邢唷>  bdfhjlnprt   !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`acdefghijklmnopqrstuvwxyz{|}~Root Entry F 黒H WorkbookySummaryInformation(DocumentSummaryInformation88 \p Ba= ThisWorkbook=Km808X@"1唕媅SO1唕媅SO1唕媅SO1唕媅SO1唕媅SO1.rTimes New Roman1唕媅SO1唕媅SO1唕媅SO1h8唕媅SO1,8唕媅SO18唕媅SO18唕媅SO1唕媅SO1唕媅SO1<唕媅SO1>唕媅SO1?唕媅SO14唕媅SO14唕媅SO1 唕媅SO1 唕媅SO1唕媅SO1唕媅SO1 唕媅SO+""#,##0;""\-#,##05""#,##0;[Red]""\-#,##07""#,##0.00;""\-#,##0.00A""#,##0.00;[Red]""\-#,##0.00i*2_ ""* #,##0_ ;_ ""* \-#,##0_ ;_ ""* "-"_ ;_ @_ .))_ * #,##0_ ;_ * \-#,##0_ ;_ * "-"_ ;_ @_ y,:_ ""* #,##0.00_ ;_ ""* \-#,##0.00_ ;_ ""* "-"??_ ;_ @_ 6+1_ * #,##0.00_ ;_ * \-#,##0.00_ ;_ * "-"??_ ;_ @_ \$#,##0_);\(\$#,##0\)\$#,##0_);[Red]\(\$#,##0\) \$#,##0.00_);\(\$#,##0.00\)% \$#,##0.00_);[Red]\(\$#,##0.00\)                                                   P  P        a>  ,  *   攆f   `  +  )                x@ @   x@ @  8@ @   8@ @  x@ @    X X/ X x@ @  ||Js鹑}-} .00\)_ *}-} .00\)_ *}-} .00\)_ *}-} .00\)_ *}-} .00\)_ *}-} .00\)_ *}-} .00\)_ *}-} .00\)_ *}-} .00\)_ *}-}  .00\)_ *}-}  .00\)_ *}-}  .00\)_ *}-}  .00\)_ *}-}  .00\)_ *}-} .00\)_ *}-} .00\)_ *}(}> .00\)_ *}(}? .00\)_ *}(}@ .00\)_ *}(}A .00\)_ *}(}B .00\)_ *}(}C .00\)_ *}(}D .00\)_ *}(}E .00\)_ *}<}F .00\)_ *_ \-#}<}G .00\)_ *ef _ \-#}(}H .00\)_ *}(}I .00\)_ *}-}2 .00\)_ *}-}3 .00\)_ *}-}+ .00\)_ *}-}, .00\)_ *}-}" .00\)_ *}-}# .00\)_ *}A}$ .00\)_ *-#,#}A}% .00\)_ *?-#,#}A}& .00\)_ *23-#,#}-}' .00\)_ *}A}) a.00\)_ *骑-#,#}A}( .00\)_ *俏-#,#}A}: 渆.00\)_ *霚-#,#}}< ??v.00\)_ *虣-#,# ;_ -"?? _ }}; ???.00\)_ *蝌-#,#??? ;_ ???-"?? ???_ ???}}- 鷠.00\)_ *蝌-#,# ;_ -"?? _ }A}1 鷠.00\)_ *-#,#}}. .00\)_ *ゥ-#,#??? ;_ ???-"?? ???_ ???}-}0 .00\)_ *}}= .00\)_ *-#,#膊 ;_ 膊-"?? 膊_ 膊}-}/ .00\)_ *}U}* .00\)_ *-#,# ;_ }A}4 .00\)_ *-#,#}A} .00\)_ *ef-#,#}A} .00\)_ *蘈-#,#}A} .00\)_ *23-#,#}A}5 .00\)_ *-#,#}A} .00\)_ *ef-#,#}A} .00\)_ *蘈-#,#}A} .00\)_ *23-#,#}A}6 .00\)_ *-#,#}A} .00\)_ *ef-#,#}A} .00\)_ *蘈-#,#}A} .00\)_ *23-#,#}A}7 .00\)_ *-#,#}A} .00\)_ *ef-#,#}A} .00\)_ *蘈-#,#}A} .00\)_ *23-#,#}A}8 .00\)_ *-#,#}A} .00\)_ *ef-#,#}A} .00\)_ *蘈-#,#}A}  .00\)_ *23-#,#}A}9 .00\)_ * -#,#}A} .00\)_ *ef -#,#}A} .00\)_ *蘈 -#,#}A}! .00\)_ *23 -#,#!20% - :_寚eW[湗r 1O20% - :_寚eW[湗r 1 ef坼 %!20% - :_寚eW[湗r 2O"20% - :_寚eW[湗r 2 ef蜉 %!20% - :_寚eW[湗r 3O&20% - :_寚eW[湗r 3 ef犟 %!20% - :_寚eW[湗r 4O*20% - :_寚eW[湗r 4 ef遴 %!20% - :_寚eW[湗r 5O.20% - :_寚eW[湗r 5 ef垲 %!20% - :_寚eW[湗r 6O220% - :_寚eW[湗r 6  ef %!40% - :_寚eW[湗r 1O40% - :_寚eW[湗r 1 蘈柑 %!40% - :_寚eW[湗r 2O#40% - :_寚eW[湗r 2 蘈婀 %!40% - :_寚eW[湗r 3O'40% - :_寚eW[湗r 3 蘈卒 %!40% - :_寚eW[湗r 4O+40% - :_寚eW[湗r 4 蘈汤 %!40% - :_寚eW[湗r 5O/40% - :_寚eW[湗r 5 蘈遁 %!40% - :_寚eW[湗r 6O340% - :_寚eW[湗r 6  蘈 %!60% - :_寚eW[湗r 1O 60% - :_寚eW[湗r 1 23暢 %!60% - :_寚eW[湗r 2O$60% - :_寚eW[湗r 2 23贄 %!60% - :_寚eW[湗r 3O(60% - :_寚eW[湗r 3 23轮 %!60% - :_寚eW[湗r 4O,60% - :_寚eW[湗r 4 23病 %! 60% - :_寚eW[湗r 5O060% - :_寚eW[湗r 5 23撏 %!!60% - :_寚eW[湗r 6O460% - :_寚eW[湗r 6  23 %"~vR詋 #h槝+h槝 I}% $h槝 1=h槝 1 I}%O伣 %h槝 2=h槝 2 I}%?ɡ &h槝 3=h槝 3 I}%23暢 'h槝 4/h槝 4 I}%(頬5頬 俏 %+8^膲 %)}Y5}Y 骑 a% *Gl;`GGl;` %O伣O伣+'^, '^[0] -梴o梴 蝌 鷠% .纇錱USCQ1000 solved structures of antibodies deposited in structure databases to realistically model CDRs and design them to recognize proteins that have not been co-crystallized with antibodies. For example, we will design novel antibodies targeting insulin, for which clinically useful diagnostics are needed. By accessing much larger sequence/structure spaces than are available to natural immunesystem repertoires and experimental methods, computational antibody design could produce higherspecificity and higher-affinity binders, even to challenging targets; and (c) develop new strategies to program conformational change in CDRs, generating, e.g., the first allosteric antibodies. These will allow targeting, in principle, of any molecule, potentially revolutionizing how antibodies are generated for research and medicine, providing new insights on the design principles of protein functional sites. : 31/8/2018jMechanisms of transcription in HIV latency; novel strategies to activateThe persistence of a transcriptionally competent but latent HIV infected memory CD4+T cell reservoir, despite the effectiveness of Highly Active Antiretroviral therapy (HAART) against active virus, presents the main impediment to HIV eradication. A novel concept in HIV eradication is to activate latent virus to subsequently eliminate with HAART. Much effort has gone into identification of protein complexes that regulate HIV LTR activity. Strategies have mainly relied on candidate approaches. However, due to technical limitations, comprehensive unbiased identification of host proteins associated with and necessary for silencing of the latent HIV LTR has not been possible. Trxn-PURGE proposes a novel multidisciplinary approach combining current knowledge of HIV transcription and new insights into eradication strategies with state of the art high though-put approaches, mycology, virology, genetics and conventional biochemistry to identify novel players in maintenance and activation of HIV transcriptional latency. We will: 1. Use a novel unbiased strategy to identify the in vivo latent LTRbound protein complex directly from infected T cells. 2. Conduct a cell-based high-throughput Haploid genetic screen to identify novel factors essential for maintenance of HIV latency. 3. Having identified three putative activators from a limited library, we will perform a large-scale screen with unbiased library of fungal supernatants to identify molecules capable of activation of latent HIV. These parallel approaches will identify novel molecular targets and molecules in activation of HIV transcriptional latency, which we will functionally and mechanistically characterize alone and in synergy with known compounds implicated in latent LTR activation in both 4. T cell lines and 5. primary human CD4+T cells harboring latent HIV. By unravelling its molecular mechanisms, Trxn-PURGE will set the stage for the development of a clinical combinatorial therapy to activate latent HIV. : 31/1/2019New chemical biology for tailoring novel therapeuticsMost of our drugs derive from natural products, many more natural products possess biological activity but our inability to synthesise novel analogues hampers our ability to use them either as tools or medicines. Cyclic peptides are common structural motifs in natural products and medicines (vancomycin, gramicidin). They are widely recognised to constitute a promising and still underexploited class of molecule for novel therapeutics; specifically an important role for cyclic peptides in the inhibition of protein-protein interactions has been demonstrated. We will harness the power of the recently identified macrocyclases from the ribosomally-derived cyanobactin superfamily to prepare diverse modified cyclic peptides. These enzymes exhibit the remarkable ability to macrocyclise unactivated peptide substrates. Different members of this family of macrocyclases process peptides into macrocycles containing from six up to twenty residues. We have characterised and re -engineered one member of the family (PatG) which makes eight residue macrocycles. We will determine the structural and biochemical features of the macrocyclases that are known to lead to six or to twenty residue macrocycles. We will use these insights to put these enzymes to work in novel chemical reactions. We will combine macrocyclases with other enzymes from the cyanobactin biosynthetic pathways (whose structures and mechanism we have largely determined) and work on solid phase peptide substrates. By bringing together the power of solid phase methods (split and pool) and the novel chemistry enabled by the enzymes, we will generate highly diverse macrocyclic scaffolds containing amino acids, enzymatically modified amino acids, non-natural amino acids and non-amino acid building blocks. Successful completion of the project will revolutionise the design of cyclic peptideinspired libraries with diverse backbone scaffolds for applications in target identification, drug discovery and tool screening. : 28/2/2019Specificity of translational control during unfolded protein responseUnfolded protein response (UPR) is activated by multiple types of cellular stress, and can promote either cell survival or apoptosis. The balance between these opposing outcomes is delicately regulated, and when lost, contributes to diverse diseases. UPR enables cells to halt general translation, while inducing translation and transcription of specific mRNAs that escape repression. Even though the general machinery controlling translation is well understood, several fundamental open questions remain: 1) how are mRNAs selected for translation during UPR, 2) what role does mRNA structure and sequence play in this selection, 3) what role does UPR pathway play in the highly differentiated cells, such as neurons? My lab employs an integrative approach to understand how RNA-binding proteins (RBPs) control specific mRNAs. We recently developed hiCLIP, a method that globally quantifies interactions between RBPs and double-stranded RNA < in live cells. Our preliminary findings demonstrate that a double-stranded RBP binds to structured motifs in mRNAs to control stress-induced translation. I propose to determine how combinatorial recognition of RNA sequence and structure by RBPs controls mRNA localisation, stability and translation during UPR. In addition, we will assess the role of UPR pathway in neuronal differentiation. Taken together, this study aims to elucidate how cells select specific mRNAs for translation, and thereby survive during stress or respond to signals that control differentiation.Structural studies of mammalian Cys-loop receptorsIn the brain, Cys-loop receptors mediate fast neurotransmission. They function as allosteric signal transducers across the plasma membrane: upon binding of one or more neurotransmitter molecules to an extracellular site, the receptors undergo complex conformational transitions that result in transient opening of an intrinsic ion channel. The Cys-loop family comprises receptors activated by serotonin, acetylcholine, glycine and GABA. Mammalian receptors are also the targets of a legion of psycho -active and therapeutic compounds (including nicotine, benzodiazepines, anti-emetics, general anaesthetics). Our structural knowledge is currently limited to invertebrate homologues. Atomic structures mammalian receptors are therefore acutely missing in order to understand their physiological role in molecular terms, and to be able to develop new drugs targeting them. The project proposes to decipher the operation mechanism, the pharmacology and conformational transitions of mammalian Cys-loop receptors. Starting with a solid body of preliminary results, we will obtain new high-resolution structures, taking advantage of antibody-based crystallization chaperones. We will try and record for the first time a  molecular movie of the gating conformational transition in cristallo. On the way, we will also investigate the potential of antibody-based modulators of Cys-loop receptors for biomedical applications.The applicant has solved in the past the structures of a bacterial Cys-loop receptor and of the mouse serotonin receptor. The proposed research will take place at the CNRS in Grenoble, France, in a very favourable environment for structural biology. : 31/5/2020\Molecular analysis of the Hedgehog signal transduction complex in the primary ciliumThe unexpected connection between the primary cilium and cell-to-cell signalling is one of the most exciting discoveries in cell and developmental biology in the last decade. In particular, the Hedgehog (Hh) pathway relies on the primary cilium to fulfil its fundamental functions in orchestrating vertebrate development. This microtubule-based antenna, up to 5 m long, protrudes from the plasma membrane of almost every human cell and is the essential compartment for the entire Hh signalling cascade. All its molecular components, from the most upstream transmembrane Hh receptor down to the ultimate transcription factors, are dynamically localised and enriched in the primary cilium. The aim of this proposal, which combines structural biology and live cell imaging, is to understand the function and signalling consequences of the multivalent interactions between Hh signal transducer proteins as well as their spatial and temporal regulation in the primary cilium. The key questions my laboratory will address are: What are the rules for assembly of Hh signal transduction complexes? How dynamic are these complexes in size and organisation? How are these processes linked to the transport and accumulation in the primary cilium?I will combine state-of-the art structural biology techniques (with an emphasis on X-ray crystallography) to study the molecular architecture of binary and higher-order Hh signal transduction complexes and live cell fluorescence microscopy (for protein localisation and direct protein interactions). These two approaches will allow me to identify and define specific proteinprotein interfaces at the atomic level and test their functional consequences in the cell in real time. My goal is to consolidate a world-class morphogen signal transduction laboratory, deciphering fundamental biological insights. Importantly, my results and reagents can potentially feed< into the development of novel anti-cancer therapeutics and reagents promoting stem cell therapy. : 31/7/2020In-cell NMR monitoring of alpha-Synuclein aggregation in neuronal cellsIntracellular aggregation of the human amyloid protein alpha-synuclein is causally involved in Parkinson s disease, a debilitating neurodegenerative disorder. The goal of this project is to combine low-resolution, fluorescence-imaging methods with high-resolution in-cell NMR and EPR spectroscopy techniques to derive macroscopic and microscopic insights into alpha-synuclein aggregate structures directly in neuronal cells. To achieve this goal, we will employ different sets of cultured neurons and investigate intracellular alpha-synuclein aggregation under defined conditions of mitochondrial dysfunction and cellular oxidative stress, two of the most common denominators of the disease. Importantly, we will also establish a human stem cell model for studying alpha -synuclein aggregation with high-resolution in-cell NMR and EPR methods, by using induced pluripotent stem cell (iPSC) derived dopaminergic neurons from Parkinson s disease patients and control individuals. Results from this study will provide novel insights into the native mechanisms of intracellular aggregate formation and ultimately enable novel pharmacological approaches for therapeutic intervention. : 31/10/2020In vivo pathogen proteome profiling using selected reaction monitoringBacterial 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. : 30/4/2018Investigating Hereditary Cancer Predisposition  a combined genomics approachBackground: Hereditary cancer is an important cause of morbidity and mortality and over the last 20 years, the majority of highly penetrant risk alleles such as BRCA1, BRCA2 in breast cancer and APC, MLH1, MSH2 in colon cancer have been identified. However, there are many men and women who have a strong family of cancer for whom we cannot provide answers because no mutation is found in known genes. Objectives: i) To identify new candidate breast cancer susceptibility loci by an innovative combination of exome sequencing technology and genome -wide allele-specific expression analysis of BRCA1/2-negative women with strong family histories of BC. This approach will be complemented by exomic sequencing of carefully selected matched cohorts of women with unilateral and bilateral breast cancer on whom extensive demographic and clinical data is available. ii) To study selected gene candidates in more detail at the DNA, RNA and protein level. iii) To apply the knowledge gained in the genomic study of breast cancer to other cancer predisposition syndromes. Significance: At present, the new combined approach of EST and ASE has several advantages over the alternative option of whole genome sequencing in the identification of rare functional variants; not only will EST plus ASE be cheaper and faster than a whole genome sequencing approach, but it will also allow us to explore the potentially unappreciated roles of allelic silencing (through regulatory or epigenetic variants) in cancer susceptibility, which would not be captured using genomic sequencing in isolation. We will commence the project with breast < cancer families and then apply the same approach to other types of hereditary cancers. This proposal is focused on individuals who face a truly high risk for cancer but for whom predictive information is lacking and therefore this proposal is likely to have a direct translational benefit.tEvolutionary genomics of long, non-coding RNAsRecent genomics analyses have facilitated the discovery of a novel major class of stable transcripts, now called long non-coding RNAs (lncRNAs). A growing number of analyses have implicated lncRNAs in the regulation of gene expression, dosage compensation and imprinting, and there is increasing evidence suggesting the involvement of lncRNAs in various diseases such as cancer. Despite recent advances, however, the role of the large majority of lncRNAs remains unknown and there is current debate on what fraction of lncRNAs may just represent transcriptional noise. Moreover, despite a growing number of lncRNAs catalogues for diverse model species, we lack a proper understanding of how these molecules evolve across genomes. Evolutionary analyses of protein-coding genes have proved tremendously useful in elucidating functional relationships and in understanding how the processes in which they are involved are shaped during evolution. Similar insights may be expected from a proper evolutionary characterization of lncRNAs, although the lack of proper tools and basic knowledge of underlying evolutionary mechanisms are a sizable challenge. Here, I propose to combine state-of-the-art computational and sequencing techniques in order to elucidate what evolutionary mechanisms are shaping this enigmatic component of eukaryotic genomes.The first goal is to enable large-scale phylogenomic analyses of lncRNAs by developing, for these molecules, methodologies that are now standard in the evolutionary analysis of protein-coding genes. The second goal is to explore, at high levels of resolution, the evolutionary dynamics of lncRNAs across selected eukaryotic groups for which novel genome-wide data will be produced experimentally using recently developed sequencing techniques that enable obtaining genome-wide footprints of RNA secondary structure. Finally, this dataset will be used to test the impact on lncRNAs evolution of processes known to be important in protein-coding genes. : 31/12/2017Harvesting the power of a new model organism: stem cells, regeneration and ageing in Macrostomum lignanoThe  stem-cell theory of ageing posits that the functional decline in adult stem cells is one of the factors contributing to ageing. Importantly, the number of stem cells does not diminish with age in many tissues but rather there are intrinsic and extrinsic changes that affect their functionality. Is it possible to reverse these changes? Experiments in the emerging model Macrostomum lignano suggest that this is indeed the case. Remarkably, induced regeneration in this animal leads to extended lifespan: repeated amputation, followed by regeneration, results in animals that live far beyond the median lifespan of 205 days. Regeneration in M. lignano is facilitated by stem cells called neoblasts, and it appears that regeneration resets the  ageing program in these animals. Due to its high regeneration capacity, small size, transparency and clear morphology, ease of culture, short generation time and amenability to genetic manipulation, M. lignano has great potential as a model organism for stem cell research. I have recently started developing genomic and genetic tools and resources for this model, and at present my group has generated a draft genome assembly, produced de novo transcriptome assembly, discovered several neoblast marker genes and made the first stable transgenic lines in this animal. Here I propose to study molecular mechanisms underlying rejuvenation in M. lignano, and to further advance M. lignano as a model organism through development of missing genetic tools and resources. I will address how young, aged and regenerated worms differ in their gene and small RNA expression profiles, and what are the differences and variation levels between neoblasts of young, old and regenerated animals. The biological roles of the identified candidate genes and their effects on the lifespan and neoblast activity will be investigated. In parallel, methods for efficient transgenesis and gene manipulation will be developed, and the genome annotation improved.Comparative genomics /  wildlife transcriptomics uncovers the mechanisms of halted ageing in mammalsAgeing is the gradual and irreversible breakdown of living systems associated with the advancement of time, which leads to an increase in vulnerability and eventual mortality. Despite recent advances in ageing research, the intrinsic complexity of the ageing process has prevented a full understanding of this process, therefore, ageing remains a grand challenge in contemporary biology. In AGELESS, we will tackle this challenge by uncovering the molecular mechanisms of halted ageing in a unique model system,<  the bats. Bats are the longest-lived mammals relative to their body size, and defy the  rate-ofliving theories as they use twice as much the energy as other species of considerable size, but live far longer. This suggests that bats have some underlying mechanisms that may explain their exceptional longevity. In AGELESS, we will identify the molecular mechanisms that enable mammals to achieve extraordinary longevity, using state-of-the-art comparative genomic methodologies focused on bats. We will identify, using population transcriptomics and telomere/mtDNA genomics, the molecular changes that occur in an ageing wild population of bats to uncover how bats  age so slowly compared with other mammals. In silico whole genome analyses, field based ageing transcriptomic data, mtDNA and telomeric studies will be integrated and analysed using a networks approach, to ascertain how these systems interact to halt ageing. For the first time, we will be able to utilize the diversity seen within nature to identify key molecular targets and regions that regulate and control ageing in mammals. AGELESS will provide a deeper understanding of the causal mechanisms of ageing, potentially uncovering the crucial molecular pathways that can be modified to halt, alleviate and perhaps even reverse this process in man.Genome-wide identification of factors controlling the telomere damage response and telomeredriven genomic instability.Telomeres are specialized nucleoprotein complexes that protect chromosome ends against recognition as DNA breaks. In somatic cells telomeres shorten every cell division, eventually compromising telomere function. This leads to activation of a DNA damage response that induces irreversible growth arrest or cell death and serves to suppress tumorigenesis by preventing outgrowth of incipient cancer cells. Furthermore, by limiting replicative potential, telomere dysfunction contributes to aging. However, deprotected chromosome ends are also subject to DNA repair activities that lead to chromosome end-to-end fusions. Upon cell division these fusions give rise to genomic instability through breakage-fusion-bridge cycles generating complex, unbalanced chromosome rearrangements. Cells with such instable genomes are highly prone to develop into cancer. The mechanisms underlying the telomere damage response and telomere-driven genomic instability are poorly understood. To increase our understanding of the cellular consequences of telomere dysfunction we will perform genome-wide functional genetic screens to identify factors with important roles in the telomere damage response and telomere-driven genomic instability. We will mechanistically study these genes for their role in the cellular response to telomere dysfunction. In addition, we will address if thesefactors act uniquely at telomeres or also affect the response to DNA lesions. Due to their unbiased nature these screens represent a unique opportunity to obtain highly novel and potentially unsuspected insights in the events following telomere deprotection. This work will lead to significantly increased mechanistic understanding of how dysfunctional telomeres affect genome stability, cancer development and aging, but might also lead to new insights in responses to DNA damage in general. Furthermore our research findings will facilitate development of new therapeutic strategies for inhibiting cancer and aging. : 30/9/2017Cis-regulatory variation: Using natural genetic variation to dissect cis-regulatory control of embryonic development.Embryonic development is very robust: In the midst of segregating mutations and fluctuating environments, a fertilized egg has the remarkable capacity to give rise to a precisely patterned embryo. The stereotypic progression of development is driven by tightly regulated programs of gene expression. However, this deterministic view from genetics is at odds with an emerging view of transcription from genomics as a  noisy process, variable and changing both within and between individuals. How variable transcriptional programs can regulate robust embryonic development remains a long-standing question, which this proposal aims to address. By combining population genetics, genomics, and developmental genetics in Drosophila we will dissect the relationship between DNA sequence variation, transcription factor (TF) occupancy, and the regulatory control of developmental gene expression. The backdrop for this work is extensive information generated by my lab on the location and function of over 12,000 developmental cis-regulatory elements, including accurate, predictive models of their spatio-temporal activity. To understand the impact of variation on transcription and development, we will make use of a powerful experimental