organic Thermoelectric Generators
Researcher (PI) Xavier Dominique Etienne Crispin
Summary At the moment, there is no viable technology to produce electricity from natural heat sources (T<200°C) and from 50% of the waste heat (electricity production, industries, buildings and transports) stored in large volume of warm fluids (T<200°C). To extract heat from large volumes of fluids, the thermoelectric generators would need to cover large areas in new designed heat exchangers. To develop into a viable technology platform, thermoelectric devices must be fabricated on large areas via low-cost processes. But no thermoelectric material exists for this purpose. Recently, the applicant has discovered that the low-cost conducting polymer poly(ethylene dioxythiophene) possesses a figure-of-merit ZT=0.25 at room temperature. Conducting polymers can be processed from solution, they are flexible and possess an intrinsic low thermal conductivity. This combination of unique properties motivate further investigations to reveal the true potential of organic materials for thermoelectric applications: this is the essence of this project. My goal is to organize an interdisciplinary team of researchers focused on the characterization, understanding, design and fabrication of p- and n-doped organic-based thermoelectric materials; and the demonstration of those materials in organic thermoelectric generators (OTEGs). Firstly, we will create the first generation of efficient organic thermoelectric materials with ZT> 0.8 at room temperature: (i) by optimizing not only the power factor but also the thermal conductivity; (ii) by demonstrating that a large power factor is obtained in inorganic-organic nanocomposites. Secondly, we will optimize thermoelectrochemical cells by considering various types of electrolytes. The research activities proposed are at the cutting edge in material sciences and involve chemical synthesis, interface studies, thermal physics, electrical, electrochemical and structural characterization, device physics. The project is held at Linköping University holding a world leading research in polymer electronics.
At the moment, there is no viable technology to produce electricity from natural heat sources (T<200°C) and from 50% of the waste heat (electricity production, industries, buildings and transports) stored in large volume of warm fluids (T<200°C). To extract heat from large volumes of fluids, the thermoelectric generators would need to cover large areas in new designed heat exchangers. To develop into a viable technology platform, thermoelectric devices must be fabricated on large areas via low-cost processes. But no thermoelectric material exists for this purpose. Recently, the applicant has discovered that the low-cost conducting polymer poly(ethylene dioxythiophene) possesses a figure-of-merit ZT=0.25 at room temperature. Conducting polymers can be processed from solution, they are flexible and possess an intrinsic low thermal conductivity. This combination of unique properties motivate further investigations to reveal the true potential of organic materials for thermoelectric applications: this is the essence of this project. My goal is to organize an interdisciplinary team of researchers focused on the characterization, understanding, design and fabrication of p- and n-doped organic-based thermoelectric materials; and the demonstration of those materials in organic thermoelectric generators (OTEGs). Firstly, we will create the first generation of efficient organic thermoelectric materials with ZT> 0.8 at room temperature: (i) by optimizing not only the power factor but also the thermal conductivity; (ii) by demonstrating that a large power factor is obtained in inorganic-organic nanocomposites. Secondly, we will optimize thermoelectrochemical cells by considering various types of electrolytes. The research activities proposed are at the cutting edge in material sciences and involve chemical synthesis, interface studies, thermal physics, electrical, electrochemical and structural characterization, device physics. The project is held at Linköping University holding a world leading research in polymer electronics.