resource  192 sequenced Drosophila strains, collected from a highly genetically diverse wild population. The proposed research < has three Specific Aims: 1) Perform the first high-resolution study associating SNPs and structural variants (eQTLs) with gene expression variation during embryonic development, 2) Quantify in vivo the relationship between cis-regulatory variation, TF occupancy, and gene expression, 3) Incorporate these data into an integrated, predictive model of transcription. These Aims, together with our cis-regulatory data, will offer unique, mechanistic insights into how cis-regulatory variation impacts developmental gene regulation, and into the molecular bases of robustness in developmental regulatory networks.Protein S-mycothiolation and real-time redox imaging in Corynebacterium diphtheriae during ROS stress and infection conditionsGlutathione serves as the major thiol-redox buffer in the defense against Reactive Oxygen Species (ROS) in eukaryotes. Firmicutes bacteria utilize as thiol redox buffer bacillithiol (Cys-GlcN-Mal, BSH) and Actinomycetes produce the related redox buffer mycothiol (AcCys-GlcN-Ins, MSH). In eukaryotes, proteins are post-translational modified to S-glutathionylated proteins in response to oxidative stress. S-glutathionylation has emerged as major redox-regulatory mechanism and protects cysteine residues against overoxidation to sulfonic acids. Using thiol-redox proteomics and mass spectrometry (MS) we have recently discovered protein S-bacillithiolations as mixed BSH protein disulfides in response to oxidative stress in Firmicutes bacteria. Protein S-bacillithiolation controls the activity of the redoxsensing OhrR repressor and protects active site cysteine residues of metabolic enzymes, antioxidant function proteins and translation factors. However, it is unknown if ROS and infection conditions cause protein S-mycothiolations and affect the cellular MSH redox potential in pathogenic Mycobacteria and Corynebacteria. Here we aim to explore the comprehensive mycothiolome in the major respiratory pathogen Corynebacterium diphtheriae. We apply gel-based and novel MS-based thiol-redox proteomic approaches for the quantitative analysis of the S-mycothiolome in C. diphtheriae under oxidative stress conditions (e.g. NEM-Biotin-Switch-Assay). Novel genetically encoded redox biosensors (Mrx1-roGFP2 and roGFP2-Orp1) will be developed for real-time imaging of the MSH redox potential and ROS production during infections in C. diphtheriae. The role of S-mycothiolated proteins for redox regulation, fitness, stress resistance and virulence mechanisms will be investigated. Our studies provide leads to understand the physiological role of thiol-redox switches in the defense against the host immune system and in the regulation of virulence mechanisms in Gram-positive pathogens. : 31/3/2019Dissection of tumor heterogeneity in vivoIt is now widely accepted that tumors are composed of heterogeneous population of cells, which contributeto many aspects of treatment resistance observed in clinic. Despite the acknowledgment of the tumor cellheterogeneity, little evidence was shown about complexity and dynamics of this heterogeneity in vivo,mainly because of lacking flexible genetic tools which allow sophisticated analysis in primary tumors. Werecently developed a very efficient mouse somatic brain tumor model which have a full penetrance of highgrade glioma development. Combination of this model with several transgenic mouse lines allow us toisolate and track different population of cells in primary tumors, most importantly, we also confirmed thatthis can be done on single cell level. Here I propose to use this set of valuable genetic tools to dissect thecellular heterogeneity in mouse gliomas. First we will perform several single cell lineage tracing experimentto demonstrate the contribution of brain tumor stem cell, tumor progenitors as well as the relativelydifferentiated cells, which will provide a complete data sets of clonal dynamics of different tumor cell types.Second we will further perform this tracing experiment with the presence of conventional chemotherapy.Third we will perform single cell RNA sequencing experiment to capture the molecular signature, whichdetermines the cellular heterogeneity, discovered by single cell tracing. This result will be further validatedby analysis of this molecular signatures in human primary tumors. We will also use our established in vivotarget validation approach to manipulate the candidate molecular regulators to establish the functionalcorrelation between molecular signature and phenotypic heterogeneity. This project will greatly improve ourunderstanding of tumor heterogeneity, and possibly provide novel approaches and strategies of targetinghuman glioblastomas. Systematic Decoding of Deubiquitylase-Regulated Signaling NetworksCellular processes are largely governed by sophisticated protein posttranslational modification (PTM)-dependent signaling networks, and a systematic understanding of regulatory PTM-based networks is a key goal in modern biology. Ubiquitin is a small, evolutionarily conserved signaling protein that acts as a PTM after being covalently conjugated to other proteins. Reversible ubiquitylation forms the most versatile and largest eukaryote-exclusive signaling system, and regulates the stability and function of almost all proteins in cells. Deubiquitylases (DUBs) are ubiquitin-specific proteases that remove substrate-conjugated ubiquitin, and thereby regulate virtually all ubiquitylation-dependent signaling. Because of their central role in ubiquitin signaling, DUBs have essential functions in mammalian physiology and development, and the dysregulated expression and mutation of DUBs is frequently associated with human diseases. Despite their vital functions, very little is known about the proteins and ubiquitylation sites that are regulated by DUBs and this knowledge gap is hampering our understanding of the molecular mechanisms by which DUBs control diverse biological processes. Recently, we developed a mass spectrometry-based proteomics approach that allowed unbiased and site-specific quantification of ubiquitylation on a systems-wide scale. Here we propose to comprehensively investigate DUB-regulated ubiquitin signaling in human cells. We will integrate interdisciplinary approaches to develop next-generation cell models and innovative proteomic technologies to systematically decode DUB function in human cells. This will enable a novel and detailed understanding of DUB-regulated signaling networks, and open up new avenues for further research into the mechanisms and biological functions of ubiquitylation and of ubiquitin-like modifiers. : 30/9/2020Laying the Biological, Computational and Architectural Foundations for Human Cell Lineage DiscoveryWithin a decade, advances in single-cell genomics would allow humanity to embark on a coordinated international effort to discover the human cell lineage tree. The goal of LineageDiscovery is to lay the biological, computational and architectural foundations for this envisioned project and demonstrate its feasibility and value.An organismal cell lineage tree is a rooted, labelled binary tree where nodes represent organism cells, edges represent progeny relations and labels capture < cell state. The tree of an adult human has about 100 trillion nodes. Many fundamental open questions in biology and medicine are about the structure, dynamics and variance of the human cell lineage tree in development, health, ageing and disease. E.g., which cancer cells give rise to metastases? Do beta cells renew? Which progeny do brain stem cells produce in development, maintenance and ageing? LineageDiscovery is based on a decade of research on this challenge by Shapiro s lab and others. It will develop an efficient biological-computational cell lineage discovery workflow that starts with sampled cells and ends with knowledge of their cell lineage tree; and a scalable architecture for the collaborative development and the distributed deployment of this workflow. The workflow will be based on emerging single-cell technologies and will include novel algorithms to analyse single-cell data, to reconstruct cell lineage trees, and to infer ancestral cell type and state dynamics. A programmable meta-system will be developed and used for workflow optimization and evaluation. The workflow and architecture will be deployed and tested in a broad range of proof-of-concept human cell lineage discovery experiments with self-funded collaborators. Successful execution of this research plan coupled with expected advances in single-cell genomics would establish both the feasibility and the value of the envisioned large-scale human cell lineage discovery project, ideally leading to its launch. : 31/8/2020Sorting processes that ensure short and long-range action of Wnts in developing epitheliaWnts are signaling proteins that act both at short and long range in developing tissues. Several proteins, such as Wntless, are specifically devoted to Wnt secretion, indicating that Wnts may follow a distinct secretory route. Moreover, Wnts carry two lipid modifications, which are likely to interfere with diffusion in the extracellular space. Much of our work will focus on the trafficking of Wingless (the main Drosophila Wnt), which forms a concentration gradient in wing imaginal discs. To chart the route taken by Wingless from the ER to responding cells, we will devise techniques (e.g. BirA-dependent in vivo biotinylation) to pulse label endogenously expressed Wingless in the secretory pathway and at the cell surface. Wingless routing will also be investigated in conditions that alter Evi/Wntless trafficking. We will capitalize on our observation that Wingless and Wntless are present on exosomes in conditioned medium. These exosomes will be purified and characterized by mass spectrometry and the resulting information will be used to devise rigorous functional assays. Similar approaches will be used to identify and characterize proteins that associate with soluble Wingless, which is also present in conditioned medium. Our proposed approaches will also enable us to assess, for the first time, the function of exosomes in an intact animal. Once secreted, Wingless and associated proteins spread in the extracellular space while remaining associated with the epithelial surface. We will use single molecule imaging in a reconstituted system along with mathematical modeling to test the hypothesis that the glypican-Wnt interaction is sufficiently strong to ensure surface retention while allowing diffusion in two dimensions. Finally we will use biochemical approaches and molecular genetics in Drosophila and mice to investigate the mode of action of Notum, a glypican-modifying enzyme that could be relevant to the progression of Wnt signaling dependent cancers. : 30/6/2017Chromosome self-clearing completes sister chromatid separationIn this research program, we propose the new concept that sister chromatid separation in mitosis is completed as a result of the dynamic intrinsic structural changes of chromosomes, i.e. through cycles of regional chromosome stretching and recoiling, which we call the self-clearing mechanism of chromosomes. By developing several novel methods, we will establish this new concept and demonstrate that the self-clearing of chromosomes is an essential mechanism allowing complete removal of sister chromatid cohesion, and that it is a fundamentally conserved function from yeast to vertebrates. To maintain genetic integrity, eukaryotic cells must duplicate their chromosomes and subsequently segregate them to opposite poles of the cell, prior to cell division. Cohesion is established between sister chromatids during S phase and marks sister pairs to ensure proper chromosome segregation in the next mitosis. However, the cohesion must be eventually removed to allow sister chromatids to separate and segregate to opposite poles. Although recent studies have revealed how the removal of cohesion is initiated, it is still elusive how this removal is completed. Our project will address mechanisms promoting this process and will open up a new direction of research, regarding dynamic chromosome organization, in particular its compaction and condensation. At present, the structural basis for chromosome compaction and condensation is poorly understood. Our project will shed new light on this inscrutable scientific problem by revealing the process of chromosome selfclearing. The outcome of our research will give important clues to fundamental mechanisms for chromosome segregation and will contribute to our understanding of human diseases, such as cancer and congenital disorders, which are characterized by chromosome instability and aneuploidy.{The role of symplastic communication during root developmentThe symplastic route composed of plasmodesmata (PD) channels and the transporting phloem tissue (rich in PD) is the major pathway for carbon allocation in plants. How the symplastic transport route is formed during plant ontogeny and what is its significance in conducting and distributing morhogenetic signals to the growing organs is poorly understood at the moment and is addressed here. My laboratory has recently made a breakthrough that facilitates the analysis of symplastic communication. In a genetic screen we identified gain-of-function mutations in a locus that codes for a CALLOSE SYNTHASE isoform CALS3. The cals3-d mutations result in restricted< symplastic trafficking through the PD. Using the cals3-d mutations in a vector system that allows cell type specific and inducible control of expression of the transgene, icals3m, we have been able to construct a molecular tool, with which we can regulate the passage of the various signaling molecules between the neighboring cells. This tool has already opened several new lines of research on symplastic communication concerning understanding of the regulation of PD channels, phloem development and symplastically moving signals. By a combination of experimental approaches at molecular, genetic, imaging and theoretically levels we will investigate here: (1) How is symplastic trafficking regulated? (2) What are the (symplastic) signals specifying phloem development? (3) How do the signals emanating from the phloem control root development? (4) Can we predict new regulatory factors controlling symplastic trafficking in space and time, based on the experimental data (on the distribution of symplastic channels, symplastically controlled genes and symplastically mobile molecules)? : 31/5/2018Myosins and the dynamics of intracellular membranesMyosins are fascinating proteins with unique biochemical and physical properties. The multiple roles that they play in the dynamics of intracellular membranes are only beginning to emerge. Recent findings from the research team have highlighted unexpected roles in membrane deformation and in membrane fission played by two myosins (myosin 1b and myosin II) functioning at the interface between the Golgi, TGN (Trans-Golgi Network) and endosomes. Building on these results, we propose to establish a comprehensive model describing how several myosins work in concert with F-actin and with microtubule-based motors for sustaining transport events and membrane dynamics in a region of the cell at the crossroads of complex trafficking pathways. Towards this general objective, our main goals are: Goal 1: to understand the role of myosin 1b in membrane deformation Goal 2: to understand the role of nonmuscle myosin II in membrane fission Goal 3: to characterize the actin structures required for myosin functions Goal 4: to identify and to characterize other myosins functioning at the Golgi/TGN/endosome interface and to investigate their functional coordination Goal 5: to understand how myosins are functionally coordinated with microtubule-based motors. The function of myosins will be studied both at the cellular and physical level using two main original methodological approaches available to the research team: minimal in vitro assays (giant liposomes and membrane nanotubes) and normalized cell systems (micropatterns). This proposal represents a new development in the activity of the research team composed of cell biologists, experimental and theoretical physicists. Success of this proposal will rely on the strong experience of cross-disciplinary approaches that allowed the research team in the past to elucidate several physical mechanisms underlying transport processes and membrane dynamics.hSafeguarding Cell Identities: Mechanisms Counteracting Cell Fate ReprogrammingRegenerating tissues by reprogramming cells has the potential to become a therapeutic approach for replacing lost tissues in patients suffering from injury or degenerative diseases such as Alzheimer s or Muscular Dystrophy. Strategies to generate required tissues using embryonic stem cells or induced pluripotent stem cells (iPSCs) are associated with either ethical or medical safety issues. An alternative strategy is to directly reprogram cells to the required tissue type by forced expression of cell fateinducing transcription factors (TFs). Direct reprogramming (DR) has the potential to circumvent unsafe proliferative pluripotent cell stages and it allows in vivo procedures. However to date, DR is successful in only a few cell types and it is not well understood why most cells are refractory to DR. Recently, we provided evidence that inhibitory mechanisms play an important role in restricting cell fate conversion. We identified factors inhibiting direct conversion of germ cells into specific neurons or muscle cells. Additionally, preliminary studies in our group revealed other factors that inhibit ectopic cell fate induction in somatic cells. The objective of this proposal is to further understand mechanisms that restrict DR. We aim to identify and characterize factors involved in safeguarding differentiated cells and thereby counteract induction of ectopic fates in different cells. We use C. elegans as an in vivo model and apply large-scale forward and reverse genetic screenings with high-throughput. Next generation sequencing, tissue-specific biochemistry (ChIP-seq, SILAC) and 4D imaging will be used to elucidate the molecular function of identified DR-regulating factors. Finally, we will test the ability to convert cells in aged animals and assess the effects of ageing on the ability to induce ectopic cell fates. Our research has the potential to facilitate the generation of specific tissues from different cellular contexts for future biomedical approaches. : 29/2/2020JUnraveling the regulatory network of developmental programmed cell death in plantsProgrammed cell death (PCD) is a fundamental biological process that actively terminates a cell s vital functions by a well-ordered sequence of events. In both animals and plants, various types of PCD are crucial for development, health, and the responses to vario< us stresses. Despite their importance, only little is known about PCD processes and their molecular control in plants. Still, an intricate regulatory network must exist that renders specific plant cell types competent to initiate and execute PCD at precisely determined developmental stages. I recently established a powerful developmental PCD model system in Arabidopsis thaliana, based on a PCD process occurring during root cap development. This root cap model has the potential to revolutionize existing concepts of plant PCD, as it combines a precisely predictable PCD process in easily accessible cells on the root periphery with the abundance of resources available for Arabidopsis research. Exploiting the root cap system will enable me to tackle unresolved fundamental questions about the regulation of developmental PCD in plants: How do cells acquire PCD competency during differentiation? Which signals trigger PCD execution at just the right moment? What are the actual mechanisms that disrupt the vital functions of a plant cell? I will obtain answers to these questions through a comprehensive strategy combining complementary approaches, taking advantage of cell-type specific transcriptomics, forward and reverse genetics, advanced live-cell imaging, biochemistry, and computational modeling. Our unpublished data point to the existence of a common core mechanism controlling PCD not only in the root cap, but also in other vital organs including the vasculature, anthers, or developing seeds. Thus, this project will not only be significant to advance our knowledge on PCD as a general developmental mechanism in plants, but also to generate new leads to tap the so far underexploited potential of PCD in agriculture. : 31/3/2020tMolecular and cellular determinants of cell monolayer mechanicsEpithelial monolayers are amongst the simplest tissues in the body, yet they play fundamental roles in adult organisms where they separate the internal environment from the external environment and in development when the intrinsic forces generated by cells within the monolayer drive tissue morphogenesis. The mechanics of these simple tissues is dictated by the cytoskeletal and adhesive proteins that interface the constituent cells into a tissue-scale mechanical syncitium. Mutations in these proteins lead to diseases with fragilised epithelia. However, a quantitative understanding of how subcellular structures govern monolayer mechanics, how cells sense their mechanical environment and what mechanical forces participate in tissue morphogenesis is lacking.To overcome these challenges, my lab devised a new technique to study the mechanics of load-bearing monolayers under wellcontrolled mechanical conditions while allowing imaging at subcellular, cellular and tissue resolutions. Using this instrument, my proposal aims to understand the molecu      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcefghijklmnopqrstuvwxyz{|}~lar determinants of monolayer mechanics as well as the cellular behaviours that drive tissue morphogenesis. I will focus on four objectives: 1) discover the molecular determinants of monolayer mechanics, 2) characterise monolayer mechanics, 3) dissect how tension is sensed by monolayers, and 4) investigate the biophysics of individual cell behaviours participating in tissue morphogenesis.Together these studies will enable us to understand how monolayer mechanics is affected by changes in single cell behaviour, subcellular organisation, and molecular turnover. This multi-scale characterisation of monolayer mechanics will set the stage for new theoretical descriptions of living tissues involving both molecular-scale phenomena (cytoskeletal turnover, contractility, and protein unfolding) operating on short time-scales and rearrangements due to cell-scale phenomena (cell intercalation, cell division) acting on longer times.Comparative analysis of planarian regeneration - why some worms regenerate while others don tThe ability to regenerate lost body parts is widespread amongst animals, yet humans, for example, can only regenerate specific organs. Why some animals regenerate while others hardly do remains a fascinating conundrum, especially so in face of  survival of the fittest . Even amongst planarian flatworms, famous for their ability to regenerate from random tissue fragments, species exist that have completely lost the ability to regenerate. This proposal will exploit the unique diversity of planarian regenerative abilities amongst to ask why some worms regenerate while others do not. We and others have established that planarian Wnt signalling acts as critical node in the evolution of regeneration defects. Using this finding as strategic focus for comparisons between regenerating and nonregenerating species, we will investigate i) the cell biological mechanisms that shape Wnt pathway activity; ii) the genomic mechanisms that differentially deploy critical pathway regulators; and iii) evolutionary mechanisms in form of life history trait trade-offs as possible driving force behind the drift of regenerative abilities. Key to the project is a diverse collection of regenerating and regenerationdeficient species that my lab has established. Focused comparisons between our two primary model species D. lacteum and S. mediterranea, employing pan-planarian antibodies and functional genomics, will allow us to understand the detailed causes of altered pathway activity. Comparisons amongst the entire collection of 50 species will provide the necessary breadth for identifying and studying the evolutionary principles that  naturally select regeneration-deficient planarians. The comparative approach of RegEvolve will thus uniquely bridge the proximate (molecular)- with the ultimate (evolutionary) causes of regeneration defects and such interdisciplinary endeavour between molecular a< nd evolutionary regeneration research will lead to new and profound insights into both fields.Understanding Cytokinetic Actomyosin Ring Assembly Through Genetic Code Expansion, Click Chemistry, DNA origami, and in vitro ReconstitutionThe mechanism of cell division is conserved in many eukaryotes, from yeast to man. A contractile ring of filamentous actin and myosin II motors generates the force to bisect a mother cell into two daughters. The actomyosin ring is among the most complex cellular machines, comprising over 150 proteins. Understanding how these proteins organize themselves into a functional ring with appropriate contractile properties remains one of the great challenges in cell biology. Efforts to generate a comprehensive understanding of the mechanism of actomyosin ring assembly have been hampered by the lack of structural information on the arrangement of actin, myosin II, and actin modulators in the ring in its native state. Fundamental questions such as how actin filaments are assembled and organized into a ring remain actively debated. This project will investigate key issues pertaining to cytokinesis in the fission yeast Schizosaccharomyces pombe, which divides employing an actomyosin based contractile ring, using the methods of genetics, biochemistry, cellular imaging, DNA origami, genetic code expansion, and click chemistry. Specifically, we will (1) attempt to visualize actin filament assembly in live cells expressing fluorescent actin generated through synthetic biological approaches, including genetic code expansion and click chemistry (2) decipher actin filament polarity in the actomyosin ring using total internal reflection fluorescence microscopy of labelled dimeric and multimeric myosins V and VI generated through DNA origami approaches (3) address when, where, and how actin filaments for cytokinesis are assembled and organized into a ring and (4) reconstitute actin filament and functional actomyosin ring assembly in permeabilized spheroplasts and in supported bilayers. Success in the project will provide major insight into the mechanism of actomyosin ring assembly and illuminate principles behind cytoskeletal self-organization.gExploring the tumor as a communicating organThe 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. : 28/2/2018The Role of Ectopic Adipocyte Progenitors in Age-related Stem Cell Dysfunction, Systemic Inflammation, and Metabolic DiseaseAgeing is accompanied by ectopic white adipose tissue depositions in skeletal muscle and other anatomical locations, such as brown adipose tissue and the bone marrow. Ectopic fat accrual contributes to organ dysfunction, systemic insulin resistance, and other perturbations that have been implicated in metabolic diseases. This research proposal aims to identify the regulatory cues that control the development of ectopic progenitor cells that give rise to this type of fat. It is hypothesized that an age-related dysfunction of the stem cell niche leads to an imbalance between (1) tissue-specific stem cells and (2) fibroblast-like, primarily adipogenic progenitors that reside within many tissues. Novel methodologies that assess stem/progenitor cell characteristics on the single cell level will be combined with animal models of lineage tracing to determine the developmental origin of these adipogenic progenitors and processes that regulate their function. Notch signalling is a key signalling pathway that relies on direct physical interaction to control stem cell fate. It is proposed that impaired Notch activity contributes to the phenotypical shift of precursor cell distribution in aged tissues. Lastly, the role of the stem cell niche in ectopic adipocyte progenitor formation will be analyzed. External signals originating from the surrounding niche cells regulate the developmental fate of stem cells. Secreted factors and their role in the formation of ectopic adipocyte precursors during senescence will be identified using a combination of biochemical and systems biology approaches. Accomplishment of these studies will help to understand the basic processes of stem cell ageing and identify mechanisms of age-related functional decline in tissue regeneration. By targeting the population of tissue-resident adipogenic progenitor cells, therapeutic strategies could be developed to counteract metabolic complications associated with the ageing process.RNA-based regulation of signal transduction  Regulation of calcineurin/NFAT signaling by microRNA-based mechanismsHeart failure is a serious clinical disorder that represents the primary cause of hospitalization and death in Europe and the United States. There is a dire need for new paradigms and therapeutic approaches for treatment of this devastating disease. The heart responds to mechanical load and various extracellular stimuli by hypertrophic growth and sustained pathological hypertrophy is a major clinical predictor of heart failure. A variety of stress-responsive signaling pathways promote cardiac hypertrophy, but the precise mechanisms that link these pathways to cardiac disease are only beginning to be u< nveiled. Signal transduction is traditionally concentrated on the protein coding part of the genome, but it is now appreciated that the protein coding part of the genome only constitutes 1.5% of the genome. RNA based mechanisms may provide a more complete understanding of the fundamentals of cellular signaling. As a proof-of-principle, we focus on a principal hypertrophic signaling cascade, cardiac calcineurin/NFAT signaling. Here we will establish that microRNAs are intimately interwoven with this signaling cascade, influence signaling strength by unexpected upstream mechanisms. Secondly, we will firmly establish that microRNA target genes critically contribute to genesis of heart failure. Third, the surprising stability of circulating microRNAs has opened the possibility to develop the next generation of biomarkers and provide unexpected mechanisms how genetic information is transported between cells in multicellular organs and fascilitate inter-cellular communication. Finally, microRNA-based therapeutic silencing is remarkably powerful and offers opportunities to specifically intervene in pathological signaling as the next generation heart failure therapeutics. CALMIRS aims to mine the wealth of these RNA mechanisms to enable the development of next generation RNA based signal transduction biology, with surprising new diagnostic and therapeutic opportunities. : 31/1/2018Role of Liver Estrogen Receptor in female Energy Metabolism, Reproduction and Aging: What About Your Liver Sexual Functions?In mammals, the liver is the peripheral integrator of nutrient availability and energetic needs of the entire organism. We recently demonstrated that dietary amino acids (AA) activate liver Estrogen Receptors (ER) and that, in case of food scarcity, the lowered circulating AA decrease liver ER activity and reduce IGF-1 synthesis with the consequent blockage of the estrous cycle. Here, we hypothesize that in females liver ERa is also a sensor of the endogenous signalling induced by transitions among reproductive stages and a key organizer for the changes required to adapt energy metabolism to reproductive necessities. Thus, we propose that in mammals liver ERa is regulated by reproductive functions and that, in case of ovary malfunctioning, the altered estrogenic signalling causes metabolic impairment leading to local and perhaps systemic disruption of energy homeostasis. To demonstrate our theory, we will explore: i) the molecular pathways activating liver ERa and the related ERa transcriptome by genome-wide analytical tools; ii) the hepatic metabolism and the systemic consequences of liver ER pharmacological and genetic manipulations by means of metabolomic technologies; iii) the association between altered signalling on liver ER and the onset of metabolic disorders; iv) the molecular interactions between ER and PPAR activity and the effect of estrogens on liver autophagy. WAYS research is facilitated by a series of tools such as ER conditional KO, reporter mice, arrays of genes known as target of liver ERa, and others generated by our laboratory in collaboration with EU groups in previous EU programs. The vision of the liver as a functional unit with reproductive organs constitutes a paradigm shift in our understanding of woman physiology; thus, the full comprehension of liver ERa activity and regulation will be a critical step for the conception of new therapies for several diseases affecting women including the metabolic syndrome or the non-alcoholic steatosis.o?-cell Dysfunction in Diabetes: Elucidating the Role of Islet-Associated Mesenchymal CellsGlucose homeostasis relies on tightly controlled release of insulin by pancreatic beta-cells. Diabetes, characterized by increased blood glucose levels, is a chronic disease now reaching epidemic proportions. The most common form of this disease is Type 2 diabetes (T2D), which was previously regarded as a disease of insulin resistance. However, work over the past decade had shifted this paradigm by implicating beta-cell failure as a key factor in this disease. Despite major progress, the cellular and molecular basis of this T2D is far from being elucidated. Here, I present a novel pancreatic cell population, islet-associated mesenchymal cells (isMCs), which are with close contact to beta-cells in both human and mouse pancreata. My preliminary findings revealed that isMCs function to maintain beta-cells maturity and functionality. I therefore hypothesize that impaired isMCs function serve as an underlying cause for diabetes. To test this hypothesis, we will characterize the continuous requirement of isMCs for glucose homeostasis by their specific depletion in vivo. Next, we will link genes associated with T2D to isMCs function, by manipulating their expression and elucidating the effect on beta-cell function. Finally, we will investigate the source of diabetes prevalence found in pancreatic cancer and pancreatitis patients, by identifying how isMCs ability to maintain beta-cell function is affected in these diseases. To this end, we will use transgenic mouse models and culture systems to specifically manipulate cells and genes, and to study the resultant effect on beta-cell phenotype and glucose homeostasis. The implications of this work are far reaching as they will point to isMCs as a new player in glucose regulation, and as a contributor to beta-cell dysfunction in diabetes. Furthermore, the findings of this study will implicate isMCs a novel target for therapeutic approaches to diabetes, a currently unmet medical need. : 30/9/2018The RNA bridge between IRE-1 and PKR leading to metaflammation: discovery and intervention in atherosclerosisA close functional and molecular integration between metabolic and immune systems is crucial for systemic homeostasis and its deregulation is causally linked to obesity and associated diseases including insulin resistance, diabetes and atherosclerosis and known as cardiometabolic syndrome (CMS). Metabolic overload initiates a chronic inflammatory and stress response kno wn as metaflammation and promotes the complications of CMS. The precise molecular mechanisms linking metabolic stress to immune activation and stress responses, however, remain elusive. Earlier studies demonstrated metabolic overload stresses the endoplasmic reticulum (ER) and activates the unfolded protein response (UPR). ER is a critical intracellular metabolic hub orchestrating protein, lipid and calcium metabolism. These vital functions of ER are maintained by a conserved, adaptive stress response or UPR that emanates from its membranes. ER stress has emerged as a centr< al paradigm in the pathogenesis of CMS and its reduction prevents atherosclerosis and promotes insulin sensitivity. However, a clear understanding of how metabolic stress is sensed and communicated by the ER is fundamental in designing specific and targeted therapy to ER stress in CMS. This application will investigate the ER stress response that can sense excess lipids and couple to inflammatory and stress responses, and whether its unique operation under metabolic stress can be suitable for therapeutic exploitation in CMS. This proposal tackles the unique modes of operation of two important players in the ER stress response that are coupled by metabolic stress, inositol-requiring enzyme-1 (IRE-1) and double-stranded RNA-activated kinase (PKR), by taking advantage of chemical-genetics to specifically modify their activities. When completed the proposed studies will have shed light on a little explored but central question in the field of immunometabolism regarding how nutrients engage inflammatory and stress pathways. : 31/12/2018GMetabolic actions of brain leptin receptors signaling in type 1 diabetesAn established dogma is that insulin is absolutely required for survival. This notion has been supported by the fact that the sole life-saving intervention available to the millions affected by type 1 diabetes mellitus (T1DM; an illness caused by pancreatic -cell loss and hence insulin deficiency) is insulin therapy. This treatment however does not restore normal metabolic homeostasis. In fact, the lifeexpectancy and -quality of T1DM people is worse compared to normal subjects. In part, this is due to challenging morbidities of T1DM, as for example heart disease and hypoglycemia, both of which are thought to be caused by insulin therapy itself. Indeed, owing to insulin s lipogenic actions, this treatment likely contributes to the ectopic lipid deposition (i.e.: in non-adipose tissues) and extremely high incidence of coronary artery disease seen in T1DM subjects. Also, due to insulin s potent, fastacting, glycemia-lowering action, this therapy significantly increases the risk of hypoglycemia; a disabling and life threatening event. Because insulin therapy does not restore metabolic homeostasis in T1DM subjects, better intervention is urgently needed. To these ends, we and others have shown that the hyperglycemic and lethal consequences of insulin deficiency can be rescued by administration of the adipocyte-secreted hormone leptin. Not only these results challenge an established view, they also raise a fundamental biological and medical question: what are the mechanisms by which leptin improves hyperglycemia and permits survival in the context of insulin deficiency? This proposal aims at identifying the critical cellular and molecular components underlying the beneficial effects of leptin in the context of insulin deficiency. Once identified, manipulation of these components has the potential to improve life-expectancy and -quality of the millions affected by insulin deficiency (e.g.: T1DM and also some late-stage type 2 diabetics). : 31/5/2019fmTOR pathophysiology in rare human diseasesThe mammalian Target Of Rapamycin (mTOR) is a master regulator of growth. mTOR is a protein kinase that exists in two distinct complexes in the cell and transduces virtually all anabolic signals from the environment: nutrients, such as glucose and amino acids, growth factor peptides, such as insulin and insulin like growth factors, oxygen, mitochondrial metabolites, energy status. mTOR is required to sustain cell responses to nutrient availability including cell growth, proliferation, macromolecule biosynthesis, and suppress autophagy. During the past ten years we have generated and characterized a wide panel of mouse mutants in the mTOR pathway. We were involved in revealing specific phenotypes that increased our knowledge of mTOR roles in pathophysiology: mutants with small cells, mutants resistant to tumorigenesis in specific tissues and after specific oncogenic insults, mutants mimicking caloric restriction and promoting longevity, mutants with muscle dystrophy, mutants with altered insulin action. The overall goal of our research proposal for the next five years is twofold. From one hand we want to better understand fundamental processes including cell size control and organismal longevity. To this end we want to determine the molecular targets of the mTORC1/S6 kinase cassette that may explain the alterations in cell size and lifespan when these kinases are deregulated (project 1). From the other hand we want to understand and cure rare human genetic diseases that arise from pathological changes in the activity of the mTOR pathway in children or that may benefit from therapeutical intervention on this pathway. These diseases include Tuberous Sclerosis Complex, PEComas and hemangiomas (project 2), metabolic diseases (projects 3), lysosomal storage diseases (project 4). The translational approaches in this proposal will stem from a close interaction with multiple Medical Dept. in our shared research campus of the Necker Children Hospital. : 31/1/2020Positioning the nucleus for cell migration and muscle fiber functionThe cell nucleus is positioned at specific places within the cytoplasm and this position is important for different cellular, developmental and physiological processes. Nuclear positioning depends on connections between nuclear envelope proteins and the cytoskeleton. In migrating cells, we found that the nucleus is positioned away from the front of the cell and this event is important for cell migration. We performed an RNAi screen for nuclear positioning and found new nuclear envelope proteins involved in nuclear positioning. In fully developed myofibers, nuclei are specifically positioned at the per< iphery of the myofiber, while during development and regeneration, as well as in multiple muscle pathologies, the nucleus is centrally positioned. We found new mechanisms drive nuclear movement during myofiber formation. We also showed that nuclear position is important for muscle function. However why nuclear positioning is important for myofiber activity remains an open question. We now propose to use unique systems to monitor cell migration and myofiber formation in combination with biochemistry, cell biology, high- and super-resolution microscopy approaches to: 1) Identify novel molecular mechanisms that mediate nuclear positioning during cell migration and myofiber formation. 3) Determine a role for nuclear positioning in myofiber function as well as the significance of altered nuclear positioning in different forms of muscle pathology. The proposed work will establish new mechanisms for nuclear positioning. Importantly, by identifying mechanisms and understanding the role of nuclear positioning in myofiber function, we will lay the foundations for future studies to ameliorate or treat muscle disorders as well as other conditions where nucleus positioning may prove to play a role such as cancer. : 30/6/2019Tissue-specific mitochondrial signaling and adaptations to mistranslationMitochondria play a central role in the energy metabolism of our bodies and their defects give rise to a large variety of clinical phenotypes that can affect practically any tissue. The mechanisms for the tissue-specific outcomes of mitochondrial diseases are poorly understood. Mitochondrial energy production relies on two separate protein synthesis machineries, cytoplasmic and mitochondrial, but the mechanisms regulating the concerted actions between the two are largely to be discovered. Defects in either protein synthesis system that lead to accumulation of mistranslated mitochondrial proteins, intrinsic or imported from the cytoplasm, result in stress signals from mitochondria and in adaptive responses within the organelle and the entire cell. My hypothesis is that some of these signals and adaptive mechanisms are tissue-specific. My group will test the hypothesis by 1) generating and characterizing mouse models of cytoplasmic and mitochondrial mistranslation to be able to address our questions in different tissues. 2) We will develop methods for detection of ribosome stalling in mouse tissues to identify the consequences of mistranslation for individual proteins. 3) We will use systems biology approaches to identify stress signal responses to mitochondrial and/or cytoplasmic mistranslation using different tissues of our models, to identify those that are unique or global. 4) Our previous study has identified an interesting candidate responder to mistranslation stress and we will test the role of this factor in knockout animal models and by crossing with the mistranslation mice. I expect to gain important new knowledge of in vivo responses to mistranslation and execution of quality control. This proposal investigates key questions in understanding differential tissue involvement in metabolic defects, and will provide new directions for utilization of tissue -specific adaptations in finding interventions for mitochondrial diseases. : 30/6/2020Epistasis analysis of angiogenes with high cellular definitionBlood and lymphatic vessels have been the subject of intense investigation due to their important role in cancer development and in cardiovascular diseases. The significant advance in the methods used to modify and analyse gene function have allowed us to obtain a much better understanding of the molecular mechanisms involved in the regulation of the biology of blood vessels. However, there are two key aspects that significantly diminish our capacity to understand the function of gene networks and their intersections in vivo. One is the long time that is usually required to generate a given double mutant vertebrate tissue, and the other is the lack of single-cell genetic and phenotypic resolution. We have recently performed an in vivo comparative transcriptome analysis of highly angiogenic endothelial cells experiencing different VEGF and Notch signalling levels. These are two of the most important molecular mechanisms required for the adequate differentiation, proliferation and sprouting of endothelial cells. Using the information generated from this analysis, the overall aim of the proposed project is to characterize the vascular function of some of the previously identified genes and determine how they functionally interact with these two signalling pathways. We propose to use novel inducible genetic tools that will allow us to generate a spatially and temporally regulated fluorescent cell mosaic matrix for quantitative analysis. This will enable us to analyse with unprecedented speed and resolution the function of several different genes simultaneously, during vascular development, homeostasis or associated diseases. Understanding the genetic epistatic interactions that control the differentiation and behaviour of endothelial cells, in different contexts, and with high cellular definition, has the potential to unveil new mechanisms with high biological and therapeutic relevance."Molecular Subtype Specific Stem Cell Dynamics in Developing and Established Colorectal CancersAnnually 1.2 million new cases of colorectal cancer (CRC) are seen worldwide and over 50% of patients die of the disease making it a leading cause of cancer-related mortality. A crucial contributing factor to these disappointing figures is that CRC is a heterogeneous disease and tumours differ extensively in the clinical presentation and response to therapy. Recent unsupervised classification studies highlight that only a proportion of this heterogeneity can be explained by the variation in commonly found (epi-)genetic aberrations. Hence the origins of CRC heterogeneity remain poorly understood. The central hypothesis of this research project is that the cell of origin contributes to the phenotype and functional properties of the pre-malignant clone and the resulting malignancy. To study this concept I will generate cell of origin- and mutation-specific molecular profiles of oncogenic clones and relate those to human CRC samples. Furthermore, I will quantitatively investigate how mutations and the cell of origin act in concert to determine the functional characteristics of the pre-malignant clone that ultimately develops into an invasive intestinal tumour. These studies are paralleled by the investigation of stem cell dynamics within established human CRCs by means of a novel marker independent lineage tracing strategy in combination with mathematical analysis techniques. This will provide critical and quantitative information on the relevance of the cancer stem cell concept in CRC and on the degree of inter-tumour variation with respect to the frequency and functional features of stem-like cells within individual CRCs and molecular subtypes of the disease. I am convinced that a better and quantitative understanding of the dynamical properties of stem cells during tumour development and within established CRCs will be pivotal for an improved classification, prevention and treatment of CRC.gCircadian Regulation Of Brown Adipose ThermogenesisObesity and diabetes have reached pandemic proportions and new therapeutic strategies are critically needed. Brown adipose tissue (BAT), a major source of heat production, possesses significant energydissipating capacity and therefore represents a promising target to use in combating these diseases. Recently, I discovered a novel link between circadian rhythm and thermogenic stress in the control of the conserved, calorie-burning functions of BAT. Circadian and thermogenic signaling to BAT incorporates blo< od-borne hormonal and nutrient cues with direct neuronal input. Yet how these responses coordinately shape BAT energy-expending potential through the regulation of cell surface receptors, metabolic enzymes, and transcriptional effectors is still not understood. My primary goal is to investigate this previously unappreciated network of crosstalk that allows mammals to effectively orchestrate daily rhythms in BAT metabolism, while maintaining their ability to adapt to abrupt changes in energy demand. My group will address this question using gain and loss-of-function in vitro and in vivo studies, newly-generated mouse models, customized physiological phenotyping, and cutting-edge advances in next generation RNA sequencing and mass spectrometry. Preliminary, smallscale validations of our methodologies have already yielded a number of novel candidates that may drive key facets of BAT metabolism. Additionally, we will extend our circadian and thermogenic studies into humans to evaluate the translational potential. Our results will advance the fundamental understanding of how daily oscillations in bioenergetic networks establish a framework for the anticipation of and adaptation to environmental challenges. Importantly, we expect that these mechanistic insights will reveal pharmacological targets through which we can unlock evolutionary constraints and harness the energy-expending potential of BAT for the prevention and treatment of obesity and diabetes. : 30/4/2020vOrgan-specific mechanisms of lymphatic vascular development and specialisationLymphatic vasculature maintains tissue fluid homeostasis and has important emerging roles in inflammation, immunity, lipid metabolism, blood pressure regulation and cancer metastasis. Lymphatic vessels are specialised to fulfil the functional needs of different organs while diseases associated with lymphatic dysfunction frequently affect vessels of specific tissues. How functional specialisation of vessels is achieved and what underlies tissue-specific vessel failure is not understood. I hypothesise that organ-specific manifestation of lymphatic dysfunction in disease is due to vascular bed-specific differences in vessel formation. In this project my aim is to identify genes and mechanisms required for organ-specific lymphatic development. Building on our recent discovery of a previously unknown progenitor cell type that is required for lymphatic development in an