Project acronym PATHOPROT
Project In vivo pathogen proteome profiling using selected reaction monitoring
Researcher (PI) Anders Johan Malmström
Summary Bacterial infections represent a major and global health problem, which is further aggravated by the rapid and ongoing increase in antibiotic resistance. The limited success in the development of targeted therapies for particular invasive strains can be attributed to our limited knowledge how pathogens modulate their proteome homeostasis in vivo, knowledge that has so far remained elusive due to technical limitations. Here I propose the use of proteome-wide selected reaction monitoring mass spectrometry (SRM-MS) for pathogen proteome profiling from samples obtained directly from in vivo using group A streptococci (GAS) as a model system. The proposal describes the use of SRM-MS to facilitate the construction of comprehensive and quantitative molecular anatomy knowledge models outlining spatial organization, pathway organization, absolute protein concentration estimations and interaction partners with host for complete microbial proteomes. Using the molecular anatomy as benchmark I intend compare how the proteome homeostasis is controlled in pathogens isolated directly from patients with different degree of disease severity to understand how disease severity, anatomical location and host dependencies effects the proteome homeostasis. The outlined proposal describes a generic strategy to provide comprehensive understanding of the pathogen adaption directly in vivo and represents a paradigm shift in the field of bacterial infectious disease. This proposal addresses central aspects within the medical microbiology field that has been long sought for but never studied due to technology limitations and will influence the development of the next generation targeted vaccine and therapeutic development programs.
Bacterial infections represent a major and global health problem, which is further aggravated by the rapid and ongoing increase in antibiotic resistance. The limited success in the development of targeted therapies for particular invasive strains can be attributed to our limited knowledge how pathogens modulate their proteome homeostasis in vivo, knowledge that has so far remained elusive due to technical limitations. Here I propose the use of proteome-wide selected reaction monitoring mass spectrometry (SRM-MS) for pathogen proteome profiling from samples obtained directly from in vivo using group A streptococci (GAS) as a model system. The proposal describes the use of SRM-MS to facilitate the construction of comprehensive and quantitative molecular anatomy knowledge models outlining spatial organization, pathway organization, absolute protein concentration estimations and interaction partners with host for complete microbial proteomes. Using the molecular anatomy as benchmark I intend compare how the proteome homeostasis is controlled in pathogens isolated directly from patients with different degree of disease severity to understand how disease severity, anatomical location and host dependencies effects the proteome homeostasis. The outlined proposal describes a generic strategy to provide comprehensive understanding of the pathogen adaption directly in vivo and represents a paradigm shift in the field of bacterial infectious disease. This proposal addresses central aspects within the medical microbiology field that has been long sought for but never studied due to technology limitations and will influence the development of the next generation targeted vaccine and therapeutic development programs.
Project acronym PERICYTESCAR
Project The role of pericytes in central nervous system scarring and fibrosis
Researcher (PI) Christian Göritz
Summary Damage to the central nervous system (CNS) often leads to persistent functional deficits, causing great individual suffering and enormous cost to society. The manifestation of these deficits is believed to be associated with the scar tissue that forms locally at lesions, causing permanent tissue alteration and blocking regeneration. Research on CNS scar tissue has primarily focused on astrocytes and it is often referred to as the glial scar. However, although it has received much less attention, there is also a connective tissue or stromal, non-glial, component of the scar. While studying spinal cord injury-induced scarring, I recently discovered a new subpopulation of perivascular cells, named type A pericytes, as a major source of connective scar tissue. Type A pericytes are embedded in the vascular wall but proliferate and leave the blood vessel upon injury, differentiating into fibroblast-like cells that deposit extracellular matrix to seal the lesion and form the persistent stromal scar core. The aim of the proposal is to determine whether type A pericytes are a general source of pathological connective tissue in the CNS, to understand the nature of type A pericytes, and to uncover the signaling mechanisms mediating their recruitment. By comparing several different injury and disease models the proposed research intends to uncover common mechanisms of scarring and fibrosis and to identify new targets for human treatment after CNS injury.
Damage to the central nervous system (CNS) often leads to persistent functional deficits, causing great individual suffering and enormous cost to society. The manifestation of these deficits is believed to be associated with the scar tissue that forms locally at lesions, causing permanent tissue alteration and blocking regeneration. Research on CNS scar tissue has primarily focused on astrocytes and it is often referred to as the glial scar. However, although it has received much less attention, there is also a connective tissue or stromal, non-glial, component of the scar. While studying spinal cord injury-induced scarring, I recently discovered a new subpopulation of perivascular cells, named type A pericytes, as a major source of connective scar tissue. Type A pericytes are embedded in the vascular wall but proliferate and leave the blood vessel upon injury, differentiating into fibroblast-like cells that deposit extracellular matrix to seal the lesion and form the persistent stromal scar core. The aim of the proposal is to determine whether type A pericytes are a general source of pathological connective tissue in the CNS, to understand the nature of type A pericytes, and to uncover the signaling mechanisms mediating their recruitment. By comparing several different injury and disease models the proposed research intends to uncover common mechanisms of scarring and fibrosis and to identify new targets for human treatment after CNS injury.
Project acronym PROSECUTOR
Project Programming Language-Based Security To Rescue
Researcher (PI) Andreas Sabelfeld
Summary It is alarming that the society's critical infrastructures are not fully prepared to meet the challenge of information security. Modern computing systems are increasingly extensible, inter-connected, and mobile. However, exactly these trends make systems more vulnerable to attacks. A particularly exposed infrastructure is the world-wide web infrastructure, where allowing the mere possibility of fetching a web page opens up opportunities for delivering potentially malicious executable content past current security mechanisms such as firewalls. A critical challenge is to secure the computing infrastructures without losing the benefits of the trends. It is our firm belief that attacks will continue succeeding unless a fundamental security solution, one that focuses on the security of the actual applications (code), is devised. To this end, we are convinced that application-level security can be best enforced, *by construction*, at the level of programming languages. ProSecuToR will develop the technology of *programming language-based security* in order to secure computing infrastructures. Language-based security is an innovative approach for enforcing security by construction. The project will deliver policies and enforcement mechanisms for protecting who can see and who can modify sensitive data. Security policies will be expressible by the programmer at the construction phase. We will devise a policy framework capable of expressing fine-grained application-level security policies. We will build practical enforcement mechanisms to enforce the policies for expressive languages. Enforcement mechanisms will be fully automatic, preventing dangerous programs from executing whenever there is a possibility of compromising desired security properties. The practicality will be demonstrated by building robust web applications. ProSecuToR is expected to lead to breakthroughs in *securing web mashups* and *end-to-end web application security*.
It is alarming that the society's critical infrastructures are not fully prepared to meet the challenge of information security. Modern computing systems are increasingly extensible, inter-connected, and mobile. However, exactly these trends make systems more vulnerable to attacks. A particularly exposed infrastructure is the world-wide web infrastructure, where allowing the mere possibility of fetching a web page opens up opportunities for delivering potentially malicious executable content past current security mechanisms such as firewalls. A critical challenge is to secure the computing infrastructures without losing the benefits of the trends. It is our firm belief that attacks will continue succeeding unless a fundamental security solution, one that focuses on the security of the actual applications (code), is devised. To this end, we are convinced that application-level security can be best enforced, *by construction*, at the level of programming languages. ProSecuToR will develop the technology of *programming language-based security* in order to secure computing infrastructures. Language-based security is an innovative approach for enforcing security by construction. The project will deliver policies and enforcement mechanisms for protecting who can see and who can modify sensitive data. Security policies will be expressible by the programmer at the construction phase. We will devise a policy framework capable of expressing fine-grained application-level security policies. We will build practical enforcement mechanisms to enforce the policies for expressive languages. Enforcement mechanisms will be fully automatic, preventing dangerous programs from executing whenever there is a possibility of compromising desired security properties. The practicality will be demonstrated by building robust web applications. ProSecuToR is expected to lead to breakthroughs in *securing web mashups* and *end-to-end web application security*.