organ-specific manner I set out to identify the origin and function of lymphatic endothelial progenitor cells (LEPC) during development and assess their potential for therapeutic lymphatic regeneration. Towards this aim, we will identify organ-specific origins of lymphatic vasculature using lineage tracing and determine genetic signatures of lymphatic endothelial progenitors by mRNA sequencing. Cells and tissues from normal and mutant mice that show organ-specific lymphatic defects will be analysed. To identify molecular and cellular mechanisms of LEPC derived vessel formation, we will functionally characterise LEPC signature genes using mouse models and visualise vessel development by in vivo two-photon microscopy. The function and therapeutic potential of LEPCs and LEPC derived vessels will be assessed using mouse models of tolerance, inflammation, obesity and lymphoedema. This work will provide novel insights into organspecific mechanisms of vascular morphogenesis and identify a progenitor cell that may be expoited to restore lymphatic function in disorders associated with lymphatic vessel failure.bGENOMIC, CELLULAR AND DEVELOPMENTAL RECONSTRUCTION OFINFANT MLL-AF4+ ACUTE LYMPHOBLASTIC LEUKEMIAInfant cancer is very distinct to adult cancer and it is progressively seen as a developmental disease. An intriguing infant cancer is the t(4;11) acute lymphoblastic leukemia (ALL) characterized by the hallmark rearrangement MLL-AF4 (MA4), and associated with dismal prognosis. The 100% concordance in twins and its prenatal onset suggest an extremely rapid disease progression. Many key issues remain elusive: Is MA4 leukemogenic? Which are other relevant oncogenic drivers? Which is th e nature of the cell transformed by MA4? Which is the leukemia-initiating cell (LIC)? Does this ALL follow a hierarchical or stochastic cancer model? How to explain therapy resistance and CNS involvement? To what extent do genetics vs epigenetics contribute this ALL?These questions remain a challenge due to: 1) the absence of prospective studies on diagnostic/remission-matched samples, 2) the lack of models which faithfully reproduce the disease and 3) a surprising genomic stability of this ALL.I hypothesize that a MultilayerOmics to function approach in patient blasts and early human hematopoietic stem/progenitor cells (HSPC) is required to fully scrutinize the biology underlying this life-threatening leukemia. I will perform genome-wide studies on the mutational landscape, DNA and H3K79 methylation profiles, and transcriptome on a uniquely available, large cohort of diagnostic/remission-matched samples. Omics data integration will provide unprecedented information about oncogenic drivers which must be analyzed in ground-breaking functional assays using patient blasts and early HSPCs carrying a CRISPR/Cas9-mediated locus/allele-specific t(4;11). Serial xenografts combined with exome-seq in paired diagnostic samples and xenografts will identify the LIC and determine whether variegated genetics may underlie clonal functional heterogeneity. This project will provide a precise understanding and a disease model for MA4+ ALL, offering a platform for new treatment strategies. : 0/1/1900UThe role of pericytes in central nervous system scarring and fibrosisDamage 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 injuryinduced 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.Role of endoplasmic reticulum in neurodegeneration: physiopathology of a form of hereditary spastic paraplegia as a modelEndoplasmic reticulum (ER) is a dynamic, tubular intracellular network implicated in a variety of cellular functions. Although it is known to play a role in neurodegeneration, its organization and precise function in neurons have been neglected. I will use the physiopathology of certain forms of hereditary spastic paraplegia (HSP) as a model to understand why and how alteration of ER dynamics in neurons can lead to neurodegeneration. I will focus on three genetic entities, SPG11, SPG15 and SPG48, which are clinically and biochemically<  related, since the proteins encoded by these genes (spatacsin, spastizin and KIAA0415) are all present in a multiprotein complex important for ER function. The project has three objectives: - Elucidate the role of spatacsin, spastizin and KIAA0415 in the regulation of ER morphology and dynamics; - Establish the link between abnormal ER function and neurodegeneration; develop and characterize physiopathological experimental models: (i) an SPG11 knockout mouse; (ii) primary cultures of neurons subjected to RNA interference to downregulate expression of the SPG11, 15 and 48 genes; (iii) neurons differentiated from induced pluripotent stem (iPS) cells derived from fibroblasts of patients with mutations in SPG11, 15 and 48. ER organization and dynamics will be analyzed in these models using electron and fluorescence microscopy (confocal microscopy, super resolution Structured Illumination Microcopy), as well as videomicroscopy on living cultured neurons. The cell culture models will allow us to determine how the functions of ER that are altered in the pathological models in culture are linked to neuronal death. This pioneering work will help understand the functions of neuronal ER in both normal and pathological conditions  HSP, but also other neurodegenerative diseases.fGlia, Smell, Food & Courtship in DrosophilaOdors are key components for sensory communication involved in behaviors such as social communication or food search. Recently, molecular receptors, neuronal architecture, physiological regulation, and behavioral consequences underlying these biological processes are starting to be revealed in an increasing number of animal models. But more and more breakthroughs are highlighting some unexpected results asking for deeper studies. The Drosophila melanogaster has proven to be a particular powerful tool to understand, to test, and to manipulate the complex neurogenetical interactions between molecular and cellular partners controlling such behaviors. We have shown that a subset of glia is mastering the activity of a population of neurons involved in chemoperception in Drosophila (e.g. glutamatergic neurons). We have also recently uncovered a striking molecular and neuronal architecture regulating courtship using food odors instead of classical pheromones in fruit flies. Our emerging team at the CSGA-UMR 6265 CNRS will expand these pioneer works to understand how glia and neurons are interacting to impact fly chemosensory choice. For this aim, we will develop powerful genetic tools in Drosophila to reveal and to manipulate the communication between glial cells and neurons in peripheral sensory organs and in projection centers in the brain. We will also look for conserved mechanisms in other insect species (mosquito). The expected data are susceptible to touch a large scientific public since olfaction plays a key sensory modality in most animal species. The collected data on glial function in neuronal activity control will have also a strong impact on finding new strategies to understand neuronal disorders in humans.yMesocorticolimbic System: functional anatomy, drug-evoked synaptic plasticity & behavioral correlates of Synaptic InhibitionThe mesocorticolimbic (MCL) system, extending from the ventral tegmental area (VTA) to the nucleus accumbens and prefrontal cortex, comprises a dopamine (DA) projection implicated in reinforcement learning. The MCL system is the target of addictive substances and of drug-evoked synaptic plasticity, a cellular mechanism that may underlie the adaptive, pathological behaviors that occur after repeated drug exposure. While most previous work has focused on excitatory transmission, recent studies suggest that inhibitory transmission may play a crucial role in mediating specific functions of the MCL system. However the identity of the inhibitory synapses and circuits and the plasticity mechanisms underlying these forms of normal and pathological learning remain elusive. We hypothesize that distinct inhibitory circuits in the MCL system mediate specific behaviors and that adaptive synaptic plasticity of these circuits are fundamental to both normal reward learning and addictive behaviors. We will test this hypothesis using optogenetic projection targeting to characterize specific inhibitory projections, to selectively change the activity of these neurons in freely behaving animals to explore their behavioral relevance, and to identify precise circuit changes that underlie behavioral alterations after drug exposure. Taken together, the experiments we propose will not only identify the specific circuits and basic role of inhibition in mediating reward-related behaviors, but will allow us to understand how the alteration of these circuits after drugs can result in pathological behavior. Ultimately, our results will establish the importance of inhibitory synaptic transmission in the MCL system, are likely to fundamentally change current views of this important modulatory system, and will allow us to design strategies to interfere with drug-evoked synaptic plasticity to revert addictive behavior.Epilepsies of the temporal lobe: emergence, basal state and paroxysmal transitionsThis proposal focuses on a human disease: epilepsy of the temporal lobe. This syndrome has a relatively stereotyped history. Focal seizures emerge, with a delay of several years in the human, after an initial insult that results in neuronal death. We will use physiology, imaging, anatomy and transcriptomic techniques to ask how an epileptic brain emerges, to define different neuronal cell types in the basal epileptic state and to examine factors associated with the paroxysmal transition to a seizure. Specifically we will ask whether a loss of cholesterol homeostasis is involved in the initial sclerotic neuronal death. We will ask whether proteoglycans deposited in the extracellular space as a generalised wound healing response force the establishment of aberrant synaptic contacts and so facilitate the slow process of epileptogenesis. We will then study the basal state of an epileptic brain. We will establish the physiology, anatomy, connectivity and transcriptome of functionally distinct neurons defined by different contributions to epileptiform activities in human epileptic brain slices. Finally we will seek to establish what sudden changes in field potential, ionic homeostasis, cellu< lar firing and synaptic interactions are associated with the paroxysmal moment of transition to seizure.Signal Formation in Synaptic Circuits with AstrogliaIn the past decade, astroglia have emerged as an active and critical partner in neural circuit communication in the brain, in health and disease. However, the increasing variety of mechanisms which reportedly contribute to astroglia-neuron signal exchange is nearing a conceptual bottleneck. How these multiple and diverse mechanisms relate to the functional organisation of astroglia, whether this relationship persists or whether it adapts to neural activity remains poorly understood. Building upon substantial preliminary work and extensive collaboration, our overall objective is to establish principles that guide signal formation, integration and propagation in neural circuits interacting with astroglia. We will focus mainly on hippocampal circuitry and combine single-cell electrophysiology,multi-photon excitation imaging, time-resolved and super-resolution fluorescence microscopy, pharmaco- and optogenetic tools and extensive biophysical and neural network modelling. Firstly, we will establish whether and how glia-neuron signal exchange relates to the structure and function of individual synaptic connections represented by postsynaptic dendritic spines and presynaptic axonal boutons. Secondly, we will identify cellular mechanisms by which individual astrocytes integrate, in space and time, calcium signals arising from distinct types of local physiological input. Thirdly, we will determine physiological machinery that prompts use-dependent, meta-plastic changes in the neural circuit-astroglia exchange and in glial signal processing. Fourthly, we will establish the relationship between neural network oscillations and periodic activities of astroglial assemblies. Finally, we will undertake a computational and theoretical analysis of principles that govern the role astroglia in information handling by neural networks. We expect that the results will provide novel and conceptual insights into the basic machinery underpinning the activity of brain circuits.The human Parietal LobeWe will use univariate and multivariate functional Magnetic Resonance Imaging (fMRI) techniques, surface and stereo EEG, and in depth single cell recording to investigate the role of human parietal lobe in the monocular or stereoscopic observation of actions performed by conspecifics either using their biological effectors or artificial implements (tools, spears, bicycle, microphone, etc). The fMRI techniques will provide evidence for segregated processing of different types of observed actions within the parietal cortex. The EEG techniques will provide the time course of the electric activity in the parietal regions in comparison to the events and dynamic changes in the video and the time course in other parts of the action observation network. The stereo EEG also provides a more precise localization than fMRI, serving as an important confirmation of the fMRI results. The single cell recordings are crucial to demonstrate the selectivity of the neuronal processes for actions observed, their postural or kinematic parameters or localization in the visual field. This selectivity is crucial to show the presence of mirror neurons for the different types of actions and the use of tools, to document the contribution of the parietal neurons to discrimination between actions, and to assess the benefits of stereoscopic viewing. This project should yield a comprehensive view of the role of parietal lobe in action planning and understanding, including using artificial implements, and pave the way for understanding how higher-order parietal cognitive processes are rooted in the simpler action planning and understanding capacities.9Function of Chemosensory CircuitsSmell and taste are the least studied of all senses. Very little is known about chemosensory information processing beyond the level of receptor neurons. Every morning we enjoy our coffee thanks to our brains ability to combine and process multiple sensory modalities. Meanwhile, we can still review a document on our desk by adjusting the weights of numerous sensory inputs that constantly bombard our brains. Yet, the smell of our coffee may remind us that pleasant weekend breakfast through associative learning and memory. In the proposed project we will explore the function and the architecture of neural circuits that are involved in olfactory and gustatory information processing, namely habenula and brainstem. Moreover we will investigate the fundamental principles underlying multimodal sensory integration and the neural basis of behavior in these highly conserved brain areas. To achieve these goals we will take an innovative approach by combining two-photon calcium imaging, optogenetics and electrophysiology with the expanding genetic toolbox of a small vertebrate, the zebrafish. This pioneering approach will enable us to design new types of experiments that were unthinkable only a few years ago. Using this unique combination of methods, we will monitor and perturb the activity of functionally distinct elements of habenular and brainstem circuits, in vivo. The habenula and brainstem are important in mediating stress/anxiety and eating habits respectively. Therefore, understanding the neural computations in these brain regions is important for comprehending the neural mechanisms underlying psychological conditions related to anxiety and eating disorders. We anticipate that our results will go beyond chemical senses and contribute new insights to the understanding of how brain circuits work and interact with the sensory world to shape neural activity and behavioral outputs of animals.Neurovascular Interactions and Pathfinding in the Spinal Motor SystemNeurons and blood vessels rely on common guidance signals to wire into elaborate neural and vascular networks that are closely juxtaposed and interdependent: vascular supply of oxygen and nutrients is essential to sustain the high metabolic rate of the nervous system, and conversely neural control of vascular tone is crucial for circulatory homeostasis. However, it remains unclear how the nervous and vascular systems establish an intimate physical and functional relationship. This proposal seeks to reveal the developmental mechanisms that link neuronal connectivity and vascularization of the nervous system, focusing on the interactions between vascular endothelial cells and spinal motor neurons that control locomotion, respiration and autonomic responses. Motor neuron diseases and a variety of other neurodegenerative conditions are precipitated by vascular abnormalities. Thus, understanding the molecular basis of neurovascular crosstalk may offer novel therapeutic opportunities. My group will use mutagenesis-based forward genetics in reporter mice combined with gene profiling of motor neurons and endothelial cells to screen for novel regulators of neurovascular interactions and pathfinding. Candidate genes will be further characterized using in vivo mouse and chick models, in addition to in vitro studies to uncover the mechanisms of action. Through this multidisciplinary approach, the proposal will address these fundamental questions: (i) Do neurovascular interactions instruct the assembly of neural and vascular networks? (ii) What signaling pathways connect region-specific vascularization of the CNS to the local metabolic and functional demand of neuronal tissues? (iii) What mechanisms account for specificity, spatiotemporal control and integration of guidance signaling? In addition, this research plan will generate comprehensive transcriptional/proteomic datasets < and novel mouse mutants for future studies of neurovascular communication and patterning. : 31/12/2019uMolecular neurobiology of a moonlight entrained circalunar clockNumerous scientific studies have established that the lunar cycle synchronizes reproductive behaviour and sexual maturation of animals as diverse as corals, polychaetes and fishes. Classical and recent work shows that in animals such as the annelid Platynereis dumerilii, dim nocturnal light serves as entrainment cue for an endogenous oscillator  a circalunar clock  that orchestrates reproductive and behavioral cycles. As circalunar clocks run with a (semi-)monthly period, they represent a fundamental biological phenomenon clearly distinct from the widely studied, solar light-entrained circadian (24h) clocks. Despite the vital importance of circalunar clocks, very little is known about the underlying molecular processes and responsible neuron types. This knowledge gap reflects the fact that until now, no suitable model system has been available to study circalunar clocks on the molecular and cellular level. This proposal takes full advantage of the recent establishment of substantial molecular resources and critical techniques for functional analyses in Platynereis, as well as our pioneering work on the first circalunar clock-regulated genes and the identification of four molecular candidates for the nocturnal light receptor. This now allows us to tackle two fundamental objectives: First, we aim to discover the molecular and cellular nature of the lunar light sensor(s) and their interplay with solar light photoreceptors. Second, we aim to characterize circalunar oscillatory genes and their associated neuron types that will pave the way to unravel the molecular and cellular nature of the circalunar oscillator. This work will provide new mechanistic insight into an unexplored biological mysterycircalunar clocks and their regulation by light. It also offers new conceptual advance into how animals accomplish the separation of diurnal versus nocturnal light information for the synchronization of reproductive behaviour, a challenge common in the natural environment.3The Role of Neuropeptides in Learning and Memory.Humanity has always been intrigued by the nearly mythical properties of the brain. With its billions of neurons and innumerable connections, the brain is of such complex nature, that trying to understand it may seem a vain project. Yet, by using the  mini-brain of the model organism Caenorhabditis elegans, which shares many components with the human brain but counts only 302 neurons, thorough research can penetrate into this complexity. We here pursue to deliver a much-needed understanding of how learning and memory processes are regulated by neuropeptide signaling in the brain. Neuropeptides are small regulatory proteins that are implicated in a variety of processes. Growing evidence exists for their involvement in learning and memory, but how they exert these effects is largely unexplored. In C. elegans we recently disentangled a conserved vasopressin/ocytocin-related system that  as in humans mediates associative learning. As such, we can deliver the experience, model and logical approach to provide detailed insights in neuropeptidergic control of learning and memory. We will first identify the endogenous ligand of all orphan C. elegans neuropeptide GPCRs, as this will provide the essential basis to build this project on. Mutants of neuropeptide-receptor pairs will then be tested for their ability to learn or maintain associative short- or long-term memory. We will also define in which cells and circuits relevant neuropeptides and receptors are needed for these functions, in order to generate models of neuropeptidergic control of learning and memory. We envisage the use of novel tools and cutting-edge experimental setups to take this research beyond its current horizon. Via single cell RNA sequencing, optogenetic analyses and in vivo calcium imaging, we will devel< op a workflow to build integrative models of associative learning and memory processes mediated by neuropeptides, which will serve as a scaffold for the study of these processes in more complex brains.LEvolution of olfactory circuitsNervous systems have undergone remarkable diversification in their structure and function as animals have adapted to distinct ecological niches. What are the genetic mechanisms underlying neural circuit evolution? The project addresses this fundamental question in the Drosophila olfactory system, a superior "evo-neuro" model for several reasons: (i) as in mammals, the Drosophila olfactory system has a modular organization, with individual olfactory receptors functionally and anatomically defining discrete sensory circuits that can be traced from the periphery to the brain; (ii) these circuits are dynamically evolving, with frequent acquisition (and loss) of receptors, olfactory neurons and odorevoked behaviors with the ever-changing landscape of environmental volatiles; (iii) Drosophila offers unparalleled experimental accessibility to visualize and manipulate neural circuits; (iv) a wealth of insect genomes permits comparative studies to relate intra- and interspecific genotypic and phenotypic variation. Five aims address distinct aspects of olfactory circuit evolution: 1. Evolution of receptor specificity; 2. Evolution of receptor expression; 3. Evolution of sensory neuron targeting; 4. Evolution of interneuron wiring; 5. Evolution of olfactory behavior. This multidisciplinary project uses cutting -edge approaches in comparative genomics, electrophysiology, neurogenetics, transcriptomics, behavioral tracking and population genetics. By addressing how particular olfactory circuits and behaviors have evolved in Drosophila, it will provide general insights into the genetic mechanisms of nervous system evolution relevant both for other brain regions and for other species. We also anticipate that determining how brains have been sculpted through random mutation and natural selection in the past may enable future directed manipulation of the connectivity and activity of neural circuits, to enhance our understanding of brains and our ability to repair them.bLong-term molecular nanoscale imaging of neuronal functionSynaptic function is difficult to analyze in living neurons using conventional optics, since the synaptic organelles and protein clusters are small and tightly spaced. The solution to this problem can come from the field of super-resolution fluorescence microscopy, or nanoscopy. However, the current approaches to nanoscopy are still far from reaching this goal. Single molecule-based approaches (including STORM and PALM) provide high spatial resolution, but slow recording, insufficient for live imaging. Ensemble approaches (including SSIM and STED) are able to record faster, but with poorer resolution or with high, potentially toxic, laser powers. It is currently impossible to image the same neuron for hours and days, with both high spatial (~30 nm) and temporal (10-1000 Hz) resolution, and with minimal photodamage. My aim is to fill this gap, by developing, for the first time, a microscope that combines the advantages of both single molecule-based and ensemble approaches. I will base the microscope on RESOLFT, a low-photodamage ensemble approach that I have pioneered recently. I will use line patterns to speed up the recording and 2photon-switching for 3D ability. I will combine this with sensitive detection schemes that allow single-molecule detection and counting, relying on my previous expertise with PALM and GSDIM. The new set-up, termed molecular nanoscale long-term imaging with sequential acquisition (MoNaLISA), will track neuronal organelles and proteins on different time scales, spanning from milliseconds to days, with a resolution close to the molecular scale. To obtain the first proof-of-principle results, I will address several issues still open in the synaptic transmission field, relating to synaptic vesicle recycling, biogenesis and degradation. Overall, my project will introduce a novel paradigm to imaging in the life sciences, which will enable fast and quantitative nano-imaging of cells and tissues.gThe role of 5HT3a inhibitory interneurons in sensory processingHow do cortical circuits process sensory stimuli that leads to perception? Sensory input is encoded by complex interactions between principal excitatory neurons and a diverse population of inhibitory cells. Distinct inhibitory neurons control different subcellular domains of target principal neurons, suggesting specific roles of different cells during sensory processing. However, the individual contribution of these inhibitory subtypes to sensory processing remains poorly understood. This is mainly due to the technical challenges of recording the activity of identified cell types in-vivo, in response to quantified sensory stimuli. Therefore, I propose a novel approach based on four pillars: 1) An optically accessible circuit in the superficial layers of the cortex, comprised of inhibitory cells expressing the serotonin receptor 5HT3a, and the distal dendrites of pyramidal neurons. 2) A novel combination of electrophysiology and 3D two-photon imaging to simultaneously record the activity of morphologically identified 5HT3a cells and their dendritic targets. 3) A head-fixed perceptual decision task, whereby mice use their whiskers to determine the location of an object, allowing an accurate description of the sensory stimulus. 4) The integration of experimental data and computer models to gain mechanistic insights into circuit functions. The 5HT3a cells and the distal dendrites of pyramidal neurons receive  top-down contextual information from other cortical areas that is essential for constructing meaningful perceptions of sensory stimuli. Thus I hypothesize that 5HT3a cells influence sensory perceptions by controlling the excitability of the pyramidal cell distal dendrites that integrate top-down< and sensory input. Thus, I will not only reveal novel functions of inhibitory neurons, I will also shed light on how top-down and sensory input is integrated, and I will provide novel methods to test the functions of other cell types in normal mice and disease models.MCerebellar circuit mechanisms of coordinated locomotion in miceA remarkable aspect of motor control is our seemingly effortless ability to generate coordinated movements. How is activity within neural circuits orchestrated to allow us to engage in complex activities like gymnastics, riding a bike, or walking down the street while drinking a cup of coffee? The cerebellum is critical for coordinated movement, and the well-described, stereotyped circuitry of the cerebellum has made it an attractive system for neural circuits research. Much is known about how activity and plasticity in its identified cell types contribute to simple forms of motor learning. In contrast, while gait ataxia, or uncoordinated walking, is a hallmark of cerebellar damage, the circuit mechanisms underlying cerebellar contributions to coordinated locomotion are not well understood. One limitation has been the difficulty in extracting quantitative measures of coordination from the complex, whole body action of locomotion. We have developed a custom-built system (LocoMouse) to analyze mouse locomotor coordination. It tracks continuous paw, snout, and tail trajectories in 3D with unprecedented spatiotemporal resolution and it has allowed us to identify specific, quantitative locomotor elements that depend on intact cerebellar function. Here we will combine this quantitative behavioral approach with electrophysiology and optogenetics to investigate circuit mechanisms of locomotor coordination. We will 1) Optogenetically silence the output of cerebellar subregions to understand their distinct contributions to locomotion. 2) Record from identified neurons and correlate their activity with specific locomotor parameters. 3) Optogenetically stimulate defined cell types to investigate circuit mechanisms of coordinated locomotion. These experiments will establish causal relationships between neural circuit activity and coordinated motor control, a problem with important implications for both health and disease.`Striatal cholinergic cell assemblies in movement disordersPathological neuronal synchrony is the hallmark of many neurological disorders, including Parkinson s disease (PD) and Huntington s disease (HD), which further share deficits in cholinergic signaling. Moreover, recent findings have underscored the therapeutic relevance of the synchrony among striatal cholinergic interneurons (ChI) that orchestrate this signaling. They have shown that excessively synchronous ChI discharge induces di-synaptic release of dopamine, GABA and glutamate. Here, I propose to elucidate how ChI synchronization is generated under normal and pathological conditions and thereby identify novel therapeutic targets to treat PD and HD. This study has only very recently become feasible with the advent of powerful tools that I have mastered to explore ChI synchrony. We will employ a combination of cutting-edge in vitro and in vivo techniques to simultaneously record a far larger population of pre-identified ChIs than is currently possible. We will express GCaMP6, a genetically encoded calcium indicator (GECI), exclusively in ChIs, and use multiphoton microscopy to image calcium transients from several ChIs simultaneously in conjunction with intracellular recording from individual ChIs in acute brain slices and in anesthetized mice. Additionally, we will use endoscopic GECI imaging in freely-moving classically conditioned mice. We will employ modern analyses that reveal low-dimensional structures in large neuronal datasets to quantify synchrony (1) during on-going activity; (2) during optogenetic activation of afferents; and (3), in the freely-moving mice, while presenting conditioned cues. Finally, we will study the origins of pathological synchrony in PD and HD mouse models and explore means to correct this condition. This comprehensive approach should explain the pathological ChI synchrony observed in PD; identify novel targets to treat PD and HD; and create a general methodology to study pathological synchrony in many other neurological disorders.Rounding the circle: Unravelling the biogenesis, function and mechanism of action of circRNAs in the Drosophila brain.Tight regulation of RNA metabolism is essential for normal brain function. This includes co and posttranscriptional regulation, which are extremely prevalent in neurons. Recently, circular RNAs (circRNAs), a highly abundant new type of regulatory non-coding RNA have been found across the animal kingdom. Two of these RNAs have been shown to act as miRNA sponges but no function is known for the thousands of other circRNAs, indicating the existence of a widespread layer of previously unknown gene regulation.The present proposal aims to comprehensively determine the role and mode of actions of circRNAs in gene expression and RNA metabolism in the fly brain. We will do so by studying their biogenesis, transport, and mechanism of action, as well as by determining the roles of circRNAs in neuronal function and behaviour. Briefly, we will: 1) identify factors involved in the biogenesis, localization, and stabilization of circRNAs; 2) determine neuro-developmental, molecular, neural and behavioural phenotypes associated with down or up regulation of specific circRNAs; 3) study the molecular mechanisms of action of circRNAs: identify circRNAs that work as miRNA sponges and determine whether circRNAs can encode proteins or act as signalling molecules and 4) perform mechanistic studies in < order to determine cause-effect relationships between circRNA function and brain physiology and behaviour. The present proposal will reveal the key pathways by which circRNAs control gene expression and influence neuronal function and behaviour. Therefore it will be one of the pioneer works in the study of this new and important area of research, which we predict will fundamentally transform the study of gene expression regulation in the brain : 31/1/2021>Host-intestinal bacteria mutualism: "Learning on the fly"Metazoans establish reciprocal interactions with the bacterial communities that colonize their mucosal surfaces. These interactions contribute to many aspects of host physiology including the promotion of digestive efficiency and proper immune system development and homeostasis. In return, the microbiota derives benefit from the association with its host by inhabiting a nutrient rich environment. When deregulated this relationship results in pathological outcomes such as episodic infectious diseases, chronic inflammatory diseases, metabolic disorders or even some cancers. Despite recent progress, a clear view of the physiological benefits associated with host/microbiota relationship remains elusive. Hence the molecular mechanisms through which the microbiota exerts its beneficial influences are still largely undefined. The goal of this research proposal is to decipher the molecular dialogue governing the mutualistic interaction between intestinal bacteria and their host. To this end, we will use an animal model, Drosophila melanogaster and one of its natural commensals, Lactobacillus plantarum. We aim to develop a multiscale functional approach to study the molecular mechanisms underlying their mutualistic association. This integrated approach will couple a host and a bacteria centred-view of this beneficial interaction to identify, the bacterial and host genetic networks required to sustain a mutualistic relationship. We will reveal how these molecular activities translate into cellular, tissular and organismal functional benefits and will uncover the interdependency of these benefits. Using a model lactic acid bacteria species and an animal host model with evolutionary conserved molecular and physiological features, our approach is relevant to most lactobacilli/host interactions including those occurring in humans. This project will provide fresh and unbiased insight into the fundamental biological question of host/microbe mutualism.A combined evolutionary and proteomics approach to the discovery, induction and application of antiviral immunity factorsHumans are equipped with a variety of intrinsic immunity or host restriction factors. These evolved under positive selection pressure for diversification and represent a first line of defence against invading viruses. Unfortunately, however, many pathogens have evolved effective antagonists against our defences. For example, the capability of HIV-1 to counteract human restriction factors that interfere with reverse transcription, uncoating and virion release has been a prerequisite for the global spread of AIDS. We are just beginning to understand the diversity and induction of antiretroviral factors and how pandemic HIV-1 group M (major) strains evolved to counteract all of them. Here, I propose to use a genetics, proteomics and evolutionary approach to discover and define as-yetunknown antiviral effectors and their inducers. To identify novel antiviral factors, we will examine the capability of all primate genes that are under strong positive selection pressure to inhibit HIV and its simian (SIV) precursors. This examination from the evolutionary perspective of the invading pathogen will also reveal which adaptations allowed HIV-1 to cause the AIDS pandemic. Furthermore, complex peptide-protein libraries representing essentially the entire human peptidome, will be utilized to identify novel specific inducers of antiviral restriction factors. My ultimate aim is to unravel the network of inducers and effectors of antiviral immunity - the "Anti-Virome" - and to use this knowledge to develop novel effective preventive and therapeutic approaches based on the induction of combinations of antiviral factors targeting different steps of the viral life cycle. The results of this innovative and interdisciplinary program will provide fundamental new insights into intrinsic immunity and may offer alternatives to conventional vaccine and therapeutic approaches because most restriction factors have broad antiviral activity and are thus effective against various pathogens.Epithelial cells in inflammationThe cross talk between the host and the microbiota is believed to be the major determinant of health and disease in the gastrointestinal tract. Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the intestine with unclear aetiology. Deregulation of the cross talk between the intestinal microbiota and the host immune system is considered a main factor contributing to IBD. Genomic studies revealed associations of NOD2 and of genes regulating autophagy and ER stress with an increased risk for IBD. Mutations in these pathways compromise Paneth cell depende nt epithelial antibacterial defences causing alterations in the intestinal microbiota, termed dysbiosis. However, mutations in NOD2 or autophagy genes are not sufficient to cause intestinal inflammation in humans or in mice, suggesting that dysbiosis by itself cannot cause inflammation but additional, as yet unidentified, factors are required to precipitate the pathogenesis of IBD in genetically susceptible individuals. Mouse model studies revealed that epithelial specific mutations sensitizing intestinal epithelial cells to apoptosis or necroptosis triggered spontaneous intestinal pathologies with many features of human IBD, including loss of Paneth cells, impaired epithelial antimicrobial defences and chronic intestinal inflammation. We hypothesize that pathways controlling programmed cell death critically contribute to the pathogenesis of IBD by acting on Paneth cells to regulate epithelial antibacterial defences and simultaneously regulating intestinal epithelial cell survival and the integrity of the epithelial barrier. The aims of this research proposal are: a) to dissect the pathways regulating Paneth cell death and the development of dysbiosis in the gut, and b) to elucidate the additional genetic or environmental factors regulating intestinal epithelial barrier integrity that are likely to synergise with Paneth cell dysfunction and dysbiosis to trigger chronic intestinal inflammation.Interplay between influenza viruses and host SUMO pathwaysInfluenza viruses cause a significant seasonal disease burden and continually threaten to initiate human pandemics. Antivirals are available for treatment of influenza, however drug-resistant viruses often emerge. Thus, there is urgent need to develop new antivirals with lower chances of selecting resistance. As viruses rely extensively on cellular functions, one way to minimise resistance is to target new antivirals against host factors. This concept requires a fundamental understanding of mechanisms underpinning the interplay between influenza viruses and their hosts. In this project, we will investigate the role that host SUMO pathways play during influenza virus replication. SUMO proteins are important regulators of cell signalling, and are covalently linked to other proteins in order to alter structure, localization or function. As such, SUMO conjugation regulates many diverse aspects of biology. Our own work shows that global cellular SUMOylation increases during influenza virus infection, and that virus replication is severely imp< aired when cells are depleted of key enzymes a nd components required for general SUMO conjugation. Here, we will determine what viral components trigger SUMOylation, and which specific cellular enzymes are involved. We will characterize where in the cell SUMO conjugates accumulate, and for the first time apply large-scale affinity-based quantitative proteomics to the identification of proteins that become SUMO modified during infection. A key aim will be to correlate changes to the SUMO sub-proteome with the function of specific host SUMO-modifying enzymes, thereby establishing the mechanistic role of these modifications during virus replication. Understanding basic mechanisms underlying SUMOylation during influenza virus infection will provide new insights into the fundamental biology of these important pathogens. The work could also lead to identification of key cellular pathways that can be exploited as novel therapeutic targetsNoise in gene expression as a determinant of virulence of the human pathogen Streptococcus pneumoniaeNot all cells in bacterial populations exhibit exactly the same phenotype, even though they grow in the same environment and are genetically identical. One of the main driving forces of phenotypic variation is stochasticity, or noise, in gene expression. Possible molecular origins contributing to noise in protein synthesis are stochastic fluctuations in the biochemical reactions of gene expression itself, namely transcription and translation. The driving hypothesis of this application is that the human pathogen Streptococcus pneumoniae utilizes noisy gene expression to successfully colonize and invade its host. To test this supposition, the total amount of noise in key regulatory networks for virulence factor production will be quantified. Using natural and synthetic bistable switches as highly sensitive probes for noise, in combination with state-of-the-art single-cell imaging, microfluidics and direct transcriptome sequencing, the molecular mechanisms underlying noise generation in S. pneumoniae will be determined. By constructing strains with altered levels of phenotypic variation, the importance of noisy gene expression in S. pneumoniae pathogenesis will be tested. S. pneumoniae is a leading cause of bacterial pneumoniae, meningitis, and sepsis worldwide. The molecular mechanisms that cause switching of S. pneumoniae to its virulent states are barely understood, although it becomes increasingly clear that noise-driven phenotypic variation plays an important role in pneumococcal pathogenesis. Therefore, understanding the molecular origins of phenotypic variation in S. pneumoniae might not only provide novel fundamental insights in gene expression, but also result in the identification of new anti-pneumococcal targets. : 31/10/2018 Mesenchymal Cells of the Lamina Propria in Intestinal Epithelial and Immunological Homeostasis.Mesenchymal cells (MCs) of the intestinal lamina propria refer to a variety of cell types, most commonly intestinal myofibroblasts, fibroblasts, pericytes, and mesenchymal stromal cells, which show many similarities in terms of origin, function and molecular markers. Understanding the physiological significance of MCs in epithelial and immunological homeostasis and the pathophysiology of chronic intestinal inflammatory and neoplastic disease remains a great challenge. In this proposal, we put forward the challenging hypothesis that, especially during acute or chronic inflammatory and tumorigenic conditions, MCs play important physiological roles in intestinal homeostasis regulating key processes such as epithelial damage, regeneration and tumorigenesis, intestinal inflammation and lymphoid tissue formation. We further posit that a unifying principle underlying such functions would be the innate character of MCs, which we hypothesize are capable of directly sensing and metabolizing innate signals from microbiota or cytokines in order to exert homeostatic epithelial and im munological regulatory functions in the intestine. We will be using genetic approaches to target innate pathways in MCs and state of the art phenotyping to discover the physiologically important signals orchestrating intestinal homeostasis in various animal models of intestinal pathophysiology. We will also study MC lineage relations and plasticity during disease and develop ways to interfere therapeutically with MC physiology to achieve translational added value for intestinal diseases, as well as for a range of other pathologies sharing similar characteristics.Regulation of inflammatory response by extracellular ATP and P2X7 receptor signalling: through and beyond the inflammasome.Inflammatory diseases affect over 80 million people worldwide and accompany many diseases of industrialized countries, being the majority of them infection-free conditions. There are few efficient anti-inflammatory drugs to treat chronic inflammation and thus, there is an urgent need to validate novel targets. We now know that innate immunity is the main coordinator and driver of inflammation. Recently, we and others have shown that the activation of purinergic P2X7 receptors (P2X7R) in immune cells is a novel and increasingly validated pathway to initiate inflammation through the activation of the NLRP3 inflammasome and the release of IL-1 and IL-18 cytokines. However, how NLRP3 sense P2X7R activation is not fully understood. Furthermore, extracellular ATP, the physiological P2X7R agonist, is a crucial danger signal released by injured cells, and one of the most important mediators of infection-free inflammation. We have also identified novel signalling roles for P2X7R independent on the NLRP3 inflammasome, including the release of proteases or inflammatory lipids. Therefore, P2X7R has generated increasing interest as a therapeutic target in inflammatory diseases, being drug like P2X7R antagonist in clinical trials to treat inflammatory diseases. However, it is often questioned the functionality of P2X7R in vivo, where it is thought that extracellular ATP levels are below the threshold to activate P2X7R. The overall significance of this proposal relays to elucidat< e how extracellular ATP controls host-defence in vivo, ultimately depicting P2X7R signalling through and beyond inflammasome activation. We foresee that our results will generate a leading innovative knowledge about in vivo extracellular ATP signalling during the host response to infection and sterile danger. : 31/8/2019Role of myeloid cells, their mediators and their antibody receptors in allergic shock (anaphylaxis) using humanized mouse models and clinical samplesAnaphylaxis is a hyperacute allergic reaction of increasing incidence that can be of fatal consequence and that has no specific treatment. Anaphylaxis is thought to rely on mechanisms involving mast cells that bear allergen-specific IgE and that release histamine when encountering allergen. Clinical cases, however, report anaphylaxis in the absence of specific IgE or medical history of allergy. We reported that murine models of anaphylaxis rely on IgG, rather than on IgE, that enable neutrophils, monocytes and basophils, rather than mast cells, to release Platelet Activating Factor following engagement of their IgG receptors. Supporting these findings, allergen-specific IgG are found in anaphylactic patients, and we reported that anaphylaxis in mice expressing a human IgG receptor relies also on circulating myeloid cells. We aim at unravelling the parameters that control anaphylaxis in a novel clinicallyrelevant model of drug-induced anaphylaxis, strengthened by human-based studies involved patients undergoing drug-induced anaphylaxis in collaboration with clinicians and, altogether, rethink the principles of anaphylaxis. Do allergen-specific IgG concur to anaphylaxis in humans? Do these IgG antibodies regulate IgE-induced reactions? Which IgG receptors are involved? In which tissue does the anaphylactic reaction start? Which cell type(s) are responsible? Among the mediators that are released, which ones are responsible for the shock? Can an anaphylactic reaction be stopped specifically for an allergen? We propose to address these questions by exploiting humanized mice we obtained and by establishing novel models, by visualizing anaphylactic reactions in real time in vivo, by dissecting the cascade of events leading to the shock. Finally, we aim at establishing the proof of concept of allergen capture/encapsulation and propose the first allergen-specific strategy for treating the life-threatening clinical situation that represents drug-induced anaphylaxis.How complement molecules kill bacteriaThis proposal aims to provide insight into how bacteria are killed by the complement system, an important part of the host immune response against bacterial infections. Complement is a large protein network in plasma that labels bacteria for phagocytosis and directly kills them via the formation of a pore-forming complex (Membrane Attack Complex (MAC)). Currently we do not understand how complement activation results in bacterial killing. This knowledge gap is mainly caused by the lack of tools to study the enzymes that trigger MAC formation: the C5 convertases. In my lab, we recently established a novel assay system for C5 convertases that allows us for the first time to study these enzymes under purified conditions. This model, combined with my expertise in microbiology, places my lab in a unique position to understand C5 convertase biology (Aim 1), determine the enzyme's role in MAC functioning (Aim 2) and elucidate how the MAC kills bacteria (Aim 3). Thus, I aim to provide insight into the molecular events necessary for bacterial killing by the complement system. I will use biochemical, structural and microbiological approaches to elucidate the precise molecular arrangement of C5 convertases in vitro and on bacterial cells. I will generate unique tools to study how C5 convertases regulate MAC insertion into bacterial membranes. Finally, I will engineer fluorescent bacteria and labeled complement proteins to perform advanced microscopy analyses of how MAC kills bacteria. These insights will lead to fundamental knowledge about the functioning of complement and will create new avenues for blocking the undesired complement activation during systemic infections and acute inflammatory processes. Furthermore this knowledge will improve desired complement activation by therapeutic antibodies and vaccination strategies in infectious diseases. Finally, this work opens up new possibilities to understand how both humans and bacteria regulate complement.mGeneration and maintenance of long-lived memory T cells in humansDefining the molecular mechanisms governing memory T cell differentiation and homeostasis is of pivotal importance to generate durable and protective T cell responses against infections and cancers. Considerable knowledge in this regard has been acquired in mouse models but is still limited about human T cells. In particular, some mechanisms are assumed to occur in humans but were never formally