Project acronym PUZZLE_CELL
Project Solving an evolutionary jigsaw puzzle: A next-generation genomics approach to trace the origins of the eukaryotic cell
Researcher (PI) Thijs Johannes Gerardus Ettema
Summary The origin of the eukaryotic cell represents an enigmatic yet dramatically incomplete evolutionary puzzle. The few pieces of this puzzle that we have managed to identify thus far indicate that the eukaryotic cell most probably emerged via a fusion of an archaeal and an alphaproteobacterial cell. Yet, beyond this, scientific debate is mainly engulfed by speculation, which, to a large extent, is fed by our poor understanding of the identity of these bacterial and archaeal fusion partners. In the current research proposal, I aim to identify contemporary relatives of the bacterial and archaeal lineages that once founded the eukaryotic cell using novel single-cell genomics and phylogenomics approaches. Till this end, environmental samples that are enriched for the target microbial lineages will be collected and analyzed at the single cell level. A novel microdroplet-based single-cell analysis platform will be implemented that allows for the analysis of millions of individual cells. After target cells have been identified, their genomic material will be amplified, and subjected to next-generation sequencing analysis. Subsequent state-of-the-art phylogenomic analyses will elucidate the taxonomic affiliation of these target cells in relation to other archaeal and bacterial lineages, as well as to eukaryotes. The proposed strategy will identify hundreds of novel prokaryotic lineages, some of which representing close contemporary relatives of the 'parental' lineages that founded the eukaryotic cell. The genomic exploration of these lineages will add the taxonomic resolution that is needed to start solving the evolutionary puzzle of the emergence of the eukaryotic cell.
The origin of the eukaryotic cell represents an enigmatic yet dramatically incomplete evolutionary puzzle. The few pieces of this puzzle that we have managed to identify thus far indicate that the eukaryotic cell most probably emerged via a fusion of an archaeal and an alphaproteobacterial cell. Yet, beyond this, scientific debate is mainly engulfed by speculation, which, to a large extent, is fed by our poor understanding of the identity of these bacterial and archaeal fusion partners. In the current research proposal, I aim to identify contemporary relatives of the bacterial and archaeal lineages that once founded the eukaryotic cell using novel single-cell genomics and phylogenomics approaches. Till this end, environmental samples that are enriched for the target microbial lineages will be collected and analyzed at the single cell level. A novel microdroplet-based single-cell analysis platform will be implemented that allows for the analysis of millions of individual cells. After target cells have been identified, their genomic material will be amplified, and subjected to next-generation sequencing analysis. Subsequent state-of-the-art phylogenomic analyses will elucidate the taxonomic affiliation of these target cells in relation to other archaeal and bacterial lineages, as well as to eukaryotes. The proposed strategy will identify hundreds of novel prokaryotic lineages, some of which representing close contemporary relatives of the 'parental' lineages that founded the eukaryotic cell. The genomic exploration of these lineages will add the taxonomic resolution that is needed to start solving the evolutionary puzzle of the emergence of the eukaryotic cell.
Project acronym RANDOM-KAHLER
Project Kähler-Einstein metrics, random point processes and variational principles
Researcher (PI) Robert Berman
Summary In broad terms the aim of this proposal is to introduce a new probabilistic approach to the study of Kähler-Einstein (K-E) metrics on complex manifolds. A precise procedure, based on a blend of Statistical Mechanics, Pluripotential theory and Kähler Geometry. will be used to show that • when a K-E metric exists on a complex manifold X it can be obtained from the "large N limit" of certain canonical random point processes on X with N particles. The canonical point processes are directly defined in terms of algebro-geometric data and the thrust of this approach is thus that it gives a new link between algebraic geometry on one and hand and complex differential (Kähler) geometry on the other. A major motivation for this project comes from the fundamental Yau-Tian-Donaldson conjecture in Kähler geometry, which aims at characterizing the obstructions to the existence of a K-E metric on a Fano manifold in terms of a suitable notion of algebro-geometric "stability", notably K-Stability. In this project a new "probabilistic/statistical mechanical" version of stability will be introduced referred to as Gibbs stability, which also has an interesting purely algebro-geometric definition in the spirit of the Minimal Model Program in current algebraic geometry and another specific aim of this project is to prove or at least make substantial progress towards proving, • There is a (unique) K-E metric on a Fano manifold X precisely when X is asymptotically Gibbs stable The canonical random point processes will be defined as certain "beta-deformations" of determinantal point processes and share certain properties with the ones appearing in Random Matrix Theory and in the study of quantum chaos and zeroes of random polynomials (and random holomorphic sections) But a crucial new feature here is that the processes are independent of any back-ground data, such as a potential or a metric.
In broad terms the aim of this proposal is to introduce a new probabilistic approach to the study of Kähler-Einstein (K-E) metrics on complex manifolds. A precise procedure, based on a blend of Statistical Mechanics, Pluripotential theory and Kähler Geometry. will be used to show that • when a K-E metric exists on a complex manifold X it can be obtained from the "large N limit" of certain canonical random point processes on X with N particles. The canonical point processes are directly defined in terms of algebro-geometric data and the thrust of this approach is thus that it gives a new link between algebraic geometry on one and hand and complex differential (Kähler) geometry on the other. A major motivation for this project comes from the fundamental Yau-Tian-Donaldson conjecture in Kähler geometry, which aims at characterizing the obstructions to the existence of a K-E metric on a Fano manifold in terms of a suitable notion of algebro-geometric "stability", notably K-Stability. In this project a new "probabilistic/statistical mechanical" version of stability will be introduced referred to as Gibbs stability, which also has an interesting purely algebro-geometric definition in the spirit of the Minimal Model Program in current algebraic geometry and another specific aim of this project is to prove or at least make substantial progress towards proving, • There is a (unique) K-E metric on a Fano manifold X precisely when X is asymptotically Gibbs stable The canonical random point processes will be defined as certain "beta-deformations" of determinantal point processes and share certain properties with the ones appearing in Random Matrix Theory and in the study of quantum chaos and zeroes of random polynomials (and random holomorphic sections) But a crucial new feature here is that the processes are independent of any back-ground data, such as a potential or a metric.
Project acronym SEQ-CYTOTOX
Project Next generation sequencing for detection of human primary immunodeficiency syndromes characterized by impaired cytotoxic lymphocyte function
Researcher (PI) Yenan Bryceson
Summary Human primary immunodeficiencies affecting cytotoxic lymphocyte function are associated with high morbidity and mortality. They often present as hyperinflammatory syndromes triggered by viral infections, hematological malignancies, or systemic autoimmunity. Although recent advances have provided molecular diagnoses for some of the most severe cases, only a handful of genes have been identified and disease in a majority of patients cannot be explained by current insights. My work has elucidated fundamental mechanisms of lymphocyte cytotoxicity. Furthermore, my group is leading international efforts in developing sensitive assays of human lymphocyte cytotoxicity. Some of our assays have been implemented for clinical diagnostics world-wide. Recently, we have also identified new, widespread mutations that explain many cases of fatal immunodeficiencies early in life. We now seek support for taking such studies to yet a higher level. The outlined interdisciplinary approach presented here aims at evaluating cytotoxic lymphocyte development and function in large numbers of patients, in addition to healthy individuals in a complementary approach, using state-of-the-art methodology. We will employ next-generation sequencing to identify novel genes associated with disease. The significance of putative mutations for lymphocyte cytotoxicity will be assessed using cutting-edge experimental platforms. Together, such genotype-immunotype studies promise to reveal novel genes associated with disease and further provide understanding of human genetic diversity. Thus, these studies can directly benefit patients through improved diagnosis, aiding targeted treatments, and offer new insights into human cytotoxic lymphocyte development and function with relevance to health. Insights will also pave the way for prospective, population-based molecular epidemiology studies required to more accurately assess the panorama of diseases associated with congenital defects in lymphocyte cytotoxicity.