demonstrated. We showed that memory T cells adoptively-transferred with bone marrow transplantation failed to persist in recipient hosts in the absence of antigen. By contrast, self/tumorspecific na?ve T cells rapidly acquired T memory stem cell (TSCM) attributes and subsequently reconstituted the memory T cell pool by homeostatic differentiation. Current models indicate human TSCM cells as superior to conventional memory T cells in regards to effector potential and persistence capacity. Genome-wide expression analysis identified candidate TSCM cell-specific transcriptional regulators that were shown to inhibit senescence, promote self-renewal and regulate somatic differentiation. In this project, by using single cell technologies, primary human samples and in vivo humanized models, we will define the molecular mechanisms at the basis of memory T cell formation and maintenance in humans. We will initially define the antigenic requirement for the long-term persistence of memory T cells by following the fate of adoptively-transferred T cells. As the field remains unexplored, we will investigate the acquisition of memory attributes by self/tumor-specific T cells on multiple functional levels. The gene products specifically expressed by self-renewing TSCM cells will be finally tested for their capability to arrest T cell differentiation and generate long-lived memory T cells with enhanced stem cell-like properties. Our results will impact multiple physiological and pathological situations involving T cell-mediated immune responses.jPTX3 in Humoral Innate ImmunityThe innate immune system includes a cellular and a humoral arm. Structural diversity is a characteristic of humoral fluid phase pattern recognition molecules. These include complement components, collectins, ficolins, and pentraxins. We have used the long pentraxin PTX3, identified by the applicant (cDNA and genomic, mouse and human), as a prototypic fluid phase pattern recognition molecule to dissect its function, as well as to define general properties of humoral innate immunity and its interplay with the cellular arm. The general objective of this application is to explore unexpected vistas on humoral innate immunity, using PTX3 as a molecular tool. Specifically two hypothesis will be tested based on preliminary data. First the applicant will test the hypothesis that matrix and microbe recognition are related functions of PTX3 and that a microenvironmental signal (acidic pH) sets PTX3 in a matrix recognition, tissue repair mode. A second related line of work will focus on inflammation as a key component of the tumor microenvironment. The applicant will test the hypothesis that PTX3 and elements of the humoral innate immune system are essential components of cancer related inflammation. In< particular, based on preliminary data, the hypothesis will be tested that PTX3 acts as an extrinsic oncosuppressor in murine carcinogenesis and in selected human cancers by suppressing the recruitment of tumor-promoting inflammatory cells. These studies are expected to provide new unexpected vistas on the humoral arm of the innate immune system.oBio-inspired optical corrections of presbyopiaThe human crystalline lens has the capability to dynamically change its shape to focus near and far objects. By age 55, the accommodation capability is lost and optical aids are needed for near vision. Many questions remain open that are critical to understand accommodation, the failure in presbyopia, and the prospects for its correction. Multifocal presbyopic corrections are increasingly used. However, the ideal multifocal pattern, and the optical factors affecting depth-of-focus and adaptation to simultaneous vision remain to be elucidated. The most satisfactory treatment of presbyopia should rely on the restoration of the dynamic and continuous focusing ability of the eye, and this could be achieved in the form of accommodative intraocular lenses (IOLs). Current approaches, relying on potential IOL axial shifts, have proved little effective accommodative amplitude. The project will seek in nature innovative solutions to treat presbyopia. Deeper understanding of the crystalline lens changes with dynamic accommodation and aging will be gained. Novel imaging techniques will be developed and used to assess the dynamic changes of crystalline lens structure, gradient index distribution and microscopic structure of the lens fibers and capsule. In addition, the treatment of presbyopia by multifocal corrections will be explored. Wavefront sensing and optical coherence tomography will be used to understand the bases for the multifocality found in some animal species (as possible inspiration for multifocal patterns), and adaptive optics and visual simulation to understand the reasons for the limited performance of current multifocal treatments, to investigate neural adaptation to the blur in simultaneous vision and to test the proposed new multifocal patterns. Finally, the understanding of the crystalline lens properties and the biomechanics of the implanted IOLs gained in the project will allow to develop a first prototype of crystalline-lens mimicking accommodative IOL. : 30/4/2017iRadical Medicine: Redefining Oxidative StressOxidative stress, an excess of radical and other reactive oxygen species (ROS), has been suggested as a major disease mechanism. However, the major clinical trials using anti-oxidants have been failures, even suggesting serious side effects. Here, I propose completely different approaches: First, instead of letting radicals form and then scavenge them we will identify their diseases-relevant sources and prevent their formation or specifically repair the damage caused by ROS. Second, we will differentiate beneficial signalling roles of ROS. In combination, this will result in unprecedented precision and molecular specificity. In 2010, I submitted a somewhat related proposal to the ERC and received a comment as being  too focused on essential hypertension . This proposal has a much broader focus and impact beyond cardiovascular diseases. In the past months we achieved major breakthroughs by identifying a radical/ROS source (NOX4) as fundamental mechanism in stroke, the fastest growing and soon no 1 cause of death. We are also developing in phase II a radical formation inhibitor for neurotrauma. Moreover, our basic research facilitated the development of drug classes re-activating an oxidatively damaged signalling receptor, now in phase III. Further, we identified angiogenesis as a radical/ROS-dependent and protective (!) signalling event. This proposal is just the beginning: our basic science will open up new fields and leap forward in personalized medicine with groundbreaking technologies and approaches. We will contribute to the diagnosis and early identification of patients at risk and to monitor their successful treatment (in vitro/blood-based); to the localization of disease processes (in vivo/molecular imaging) before the onset of symptoms; and to a new generation of more effective, predictable, and mechanism-based drugs. We also expect to later apply our findings and tools to neurobiology and oncology, where ROS also play physiological and pathological roles. : 31/7/2017Triggerable nanomaterials to modulate cell activityThe advent of molecular reprogramming and the associated opportunities for personalised and therapeutic medicine requires the development of novel systems for on-demand delivery of reprogramming factors into cells in order to modulate their activity/identity. Such triggerable systems should allow precise control of the timing, duration, magnitude and spatial release of the reprogramming factors. Furthermore, the system should allow this control even in vivo, using noninvasive means. The present project aims at developing triggerable systems able to release efficiently reprogramming factors on demand. The potential of this technology will be tested in two settings: (i) in the reprogramming of somatic cells in vitro, and (ii) in the improvement of hematopoietic stem cell engraftment in vivo, at the bone marrow. The proposed research involves a team formed by engineers, chemists, biologists and is highly multidisciplinary in nature encompassing elements of engineering, chemistry, system biology, stem cell technology and nanomedicine.In silico and in vitro Models of Angiogenesis: unravelling the role of the extracellular matrixAngiogenesis, the formation of new blood vessels from the existing vasculature, is < a process that is fundamental to normal tissue growth, wound repair and disease. The control of angiogenesis is of utmost importance for tissue regenerative therapies as well as cancer treatment, however this remains a challenge. The extracellular matrix (ECM) is a one of the key controlling factors of angiogenesis. The mechanisms through which the ECM exerts its influence are poorly understood. MAtrix will create unprecedented opportunities for unraveling the role of the ECM in angiogenesis. It will do so by creating a highly innovative, multiscale in silico model that provides quantitative, subcellular resolution on cell-matrix interaction, which is key to the understanding of cell migration. In this way, MAtrix goes substantially beyond the state of the art in terms of computational models of angiogenesis. It will integrate mechanisms of ECM-mediated cell migration and relate them to intracellular regulatory mechanisms of angiogenesis. Apart from its innovation in terms of computational modelling, MAtrix impact is related to its interdisciplinarity, involving computer simulations and in vitro experiments. This will enable to investigate research hypotheses on the role of the ECM in angiogenesis that are generated by the in silico model. State of the art technologies (fluorescence microscopy, cell and ECM mechanics, biomaterials design) will be applied  in conjunction with the in silico model- to quantity cell-ECM mechanical interaction at a subcellular level and the dynamics of cell migration. In vitro experiments will be performed for a broad range of biomaterials and their characteristics. In this way, MAtrix will deliver a proof-of-concept that an in silico model can help in identifying and prioritising biomaterials characteristics, relevant for angiogenesis. MAtrix findings can have a major impact on the development of therapies that want to control the angiogenic response.uCounteracting psychosis by optimizing interactionPsychotic disorders are amongst the most severe mental disorders. However, current treatments have failed to reduce disability or change the prospects for recovery for patients with a psychotic disorder. In this project, I will investigate an entirely novel therapy, targeting the core vulnerability profile of altered person-environment interactions underlying psychosis, specifically increased stress-reactivity and reduced motivated and goal-directed behaviour. My colleagues and I have developed a digital apparatus, the  PsyMate , allowing real-time interventions for patients with severe mental illness. In this project, the PsyMate will be used to (1)reduce psychotic and emotional reactivity to stress with  detachment and acceptance exercises in real life situations, and (2)improve motivated and goaldirected behaviour with real-time behavioural activation therapy. In a randomized controlled trial, I will investigate whether this self-management therapy, conducted outside the office in the patient s real life, is capable of reducing psychotic reactivity to stress and of improving motivated behaviour in participants with an at-risk mental state for psychosis. In order to understand the impact of this intervention in terms of brain plasticity and prediction of response, I will use an experimental medicine approach to investigate the neural effects of the intervention. I will focus particularly on prefrontal dopamine-reactivity as the brain mechanism mediating altered person-environment interactions. In the current study, I will examine prefrontal dopamine reactivity towards positive as well as stressful negative events as the biological process mediating underlying motivated behaviour and environmental reactivity. Furthermore, I will investigate whether a self-management therapy specifically focused at aberrant person-environment interactions alters brain plast< icity at the level of prefrontal dopaminergic neurotransmission in persons at risk for psychosis.Improved Diagnosis and Management of Heart Disease by 4D Blood Flow AssessmentThe 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.fTowards evidence-based genomic medicine: filling the evidence gaps through modelling studiesAt increasingly high rate, genome-wide association and whole genome sequencing studies unravel genetic variants implicated in common diseases such as coronary heart disease, cancer, dementia and type 2 diabetes. One of the major promises is that these advances will lead to more personalized medicine, in which preventive and therapeutic interventions are targeted to individuals based on their genetic profile      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdeghijklmnopqrstuvwxyz{|}~s. There is increasing interest in the early adoption of novel applications and many commercial applications are already marketed without supporting empirical evidence. Already now, regulatory agencies like the US Food and Drug Administration face substantial gaps in empirical evidence, which hamper proper recommendations. The increasing interest in genomic medicine, the evidence gaps and the scarcity of research budgets are strong incentives to search for novel strategies that make the process of translation research more efficient and effective. This project aims to investigate modelling approaches that can be used to predict the expected outcomes of empirical studies on the basis of published epidemiological and intervention studies. This approach can be used to 1) identify genomic applications that are promising and warrant further empirical research, and 2) fill in evidence gaps by identifying applications that are not expected to improve health or health care. When they are valid, precise and simple, modelling studies can optimize the process of translational research so that time and money are allocated to the most promising applications. In this project, I will 1) characterize empirical studies in translational research in terms of the main outcome measures used and their key determinants; 2) develop simulation models that predict outcome measures; 3) investigate how accuracy and precision of the estimates vary with varying model complexity; and 4). investigate the generalizability of the modelling approaches.]Multistage-Multifunctional Porous Silicon Nanovectors for Directed TheranosticsThe progress of nanotechnology during the last decades has had a strong impact to the current research of biomedical applications, in particular against dreadful diseases such as cancer. It is estimated that more than 12 million cases of cancer are diagnosed every year worldwide. Multidrug resistance, rapid elimination by the immune system, enzymatic degradation, and poor targeting efficiency are still the major obstacles of the nanomedicines used in cancer therapy. The integration of imaging and therapeutic agents into a single carrier (theranostics) allows simultaneously detection, diagnostics, and treatment of the diseases, which may enhance both expectancy and quality of life of the patients. In the proposed project a systematic approach is taken towards developing and testing of novel multistage multifunctional nanovectors based on the fusion between stage-2 nanoporous silicon nanoparticles and stage-1 polymersomes (fused materials = protocells, cell-like particles) for directed (targeted/personalized) therapy and multimodal imaging. With this approach it is aimed to decouple the quadruple functions of the protocell nanovectors in order to generate relevant preclinical information for rapid translation into the clinic: sufficient multifunctionality to avoid biological barriers, recognition of their targets, accounting for non-invasive in vivo imaging and delivery of therapeutics. The overall distinct and final milestones are: to ligand-anchored, co-loading of drug(s)-dye(s), and dual radiolabelling of the precisely tailored protocell nanovectors for simultaneously targeting the tumour vasculature cells, stimulating the immune system response and multimodal imaging in vivo. It is also aimed to evaluate the suitability and effectiveness of the designed nanodevices by employing in vitro models and in vivo imaging techniques and to achieve a comprehensive and deeper understanding on the cellular interactions between the prot< ocell nanovectors and the cancer cells.Elucidating early pathogenic mechanisms of neurodegeneration in Parkinson's disease through a humanized dynamic in vitro modelOur understanding of Parkinson s disease (PD) pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic, most frequent, form of PD. It may be possible to overcome these challenges by reprogramming somatic cells from patients into induced pluripotent stem cells (iPSC). In preliminary studies, we have generated a collection of 50 iPSC lines representing both sporadic PD and familial PD patients, and identified distinct PD-related neurodegeneration phenotypes arising, upon long-term culture, in DAn differentiated from these PDiPSC. Here, I propose to take advantage of this genuinely human PD model to investiga te: i) mechanistic insights responsible for the PD phenotype identified in our model (by combining molecular and biochemical analyses to study mitochondrial function and redox profile, as well as genome-wide transcriptional profile of control versus PD-patient specific iPSC-derived DAn); ii) early functional alterations in patient-specific iPSC-derived DAn, which would predate neurodegeneration signs and provide valuable information as to ways to prevent, rather than rescue, neurodegeneration in PD patients (by electrophysiological recordings in in vitro reconstructed neuronal/glial networks to assess synaptic dynamics together with neuronal excitability); iii) further refinements in our iPSC-based PD model, including the generation of iPSC lines representing asymptomatic patients carrying pathogenic mutations, and the correction of known mutations by gene edition, all of which will allow exploring the relationship between pathogenic mutations and the genetic makeup of patients; and iv) whether DAn degeneration in PD is solely a cell-autonomous phenomenon, or whether it is influenced by an altered cross-talk between DAn and glial cells. These studies may impact significantly on our understanding of PD pathogenesis and on the development of new therapy strategy. : 30/6/2018Identification and functional validation of drugable targets/pathways for triple negative breast cancerPatients suffering from triple-negative breast cancer (TNBC) have a poor prognosis as these tumors frequently confer resistance against chemotherapeutic agents and lack drug targets such as estrogen receptor, progesterone receptor, and epidermal growth factor receptor 2. Insufficient knowledge on the biology of this specific breast tumor type and its heterogeneity hinder the identification of potential novel drug targets. Lethality enhancer screening is an ideal approach to identify new drug targets in tumors with specific genetic aberrations. We plan to adapt this concept of synthetic lethality by anticipating that while TNBC cells confer resistance to available anticancer drugs, specific knock down of particular genes by RNA-interference (RNAi) may result in a synergistic cell killing. Another important aspect of our approach is that we will concentrate in our screens on the top 500 candidate genes shown to be crucial in TNBC for cellular processes. The genes will be prioritized by Bayesian network analysis on prior knowledge on clinical TNBC from our own extensive genomics and proteomics studies, the literature, next generation sequencing efforts, and databases listing drugability of targets. We will employ RNAi-based knock down of drugable targets in 22 cell lines to reveal genes essential for drug resistance in TNBC. In addition to 2D cultures, screens will also be applied to 3D cultures, which are thought to better reflect the in vivo situation. The most effective combinations for each TNBC subtype will further be functionally investigated in vitro and in vivo to unravel the molecular nature of the synthetic lethality. Finally, translational studies will be performed to establish the potential clinical relevance of the identified targets/pathways in large numbers of human TNBC and non-TNBC tumors on tissue microarrays. It is expected that the newly designed (combination) therapies result in a decline in TNBC mortality and reduction of healthcare costs.Deciphering the regulatory T cell repertoire: towards biomarkers and biotherapies for autoimmune diseasesThe discovery of regulatory T cells (Tregs) is a breakthrough in immunology: it revolutionises our understanding of autoimmune disease (AID) pathophysiology and treatment opportunities. Treg numbers or function is defective in most mouse and human AIDs and their restoration induces clinical improvement, as we recently showed using low-dose IL-2 to induce Tregs in patients with AID. The TRiPoD project is based on 3 well supported assertions: - Tregs have huge therapeutic potential - Deep understanding of the Treg T cell receptor (TCR) repertoire is key to exploiting this potential - Deep sequencing technologies required for this purpose have come of age TRiPoD aims (i) to decipher the Treg repertoire against insulin and myelin at high resolution, (ii) to discover biomarkers for AIDs, and (iii) to develop therapies based on engineered Tregs. Deep sequencing of TCRs from insulin- and myelin-specific Tregs generated in vitro will identify dominant TCRs and antigen-specific Treg signatures. These will be analysed during thymocyte differentiation, at steady state and during disease progression, in mice and humans. Their potential as biomarkers (e.g. a Treg TCR specific for insulin for monitoring type 1 diabetes [T1D]) will be tested in experimental models and in clinical trials of IL-2 in T1D and multiple sclerosis (MS). < We will also generate antigen-specific Tregs expressing the dominant TCRs. These will be engineered for suicide gene expression to improve safety and for autocrine IL-2 production to ensure better survival and function. Ultimately, TRiPoD will contribute to a better understanding of the pathophysiology of T1D and MS, identify novel biomarkers for the follow-up of patients at high risk of, or with T1D or MS, and generate novel therapeutics for clinical development. More generally, our results and new approaches developed in TRiPoD should pioneer biomarker discovery and biotherapies in other immunopathologies.Isotopic records of solar nebula evolution and controls on planetary compositionsThis project has three linked strands that will combine to constrain the birth environment of the solar system and the nebular processes that shape bulk planetary compositions. Firstly, I will use ultra-high precision isotope ratio measurements in bulk meteorites to determine the stellar origin of the pre-solar of material that controls the gross compositional differences between planetary bodies. Secondly I will identify the mineralogical hosts of this isotopic variability, using in situ laser ablation analyses w ith a unique collision-cell multi-collector inductively coupled plasma mass-spectrometer, developed in close collaboration with an industrial partner (Thermo Fisher) as part of the project. Thirdly, I will establish a chronology for the mixing of the pre-solar material within the nebula, by dating individual meteorite components (chondrules) using  absolute Pb and relative 26Al-26Mg approaches and analysing the same aliquots for their mass-independent isotopic compositions. These observations will be quantitatively interpreted using novel numerical models of particle dynamics in the protoplanetary disk, in collaboration with Fred Cieala. This is an ambitious project that builds on the analytical prowess of the laboratory I have developed at Bristol and couples this with challenging technical developments and inter-disciplinary, modelling calculations. This work will radically improve our understanding of the history of the early solar system and the fundamental processes that shape its evolution.bHarnessing Cavitation for TherapyFocused Ultrasound Surgery (FUS) is rapidly emerging as a technique setting the gold-standard for the treatment of a wide range of diseases, including cancer. Current practise relies on the conversion of acoustic energy to thermal, for localised and minimally-invasive ablation with non-ionising radiation. Cavitation (the formation, and subsequent pressure driven dynamics, of bubbles) is a common occurrence at the high intensities typically employed for FUS. The extremely rapid, often violent evolution of cavitation in tissue exposed to focused ultrasound, poses a high risk of collateral damage to healthy tissue proximal to the site of pathology. TheraCav will demonstrate cavitation can be controlled and harnessed, to redefine the remit of FUS to include targeted drug delivery and rapid ablation formation via enhanced heating. Conceptually, cavitation could act to significantly permeabilise targeted tissue, rendering specific volumes highly susceptible to drug delivery through extravasation from the vasculature. Moreover, cavitation may actively pump and promote drug transport directly to the diseased tissue. If cavitation is to fulfil this potential, however, it is crucial that precise monitoring and control strategies are developed, demonstrating that it can be safely introduced and utilised tissue. Through a series of novel and ambitious objectives, TheraCav will develop techniques and devices to deliver this capability, calibrated against a recent innovation that has allowed the direct observation of cavitation at unprecedented spatial and temporal resolution. A series of translational work packages will test the monitoring and control strategies developed, in tissue-mimicking materials and ultimately soft-embalmed cadaver models, for anatomical verification. Finally, a radical and highly ambitious objective of activating photodynamic therapy drug compounds, via cavitation sonoluminescence and reactive oxygen species production, will be investigated. Development of 3D Histopathological Grading of OsteoarthritisBackground: Osteoarthritis (OA) is a common musculoskeletal disease occurring worldwide. Despite extensive research, etiology of OA is still poorly understood. Histopathological grading (HPG) of 2D tissue sections is the gold standard reference method for determination of OA stage. However, traditional 2D-HPG is destructive and based only on subjective visual evaluation. These limitations induce bias to clinical in vitro OA diagnostics and basic research that both rely strongly on HPG. Objectives: 1) To establish and validate the very first 3D-HPG of OA based on cutting-edge nano/microCT (Computed Tomography) technologies in vitro; 2) To use the established method to clarify the beginning phases of OA; and 3) To validate 3D-HPG of OA for in vivo use. Methods: Several hundreds of human osteochondral samples from patients undergoing total knee arthroplasty will be colle< cted. The samples will be imaged in vitro with nano/micro-CT and clinical high-end extremity CT devices using specific contrast-agents to quantify tissue constituents and structure in 3D in large volume. From this information, a novel 3D-HPG is developed with statistical classification algorithms. Finally, the developed novel 3D-HPG of OA will be applied clinically in vivo. Significance: This is the very first study to establish 3D-HPG of OA pathology in vitro and in vivo. Furthermore, the developed technique hugely improves the understanding of the beginning phases of OA. Ultimately, the study will contribute for improving OA patients quality of life by slowing the disease progression, and for providing powerful tools to develop new OA therapies.Exploring brain intracellular space using diffusion-weighted NMR spectroscopy in vivoAlterations of the intracellular space, including intracellular protein accumulation, organelle and cytoskeleton dislocation, and modifications in cell shape, are an early hallmark of many neurodegenerative processes. The ability to assess and quantify these alterations non-invasively would be of tremendous interest, not only in a clinical context, but also for preclinical research. However, no tool currently exists allowing such measurements. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) gives access to the apparent diffusion coefficient (ADC) of brain metabolites in vivo, which is related to their average quadratic displacement. Since metabolites are purely intracellular, their ADC is solely governed by the properties of the intracellular space. The dependency of the ADC on the delay during which displacement is measured (the  diffusion time Td) tells how metabolite motion deviates from free diffusion, which can in theory help untangle and quantify the different factors governing motion. So far, DW-MRS has only been performed in a limited number of studies, for Td ranging from ~10 to ~100 milliseconds, and has not yet demonstrated its ability to quantitatively assess the intracellular space. In the present work, we will develop cutting-edge DWMRS methods to probe brain metabolite motion for Td varying over several orders of magnitude (from ~0.1 milliseconds to ~10 seconds). The dependency of the ADC over Td will provide unique insights about the mechanisms governing metabolite motion at very different scales. Data will be modeled to quantitatively extract parameters such as the intracellular viscosity, the size of intracellular structures, and cell shape and size. Estimated parameter values will be compared to values derived from other techniques, such as microscopy. Finally, developed methods will be used to investigate early alterations of the intracellular space in animal models of neurodegeneration. : 30/11/2018Clinical ultrasound platform for the quantitative and longitudinal imaging of theranostics and cellular therapyThe success of modern medical treatments such as cellular therapy and targeted treatments requires appropriate tools for in vivo monitoring. Imaging modalities, such as magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) are key candidates due to their noninvasive nature. However, these imaging techniques are extremely expensive and can involve radiation, both of which hinder their longitudinal and repetitive use. Ultrasound has so far been unsuitable due to the absence of a label to differentiate regions of interest from tissue background, the main problem being that current ultrasound contrast agents (CAs) have active lifetimes in the order of minutes. The CoNQUeST platform (Clinical Nanoparticles for Quantitative Ultrasound with high STability) proposed here is an entirely new type of ultrasound CA that is extremely stable (lifetime of a year) and is not affected by insonation. This mechanism of contrast generation appears completely novel: The polymeric particles are under 200nm in diameter and must contain a soluble metal (M.Srinivas et al., patent pending, filed 09/2012). Based on the current state of the art, these particles are too small and do not contain the requisite gaseous component for ultrasound contrast. CoNQUeST particles are applicable to longitudinal and repeated imaging, as is necessary for cell tracking, due to their stability. Furthermore, these particles can be chemically bound to targeting agents, dyes and drugs, and are suitable for multimodal imaging, including MRI (both 1H and 19F), fluorescence and SPECT. Finally, the CoNQUeST agents are suitable for clinical use. I propose the application of the CoNQUeST agents to a clinical trial for tracking dendritic cell therapy in melanoma patients, longitudinal theranostic imaging in preclinical models and thorough characterisation of this novel mechanism of ultrasound contrast generation.Cultured Liver Organoids for Investigation and Treatment of Inherited Cho< lestatic DiseasesBile synthesis and secretion are crucial to liver function and involve multiple proteins. Disorders due to defects in this process (Inherited Cholestatic Disorders, ICDs) lead to progressive liver disease. Many ICD patients do not respond to medical treatment and need liver transplantation (LT). Although ICDs are rare, multifactorial cholestatic diseases are common and many patients will benefit from ICD research. There is acute shortage of liver donors. 10% of patients die while waiting on the liver transplant list. Therefore alternatives to LT are urgently needed. Bioengineered tissues may reduce the need for donor organs but complexity of it's organisation makes generation of functional liver challenging. The OBJECTIVE of this project is to generate Cultured Liver Organoids (CLOs) using hepatocytes cultured on 3-D scaffolds as novel models for study of liver development and disease and potential treatment of ICDs. 3-D extracellular matrix (ECM) scaffolds derived from decellularised livers and polymeric matrices (PM) have been used to mimic liver architecture but further work is needed to establish functional bile flow. Human Induced Pluripotent Stem Cells (hIPSCs) derived from reprogrammed skin fibroblasts by overexpression of pluripotency factors can proliferate and be differentiated into various cell types including hepatocytes. hIPSCs enable production of patient specific cells, which are fully immuno-compatible. Genetically corrected mutant hIPSCs differentiated into hepatocytes have been used as cell therapy in animal models of inherited metabolic disorders but direct infusion of hepatocytes into the liver is unlikely to achieve polarised bile flow and correct ICDs. Therefore hIPSCs developed from ICD patients will be used to culture hepatocytes on decellularised mouse liver ECM to generate in vitro models of ICDs. CLOs containing hepatocytes from genetically corrected hIPSC will be tested in mouse models of ICDs as potential treatment. Towards understanding cerebral small vessel disease: Innovative, MRI-based, functional markers to discover the terra incognita between large vessels and macroscopic brain lesionsSmall vessel disease (SVD) causes 25% of all cerebral strokes and is a major cause of cognitive decline (dementia) and functional disability (ageing) in the elderly. Two important challenges hamper the development of effective treatments. First, still little is known about the mechanism by which SVD leads to macroscopic, ischemic brain damage and, thus, to cognitive decline. Second, the current clinical markers and image-based markers of SVD do not reflect SVD itself, but macroscopic brain damage secondary to SVD. Unlike large vessels, small vessels are not visible with current imaging techniques, which leave, thus, a  terra incognita of small vessel pathology between large vessels on the one hand, and macroscopic brain damage on the other. The aim of this program is to remove the major current obstacle towards developing effective treatments for SVD, by innovative magnetic resonance imaging (MRI) techniques that yield non-invasive markers of small vessel (dys)function in the human brain. I will use two innovative sets of image-based markers to discover the  terra incognita . The first set comprises pulsatile tissue motion, strain and potential pulsations in the capillary flow, recognizing the role of stress and strain in cell function (including endothelial cells and neurons). The second set uses the perivascular fluid as an endogenous marker of the blood-brainbarrier function, which is located in the endothelium of the small vessels. These innovative, imagebased markers will open a window towards the mechanism by which SVD leads to brain damage. Further, these markers will enable the selection and monitoring of patients who are eligible for new treatments. I will obtain the required sensitivity and resolution, by exploiting the benefits of high field MRI (7T). I am experienced in cardiac strain imaging, high field brain imaging, and have been successful in multiple translational projects that have introduced new MRI technology into patient studies.]Citicoline and deoxyglucose as new molecular imaging probes of DNP hyperpolarized MRI for cancer and neuroimagingRadioactively labeled deoxyglucose and choline are the leading molecular imaging probes for positron emission tomography (PET). The clinical applications for this imaging modality include brain function, cardiac imaging, and inflammation, along with oncological applications which are taking the lead. The radiation exposure associated with these examinations is limiting the use of this powerful technology in repeated examinations, in specific populations (pregnant women and children), as a screening tool for the wide population, and as a clinical research tool. Hyperpolarized magnetic resonance imaging (MRI) is an evolving pre-clinical and clinical imaging modality which is non-invasive and nonradioactive. As in PET, the molecular imaging probe used is at the heart of this examination. Originally developed for the purpose of distinguishing the metabolic products of the injected molecular probe, our group, in collaborations with researchers abroad, is a pioneer in showing that direct imaging of specific molecular probes (stable isotope labeled choline and glucose analogs) with hyperpolarized MRI is capable of showing specific tissue uptake, a pre-requisite for diagnostic imaging. The purpose of the current proposal is to establish hyperpolarized MRI capabilities in our own lab and reach two g< eneral goals: 1) to use various physiological and pharmacological models to further establish and characterize the conditions in which non-radioactive choline and glucose analogs and derivatives can be useful as imaging probes; and 2) to investigate further the molecular probe that is best suitable for these imaging applications in terms of pharmacokinetics, metabolism, and imaging efficiency. Our focus will be on 1) the actual chemical entity of the probes - where citicoline and deoxyglucose are promising candidates; and 2) the stable isotope labeling strategy. The overriding goal is to aid in translation of this pre-clinical imaging approach to clinical use.JVascular remodelling and miRNA therapeuticsThe central hypothesis of VascmiR is that microRNAs (miRs) fundamentally control pathological remodelling of the vasculature. The complexity of vascular bed heterogeneity and subsequent response to injury, the potential importance of miRNA in vascular pathology and the paucity in knowledge relating to many facets of miRNA function in the vessel wall including target pathways, mechanistic features of miRNA-mediated cell:cell communication mediated by miRNA export and uptake etc. provides an excellent opportunity for groundbreaking basic and translational research in the field. VascmiR will envelop these concepts in a broad, cutting edge portfolio of high risk and indepth studies that encompass fundamental research, mouse genetics to create novel models and miR intervention studies in small and large animal models coupled with targeted miRNA therapeutics. Collective synergy by assessing pulmonary as well as peripheral venous and arterial pathological vascular remodelling models of disease under a single funding mechanism will afford substantial scientific advancement. VascmiR will go beyond current state-of-the-art and create new knowledge of miRNA in vascular pathologies, all of which have important unmet clinical need. VascmiR will streamline fundamental new opportunities for targeted miRNA-based therapeutics to improve human health in cardiovascular setting. I envisage that a co-ordinated, multifaceted and integrative programme in these vascular pathology settings to better understand the mechanistic role of miRNA in vascular remodelling will have a major impact on the field, leading to early translation of advanced miRNA therapeutics in the vasculature.SSeeing through cataracts with advanced photonicsCataract is the opacification of the crystalline lens of the human eye. It is usually related with age and is one of the leading causes of blindness. The increase in light scatter in the lens reduces the contrast in the retinal images severely degrading vision. The current solution is to perform surgery to remove the natural lens that is substituted by an artificial intraocular lens. This is a successful procedure restoring good quality of vision in most patients. However, in many situations it would be incredible advantageous to actually  see through a cataractous eye. The optics of the eye is affected by two factors: aberrations and scatter. In the last decade, correcting optical aberrations in the eye was accomplished by using adaptive optics techniques. This permitted to obtain high resolution images of the retina and also to improve vision. However, the possibility of correcting scatter in the eye was never considered before. We propose here the use of spatial and temporal advanced photonics techniques for imaging through the turbid media of the cataractous lens. We envision two direct applications of this technology: a dedicated fundus camera to register images of the retina in patients affected by cataracts and a novel type of opto-electronics spectacles restoring some vision in cataract patients. The fundus camera would offer clinicians the unique opportunity to determine if there is any retinal pathology underneath the cataractous eye. The scatter-correcting goggles would be useful in those cases where surgery were not possible for any reason or as a temporarily relieve until the surgery is performed. The same type of technology could be applied in the case of normal eyes with lower levels of scatter but desiring to achieve a better than normal vision for some specific tasks. This proposal presents a completely new and disruptive idea, which if successful would render immediate and significant benefits to patients worldwide.Surface-Based Molecular Imprinting for Glycoprotein RecognitionThere is now overwhelming evidence that glycosylation changes during the development and progression of various malignancies. Altered glycosylation has been implicated in cancer, immune deficiencies, neurodegenerative diseases, hereditary disorders and cardiovascular diseases. Currently, antibodies are playing a central role in enabling the detection of glycoprotein biomarkers using a variety of immunodiagnostic tests. Nonetheless, antibodies do have their own set of drawbacks that limit the commercialization of antibody sensing technology. They suffer from poor stability, need special handling and require a complicated, costly production procedure. More importantly, they lack specificity because they bind only to a small site on the biomarker and are not able to discriminate, for instance, among different glycosylated proteins. The current antibody diagnostic technology has well recognized limitations regarding their accuracy and timeliness of diagnose of disease. This project will focus on research into the means of developing a generic, robust, reliable and cost-effective alternative to monoclonal antibody technology. The project aims to exploit concepts and tools from nanochemistry, supramolecular chemistry and molecular imprinting to provide h< ighly innovative synthetic recognition platforms with high sensitivity and specificity for glycoproteins. Such novel type of platforms will make a profound and significant impact in the broad fields of biosensors and protein separation devices with applications in many areas such as biomedical diagnostics, pharmaceutical industry, defense and environmental monitoring. The proposed technology may open an untraveled path in the successful diagnosis, prognosis and monitoring of therapeutic treatment for major diseases such as cancer, immune deficiencies, neurodegenerative diseases, hereditary disorders and cardiovascular diseases. : 30/11/2019Disabling Radiotherapy resistance in Cancer TreatmentCancer is a devastating disease affecting 1 in 3 people in their lifetime. The incidence is rising because of our aging population and causes a huge economic impact on our society because of hospitalization and lost productivity. Radiotherapy alone or in combination with surgery and/or chemotherapy is used in ~50% of all patients and uses ionizing radiation to induce DNA breaks that are lethal to cells. While significant progress has been made, radiotherapy is often limited because of side-effects in normal tissues and tumor control often fails because of resistance and metastases. Novel treatment paradigms are urgently needed. Among the key classical biological factors that determine radiation response in normal and tumor cells are the 4R; Reoxygenation, Repopulation, Redistribution and Repair. They are determined by intrinsic (genetic) as well as extrinsic factors from the tumor microenvironment and underlie tumor heterogeneity a hallmark of cancers and a decisive factor in clinical response. Yet, standard cancer treatments are largely based on the flawed assumption that tumors are homogenous within and between patients. We hypothesized that NOTCH signaling and tumor hypoxia cause tumor heterogeneity and are tumor selective therapeutic targets. First we will study key biological mechanisms that determine intra tumor heterogeneity, second we will establish their role in therapy response and third we will exploit this knowledge to enhance radiotherapy and provide proof of concept of a highly innovative approach to selectively activate cancer therapeutics targeting the NOTCH stem cell pathway in therapy resistant tumor cells without adverse effects in normal tissues. DIRECT interrogates the molecular details of key cancer therapy response parameters providing opportunities for the next generation of tumor cell specific treatments that improve disease outcome. : 30/4/2019gGenetics-driven targeted therapy of Hairy Cell LeukemiaHairy Cell Leukemia (HCL), a chronic B-cell neoplasm, is initially sensitive to chemotherapy with purine analogs, but ~40% of patients eventually relapses and becomes less responsive to these drugs. Furthermore, purine analogs may cause myelotoxicity, immune-suppression and severe opportunistic infections. Therefore, molecularly-targeted less toxic drugs are highly desirable in HCL. However, its low incidence and the initial efficacy of purine analogs has made HCL an orphan in the world of cancer research and has spoiled the academic and industrial interest in developing better treatments for this disease. But recently we identified the V600E activating mutation in the BRAF kinase as the key genetic lesion of HCL (similar to BCR-ABL1 in chronic myeloid leukemia). Orally available specific BRAF inhibitors (e.g., Vemurafenib) have in the meantime showed remarkable efficacy in melanoma patients harboring the BRAF-V600E mutation, although resistance to such drugs eventually develops in this malignancy through reactivation of MEK (the downstream target of BRAF). The ground-breaking objective of this project is to introduce for the first time in HCL, by means of phase-2 investigatordriven pilot clinical trials, the concept of BRAF and/or MEK inhibition as an oral, non chemotherapybased, entirely out-patient, genetics-driven and rationally designed treatment strategy, first in patients with active disease despite (or severe toxicity from) previous chemotherapy with purine analogs, and then, potentially, in the frontline setting. In comparison to melanoma, deeper and longer effect of BRAF inhibition may be expected in HCL, due to its much lower genetic complexity and proliferation rate. Anyway, potential mechanisms of resistance will be searched for to identify other genes recurrently mutated or aberrantly expressed in HCL patients developing resistance to BRAF inhibition(if any), and the clinical feasibility of combined BRAF and MEK inhibition will be addressed.Common Oncogenic Mechanisms in Multi-Partner Translocation Families in Acute Myeloid LeukemiaAcute Myeloid Leukemia (AML) is the most frequent cancer of the blood system, with >80% mortality within 5 years of diagnosis. Straightforward clinical decisions are complicated by the genetic complexity of AML. In particular, fusion proteins arising from chromosomal aberrations are recurrently found in AML and often act as strong driver oncogenes. In  Multi-Partner Translocation (MPT) families, one specific gene is fused to many recipient loci. Due to this modular architecture, MPT families are of particular interest to comparative studies of oncogenic mechanisms. The three most common MPT families in AML represent translocations of the MLL, RUNX1 and NUP98 genes. Despite their clinical significance, the molecular mechanism of transformation remains unknown for the majority of fusion proteins and it is unclear if transforming mechanisms are conserved within and across different MPT families.We hypothesize that common oncogenic mechanisms of fusion proteins are encoded in physical and genetic cellular interaction networks that are specific to MPT families. We propose to delineate critical common effectors of oncogenic mechanisms in AML driven by MPT families through a comprehensive, comparative, functional analysis of 20 clinically representative MLL-, RUNX1- and NUP98-fusion proteins using a unique experimental pipeline. Characterization of protein interactomes and their effects on gene expression will identify common cellular denominators of MPT families,< whose functional contribution will be assessed through pooled shRNA screens in clinically relevant model systems. High-confidence hits will be validated in mouse models and primary cells from AML patients. This project will generate large informative datasets and novel experimental systems that are of relevance for basic and clinical cancer research. It will contribute to improved understanding of oncogenic mechanisms, which may directly impact on diagnostic and therapeutic strategies in the management of AML.Frontier Research on the Dielectric Properties of Biological TissueThe dielectric properties of biological tissues are of fundamental importance to the understanding of the interaction of electromagnetic fields with the human body. These properties are used to determine the safety of electronic devices, and in the design, development and refinement of electromagnetic medical imaging and therapeutic devices. Many historical studies have aimed to establish the dielectric properties of a broad range of tissues. A growing number of recent studies have sought to more accurately estimate these dielectric properties by standardising measurement procedures, and in some cases, measuring the dielectric properties in-vivo. However, these studies have often produced results in direct conflict with historical studies, casting doubt on the accuracy of the currently utilised dielectric properties. At best, this uncertainty could significantly delay the development of electromagnetic imaging or therapeutic medical devices. At worst, the health dangers of electromagnetic radiation could be under-estimated. The applicant will embark upon frontier research to develop improved methods and standards for the measurement of the dielectric properties of biological tissue. The research programme will accelerate the design and development of electromagnetic imaging and therapeutic devices, at a time when the technology is gaining significant momentum. The primary objective of the research is to develop a deep understanding of the fundamental factors which contribute to errors in dielectric property measurement. These factors will include in-vivo/ex-vivo measurements and dielectric measurement method used, amongst many others. Secondly, a new open-access repository of dielectric measurements will be created based on a greatly enhanced understanding of the mechanisms underlying dielectric property measurement. Finally, new electromagnetic-based imaging and therapeutic medical devices will be investigated, based on the solid foundation of dielectric data.NHow to regenerate the mammalian kidneyKidney non-endocrine functions are primarily performed by millions of individual integral units called nephrons. Although the adults of simple vertebrates (fish, amphibians and