Human primary immunodeficiencies affecting cytotoxic lymphocyte function are associated with high morbidity and mortality. They often present as hyperinflammatory syndromes triggered by viral infections, hematological malignancies, or systemic autoimmunity. Although recent advances have provided molecular diagnoses for some of the most severe cases, only a handful of genes have been identified and disease in a majority of patients cannot be explained by current insights. My work has elucidated fundamental mechanisms of lymphocyte cytotoxicity. Furthermore, my group is leading international efforts in developing sensitive assays of human lymphocyte cytotoxicity. Some of our assays have been implemented for clinical diagnostics world-wide. Recently, we have also identified new, widespread mutations that explain many cases of fatal immunodeficiencies early in life. We now seek support for taking such studies to yet a higher level. The outlined interdisciplinary approach presented here aims at evaluating cytotoxic lymphocyte development and function in large numbers of patients, in addition to healthy individuals in a complementary approach, using state-of-the-art methodology. We will employ next-generation sequencing to identify novel genes associated with disease. The significance of putative mutations for lymphocyte cytotoxicity will be assessed using cutting-edge experimental platforms. Together, such genotype-immunotype studies promise to reveal novel genes associated with disease and further provide understanding of human genetic diversity. Thus, these studies can directly benefit patients through improved diagnosis, aiding targeted treatments, and offer new insights into human cytotoxic lymphocyte development and function with relevance to health. Insights will also pave the way for prospective, population-based molecular epidemiology studies required to more accurately assess the panorama of diseases associated with congenital defects in lymphocyte cytotoxicity.
Project acronym TERAMIX
Project Study of Novel Low Noise Superconducting Mixers for Terahertz Radio Astronomy
Researcher (PI) Sergey Cherednichenko
Summary "Terahertz heterodyne receivers are valuable tools for molecular gas spectroscopy both for space (radioastronomy, planetary science) and terrestrial applications. They provide both high resolution spectral data, as well as broad bandwidth line survey data. Due to the progress in device physics, such receivers can now reach several THz. At such high radio frequencies, neither electronic nor photonic approaches for THz detectors work, but rather a combination of both is required. Superconducting devices have proven to provide sensitivity levels close to the quantum limit, hf/k. Superconducting Hot- Electron Bolometers (HEB) based on ultrathin NbN and NbTiN films are currently the only devices which are used as mixers for frequencies above 1.2THz (SIS mixer limit). However, their speed (i.e. the instantaneous bandwidth) is limited by the finite electron energy relaxation rate, of 40-100 ps. It corresponds to the bandwidth of maximum 4-5GHz. Such applications in radio astronomy as extragalactic spectroscopy, molecular line survey require this bandwidth to be doubled to say at least. In this project we will investigate response rate in ultra thin MgB2 superconducting films. Preliminary investigation measured the electron-phonon interaction time as short as 1ps. Our recent data, point out on the response rate being limited by the phonon dynamic in the thick films. We will develop technology for ultrathin MgB2 film deposition, and processing THz nanobolometers. The response rate will be investigated with regards to the film parameters. In particularly, the phonon diffusion in superconducting nanobolometers will be studied in order to enhance the instantaneous bandwidth of MgB2 mixers. We estimate that the bandwidth of the novel THz detectors will be at least doubled compared to the existing once, providing completely new functionalities for THz radio astronomical receivers."
"Terahertz heterodyne receivers are valuable tools for molecular gas spectroscopy both for space (radioastronomy, planetary science) and terrestrial applications. They provide both high resolution spectral data, as well as broad bandwidth line survey data. Due to the progress in device physics, such receivers can now reach several THz. At such high radio frequencies, neither electronic nor photonic approaches for THz detectors work, but rather a combination of both is required. Superconducting devices have proven to provide sensitivity levels close to the quantum limit, hf/k. Superconducting Hot- Electron Bolometers (HEB) based on ultrathin NbN and NbTiN films are currently the only devices which are used as mixers for frequencies above 1.2THz (SIS mixer limit). However, their speed (i.e. the instantaneous bandwidth) is limited by the finite electron energy relaxation rate, of 40-100 ps. It corresponds to the bandwidth of maximum 4-5GHz. Such applications in radio astronomy as extragalactic spectroscopy, molecular line survey require this bandwidth to be doubled to say at least. In this project we will investigate response rate in ultra thin MgB2 superconducting films. Preliminary investigation measured the electron-phonon interaction time as short as 1ps. Our recent data, point out on the response rate being limited by the phonon dynamic in the thick films. We will develop technology for ultrathin MgB2 film deposition, and processing THz nanobolometers. The response rate will be investigated with regards to the film parameters. In particularly, the phonon diffusion in superconducting nanobolometers will be studied in order to enhance the instantaneous bandwidth of MgB2 mixers. We estimate that the bandwidth of the novel THz detectors will be at least doubled compared to the existing once, providing completely new functionalities for THz radio astronomical receivers."
Project acronym TUMORGAN
Project Exploring the tumor as a communicating organ
Researcher (PI) Jan Kristian Pietras
Summary The failure to bring about major advances in cancer care over the past decades points to the need for a revolution in our view of cancer as a disease caused by a lack of growth control in malignant cells. We propose that a tumor should be considered a communicating organ made of multiple cell types that collectively evolve into a clinically manifested and deadly disease. With this proposition follows that targeting of communication within tumors to attenuate the support from the stroma is the only viable strategy to achieve long term therapeutic benefit. Our research addresses the need to study the cellular context of cancer with a higher resolution. The general aim of the proposed work is to identify subsets of different cell types within the tumor stroma that hold utility as therapeutic targets and biomarkers. The work will be performed through a set of experiments bridging basic biology, pre-clinical studies and molecular oncology. The specific aims are: 1) Identification of cellular subsets of the tumor vasculature 2) Investigation of the therapeutic utility of cellular subsets of the tumor vasculature 3) Exploration of the potential of cellular subsets of the tumor vasculature as biomarkers The aims of the study will be pursued through a series of methodological refinements. Firstly, identification of novel components of tumors will be achieved by the assembly of a mouse genetic tool box enabling isolation, lineage tracing and functional studies. Secondly, single cell transcriptome sequencing will be performed to identify cellular subsets using materials from both mouse and man. Thirdly, the utility as therapeutic targets of the new cellular subsets will be assessed using a live imaging approach. Fourthly, the clinical significance of the new cellular subsets will be investigated using exclusive patient materials. Taken together, the information provided by our studies will enable us to take cancer therapy into a new era of personalized medicine.
The failure to bring about major advances in cancer care over the past decades points to the need for a revolution in our view of cancer as a disease caused by a lack of growth control in malignant cells. We propose that a tumor should be considered a communicating organ made of multiple cell types that collectively evolve into a clinically manifested and deadly disease. With this proposition follows that targeting of communication within tumors to attenuate the support from the stroma is the only viable strategy to achieve long term therapeutic benefit. Our research addresses the need to study the cellular context of cancer with a higher resolution. The general aim of the proposed work is to identify subsets of different cell types within the tumor stroma that hold utility as therapeutic targets and biomarkers. The work will be performed through a set of experiments bridging basic biology, pre-clinical studies and molecular oncology. The specific aims are: 1) Identification of cellular subsets of the tumor vasculature 2) Investigation of the therapeutic utility of cellular subsets of the tumor vasculature 3) Exploration of the potential of cellular subsets of the tumor vasculature as biomarkers The aims of the study will be pursued through a series of methodological refinements. Firstly, identification of novel components of tumors will be achieved by the assembly of a mouse genetic tool box enabling isolation, lineage tracing and functional studies. Secondly, single cell transcriptome sequencing will be performed to identify cellular subsets using materials from both mouse and man. Thirdly, the utility as therapeutic targets of the new cellular subsets will be assessed using a live imaging approach. Fourthly, the clinical significance of the new cellular subsets will be investigated using exclusive patient materials. Taken together, the information provided by our studies will enable us to take cancer therapy into a new era of personalized medicine.