reptiles) have the ability to regenerate entire nephrons by a process called  nephron neogenesis , this capacity is absent in birds and mammals. In this regard we have observed, for the first time, that the murine neonatal kidney is able to generate new nephrons after the resection of the 20 per cent of the kidney mass. In the same manner, our recent published data on the generation of human kidney organoids ex vivo from kidney disease derived induced pluripotent stem cells (iPS), demonstrates the suitability of iPS technology to establish an unprecedented platform for drug screening, disease modelling and kidney regeneration.Thus, with support from REGMAMKID we will carry out a dual strategy for kidney regeneration and therapy. For kidney regeneration, we will make use of our newly developed mouse model of neonatal kidney regeneration and identify the molecular and epigenetic drivers responsible for this process. For kidney therapy, we will generate specific kidney cell populations with therapeutic potential such as podocytes and tubular epithelial cells by combining emerging cutting-edge technologies from the fields of cellular reprogramming and pluripotent stem cells differentiation. Making use of the tools developed in REGMAMKID we will model two different genetic kidney disorders: one affecting the podocyte (Congenital Nephrotic Syndrome) and other leading to an excessive proliferation of tubular epithelial cells (Autosomal Dominant Polycistic Disease). These studies will significantly impact on our understanding of kidney disease and healing.Study on Environmental and GenomeWide predictors of early structural brain Alterations in Young studentsMounting evidence suggests that early life factors have an important impact on the occurrence of latelife neurological diseases. From a public health perspective this is of particular relevance for dementia, the prevalence of which is increasing drastically, with no available preventive treatment, and epidemiological data suggesting that pathological processes may begin many years before clinical diagnosis. MRI-defined structural brain phenotypes are powerful intermediate markers for dementia, and can already show measurable alterations in young and middle-aged adults. These include global and regional brain volumes, gray matter volume and cortical thickness, and markers of white matter integrity. The SEGWAY project aims to: (i) explore the heritability and genetic determinants of structural brain phenotypes in young adults in their early twenties participating in the i-Share study, the largest ongoing student cohort; (ii) take a lifetime perspective by examining the shared genetic contribution to structural brain alterations in young adulthood (i-Share) and late-life, among participants of a large French population-based study (3C-Dijon); (iii) explore the interaction between genetic variants and vascular risk factors with established impact on structural brain phenotypes, in both age groups; (iv) examine the clinical significance of genetic risk variants for structural brain alterations by testing their association with cognitive performance in young < and older adults. Replication and of our findings will be sought in the multigenerational Framingham Heart Study and other independent samples. Identifying common biological mechanisms underlying both early and latelife structural brain changes would provide important information on the mechanisms and timecourse of brain aging throughout a lifetime and could be of major importance for identifying of molecular drug targets and characterizing high risk populations most likely to benefit from early interventions. : 30/11/2020gTranslating Hybrid Imaging for Interventions: Intra-operative Guidance and Evaluation using 2D and 3D Interventional X-ray Scintigraphy ImagingI propose to research, build and evaluate Interventional X-ray and Scintigraphy Imaging (IXSI). This will provide for the first time real-time, multimodality imaging during medical interventions by combininglive x-ray and live nuclear imaging simultaneously from an identical viewpoint. The hybrid x-ray/nuclear imaging device will enable surgeons and interventional radiologists to exploit the power of molecular imaging in the operating theatre and intervention room through i) live guidance using 2D imaging and ii) 3D quantitative evaluation (IXSI3D). Systems, like the successful PET/CT and SPECT/CT, have revolutionized diagnostic medical imaging; however they acquire x-ray (anatomical information) and nuclear images (molecular information) in sequence. Our new technology brings live, hybrid imaging to operations and interventions. This will have a broad and powerful impact, particularly in oncological applications, including internal radiotherapy, tumor resection and biopsies.For combined X-ray/nuclear imaging, an x-ray tube, an x-ray detector and a gamma camera with collimator are required. Our concept relies on placing these three elements in one line, thus enabling imaging of the same field-ofview. However, straight-forward combination of these elements would block the line of views. Inspired by how eyes see around the nose, I invented a gamma camera geometry that sees around the x-ray tube. I have created a prototype, and using a provisional set-up based on this novel concept (patent pending), I have demonstrated IXSI s basic principles. This proposal describes the quantum leap in medical imaging: clinical realization of IXSI for guidance, and the development of IXSI3D that enables intra-operative quantitative evaluation. I will develop algorithms and hardware, build a mobile system and prove it s potential in a clinical research protocol. This will be the start of a new era in imageguided intervention.sCancer treatment during pregnancy: from fetal safety to maternal efficacyThe evolution in drug regulation of the last 50 years has left pregnant women and their fetuses orphaned. This is particularly problematic for cancer during pregnancy, which raises a difficult and conflicting medical ethical decision process and which has recently become increasingly frequent. In 2012 we published the first prospective study indicating that antenatal exposure to cancer treatment can overall be considered safe. Building on this proof of concept, the current proposal wants to take a groundbreaking step towards developing a standard of care for cancer during pregnancy by addressing  in an integrated fashion- the challenges at the level of the fetus, the mother and the fetomaternal barrier. At the core of this proposal lies an international registry of pregnant women with cancer, along with a registry of their children, and biobanks of maternal, placental, cord blood and tumoral tissues. Research track  child aims to deliver robust evidence of fetal safety. Research track  mother aims to address the emerging concerns in the oncological management of the mother, and specifically, the possible distinct biology of pregnancy-associated breast cancer, the most frequent cancer type in pregnancy. The research approach includes large-scale clinical follow-up studies along with laboratory studies on patient biomaterials, including pharmacological investigations and RNA-sequencing studies. Complementary to these studies is research track  placenta in which cutting-edge models of human placental research are used to a< ddress the poorly understood physiological basis of the placental barrier function in this specific situation. This ambitious program will rely on a multidisciplinary team of experts. Not only may the scientific deliverables of this proposal constitute a major step forward to the well-being of both mother and fetus in a pregnancy complicated by cancer, the methodological approach may also provide critical impetus to further research in this field.Unravelling the Genomic Targets of Drugs Using High-Throughput SequencingThis proposal is centred on the development of small molecule probes derived from DNA damaging agents to identify their genomic targets using a novel unbiased approach. Although, several genotoxic drugs have been used for decades to treat cancers, the exact mechanisms by which they operate are not fully understood. It is established that these compounds interfere with the processes of transcription and replication, thereby promoting genomic instability and cell death. However, there is as yet no genome-wide map of the exact location of sites that are putative targets for these drugs in vivo. This information is critical to understand and rationalize cellular responses to genotoxic agents. Here, we propose to develop an innovative discovery- based methodology that will combine click chemistry in situ, affinity pull-down techniques and high throughput DNA sequencing (Drug-Seq), to identify the genomic interactome of DNA damaging drugs in order to elucidate their cellular activity at the molecular level. Two independent lines of enquiry will be followed. Firstly, we will establish the genomic interacting landscape of landmark drugs including etoposide, camptothecin and cisplatin using Drug-Seq. Secondly, we will perform regular chromatin immuno- precipitation sequencing (ChIP-Seq) of selected proteins linked to the cellular response of interest to validate Drug-Seq and further identify druggable genomic sites. An important aim of this proposal is to establish a universal methodology to decipher small molecule/genome interactions in vivo that trigger a particular response in diseaserelevant models. We also seek to interrogate the role of chromatin in regulating drug/genome interactions and to define whether it is possible to act on the epigenome to modulate the activity and specificity of these drugs. Collectively, we anticipate our study will lay down the foundation for personalized medicine with the implementation of rational rather than empirical clinical protocols.;Laser-induced vapour nanobubbles for intracellular delivery of nanomaterials and treatment of biofilm infectionsLasers have found widespread application in medicine, such as for photothermal therapy. Gold nanoparticles (AuNPs), are often used as enhancers of the photothermal effect since they can efficiently absorb laser light and convert it into thermal energy. When absorbing intense nano- or picosecond laser pulses, AuNPs can become extremely hot and water vapor nanobubbles (VNBs) can emerge around these particles in tissue. A VNB will expand up to several hundred nm until the thermal energy from the AuNP is consumed, after which the bubble violently collapses, causing mechanical damage to neighbouring structures. In this project the aim is to make use of the disruptive mechanical force of VNBs to enable highly controlled and efficient delivery of macromolecules and nanoparticles in cells and biofilms. First, optical set-ups and microfluidics devices will be developed for high-throughput treatment of cells and biofilms. Second, VNBs will be used to achieve efficient cytosolic delivery of functional macromolecules in mammalian cells by cell membrane perforation or by inducing endosomal escape of endocytosed nanomedicine formulations that are functionalized with AuNPs. These concepts will be applied to tumorigenesis research, generation of induced pluripotent stem cells and modulation of effector T-cells for adoptive T-cell anti-cancer therapy. Third, contrast nanoparticles for cell imaging will be delivered into the cytosol of mammalian cells through VNB induced cell membrane perforation. This will enable more reliable in vivo imaging of labelled cells, labelling of subcellular structures for time-lapse microscopy and intracellular biosensing. Finally, [... confidential...] laser-induced VNBs will be used [... confidential...] for improved eradication of biofilms. This concept will be applied to biofilm infections in dental root canals and chronic wounds. Novel Gene Therapy Based on the Activation of Endogenous Genes for the Treatment of Ischemia -Concepts of endogenetherapy, release of promoter pausing, promoter-targeted ncRNAs and nuclear RNAiBackground: Therapeutic angiogenesis with vascular endothelial growth factors (VEGFs) has great potential to become a novel, minimally invasive new treatment for a large number of patients with severe myocardial ischemia. However, this requires development of new technology. Advancing stateof-the-art: We propose a paradigm shift in gene therapy for chronic ischemia by activating endogenous VEGF-A,-B and -C genes and angiogenic transcription programs from the native promoters instead of gene transfer of exogenous cDNA to target tissues. We will develop a new platform technology (endogenetherapy) based on our novel concept of the release of promoter pausing and new promotertargeted upregulating short hairpinRNAs, tissue-specific superenhancerRNAs activating specific transcription centers involving gene clusters in different chromosomal regions, small circularRNAs formed from self-splicing exons-introns that can be regulated with oligonucleotides and small molecules such as metabolites, nuclear RNAi vectors and specific CRISPR/gRNAmutatedCas9-VP16 technology with an ability to target integration into genomic safe harbor sites. After preclinical studies in mice and in a newly developed chronic cardiac ischemia model in pigs with special emphasis on the analysis of clinically relevant blood flow, metabolic and functional outcomes based on MRI, ultrasound, photoacoustic and PET imaging, the best construct will be taken to a phase I clinical study in patients with severe myocardial ischemia. Since endogenetherapy also involves epigenetic changes, which are reversible and long-lasting, we expect to efficiently activate natural angiogenic programs. Significance: If successful, this approach will begin a new era in gene therapy. Since there is a clear lack of technology capable of targeted upregulation of endogenous genes, the novel endogenetherapy approach may become widely applicable beyond cardiovascular diseases also in other areas of medicine and biomedical research.Evolution of Pathogen and Host DiversityThe study of host-pathogen systems is of central importance to the control of infectious disease, but also provides unique opportunities to observe evolution in action. Many pathogen species have diversified under selection pressures from the host; conversely, genes that are important in host defence also exhibit high degrees of polymorphism. This proposal divides into two parts: (1) the evolution of pathogen diversity under host immune selection, and (2) the evolution of host diversity under pathogen selection. I have developed a body of theoretical work showing that discrete population structures can arise through immune selection rather than limitations on genetic exchange. The predictions of this framework concerning the structure and dynamics of antigenic, metabolic and virulence genes will be empirically tested using three different systems: the bacterial pathogen, Neisseira meningitidis, the influenza virus, and the malaria parasite, Plasmodium falciparum. The current theory will also be expanded and modified< to address a number of outstanding questions such whether it can explain the occurrence of influenza pandemics. With regard to host diversity, we will be attempting to validate and extend a novel framework incoporating epistatic interactions between malaria-protective genetic disorders of haemoglobin to understand their intriguing geographical distribution and their mode of action against the malarial disease. We will also be exploring the potential of mechanisms that can organise pathogens into discrete strains to generate patterns among host genes responsible for pathogen recognition, such as the Major Histocompatibility Complex. The co-evolution of hosts and pathogens under immune selection thus forms the ultimate theme of this proposal. : 31/5/2017The architecture of adaptation to novel environmentsOne of the central goals in evolutionary biology is to understand adaptation. Experimental evolution represents a highly promising approach to study adaptation. In this proposal, a freshly collected D. simulans population will be allowed to adapt to laboratory conditions under two different temperature regimes: hot (27癈) and cold (18癈). The trajectories of adaptation to these novel environments will be monitored on three levels: 1) genomic, 2) transcriptomic, 3) phenotypic. Allele frequency changes during the experiment will be measured by next generation sequencing of DNA pools (Pool-Seq) to identify targets of selection. RNA-Seq will be used to trace adaptation on the transcriptomic level during three developmental stages. Eight different phenotypes will be scored to measure the phenotypic consequences of adaptation. Combining the adaptive trajectories on these three levels will provide a picture of adaptation for a multicellular, outcrossing organism that is far more detailed than any previous results. Furthermore, the proposal addresses the question of how adaptation on these three levels is reversible if the environment reverts to ancestral conditions. The third aspect of adaptation covered in the proposal is the question of repeatability of adaptation. Again, this question will be addressed on the three levels: genomic, transcriptomic and phenotypic. Using replicates with different degrees of genetic similarity, as well as closely related species, we will test how similar the adaptive response is. This large-scale study will provide new insights into the importance of standing variation for the adaptation to novel environments. Hence, apart from providing significant evolutionary insights on the trajectories of adaptation, the results we will obtain will have important implications for conservation genetics and commercial breeding.Genomics of adaptive divergence in FungiUnderstanding the genetic and genomic processes behind adaptive phenotypes remains a holy grail in biology. Fungi are poorly studied regarding these processes, despite their great tractability as model eukaryote organisms and their medical, industrial, and ecological importance. This project therefore aims to investigate the major evolutionary forces in the adaptive divergence of fungi  as model eukaryotes with small genomes by the integration of high-throughput sequencing and innovative approaches. Two groups of fungi will be used to investigate different time scales and footprints of adaptation. The first model group are Penicillium fungal species. Some species being used for cheese and antibiotic production, they are excellent models for understanding adaptive processes under strong and recent selection. The second model is Microbotryum violaceum, a complex of sibling species, causing anther smut disease on different Caryophyllaceae plant species. This model is ideal to address the question of long term pathogen-host adaptation. We will integrate high-throughput sequencing and state-of-the-art inference methods to identify the evolutionary processes involved in adaptive divergence and the genomic consequences of domestication. Different experimental and sequencing approaches will then help to validate the flagged genes and genomic regions. The proposed research should yield unprecedented insights into the genomics of adaptive divergence, i.e. on the kinds of traits, the genetic architecture of these traits, the genomic regions and processes involved, and the importance of neutral processes. There are also applied implications for understanding emerging fungal diseases in plants and processes of domestication in micro-organisms, and more generally adaptation to global changes.Quantifying the atmospheric implications of the solid phase and phase transitions of secondary organic aerosolsIn our ground-breaking paper published in Nature we showed, that the atmospheric Secondary Organic Aerosol (SOA) particles formed in boreal forest can be amorphous solid in their physical phase. Our result has already re-directed the SOA related research. In the several follow-up studies, it has been shown that SOA particles generated in the laboratory chamber from different pre-cursors and in various conditions are amorphous solid. My ultimate task is to quantify the atmospheric implications of the phase state of SOA particles. Solid phase of the particles implies surface-confined chemistry and kinetic vapour uptake limitations because mass transport (diffusion) of reactants within the aerosol particle bulk becomes the rate limiting step. The diffusivity of the molecules in particle bulk depends on the viscosity of the SOA material. Hence, it would be a scientific break-through, if the kinetic limitations or the viscosity of the SOA particles could be estimated since these factors are a key to quantify the atmospheric implications of amorphous solid phase of the particles. To achieve the final goal of the research, measurement method development is needed as currently there is no method to quantify the viscosity of the SOA particles, or to study the kinetic limitations and< surface-confined chemistry caused by the solid phase of nanometer sized SOA particles. The methodology that will be developed in the proposed study, aims ambitiously to quantify the essential factors affecting the atmospheric processes of the SOA particles. The developed methodology will be use in extensive measurement campaigns performed both in SOA chambers and in atmospheric measurement sites in Europe and in US maximising the global significance of the results gained in this study. The project enables two scientific breakthroughs: 1) the new methodology applicable in the field of nanoparticle research and 2) the quantified atmospheric implications of the amorphous solid phase of particles.Coevolutionary Quantitative Genetics of Polyandry and Inbreeding in the Wild: New Theory and TestA fundamental aim in biology is to understand the (co)evolutionary dynamics of the adaptive reproductive strategies that translate ecology into evolution. However, until now, it has not been possible to explicitly test key hypotheses explaining the evolution of major reproductive strategies in wild populations experiencing real-life ecological variation. I will revolutionise our understanding of the (co)evolution of two fundamental reproductive strategies, and our approach to achieving such understanding, by deriving entirely new evolutionary quantitative genetic theory and providing the first explicit tests of this theory in nature. Genetic polyandry (female reproduction with multiple males) and inbreeding (reproduction among relatives) are fundamental reproductive strategies that profoundly influence the social, genetic and genomic structures of populations. Yet decades of research have failed to explain their (co)evolution and persistence in the face of sexually antagonistic selection. Current theory is inadequate because it does not consider ecology or coevolution or make critical quantitative predictions that permit definitive test of key hypotheses in wild populations. Key forces of direct and indirect selection on genetic variation underlying polyandry and inbreeding have consequently never been explicitly estimated. I will derive new theory that defines the (co)evolution of polyandry and inbreeding in terms of sex-specific genetic (co)variances, thereby providing the conceptual advance required to drive a new generation of empirical test. I will estimate these genetic (co)variances through state-of-the-art quantitative genetic analysis of outstanding wild population data, thereby providing the first explicit tests of key hypotheses explaining the (co)evolution of polyandry and inbreeding in nature. I will thereby initiate and implement a new approach to understanding the evolution of reproductive strategies and answer long-standing questions in biology.Fitness drivers in long-distance migrants: the interacting roles of physiology, social biology, ecological and physical environmentsLong distance migration in birds is among the most dramatic and exciting phenomena in nature. However despite many years of study, there are still huge gaps in our understanding of how this behaviour shapes individual ecology and influences population processes. For example, we have very little understanding of how migratory animals manage trade offs within and among seasons and h ow these in turn drive variation in productivity, survival or breeding phenology. Increased understanding in this area has important implications for ecology, evolution conservation and management Our lack of progress in this area is almost inevitable given the complex nature of migration. Migration is sequential in nature, meaning that an animal s state in one season is heavily influenced by previous conditions. Therefore the costs/benefits of behaviours can be carried over into subsequent seasons and thus the processes regulating fitness may not occur at the time it is being expressed. This also means that regulating processes and response can also be separated spatially making it even harder to identify cause. These effects are likely to be emphasized in migrants because fuelling flights and breeding also places huge physiological demands on migratory birds. Yet few studies have linked the stress incurred during migration with subsequent fitness. Integrating mechanism and function would provide very important insights into the ecology and evolution of migration. In order to progress we need to able to follow large numbers of individuals throughout their annual cycles, tracking the different conditions they experience and how this influences their state at each point in time. I would use state of the art technologies and statistical tools to follow migratory geese throughout the year and integrate, for the first time, how interactions among physiological, social, ecological and climatic environments underpin state and in turn fitness across the annual cycle.Macroecological studies of long-term historical constraints on functional diversity and ecosystem functioning across continentsEarth s environment is ongoing massive changes with strong impacts on ecosystems and their services to human societies. It is thus crucial to improve understanding of ecosystem functioning and its dynamics under environmental change. I propose to do this by assessing the novel hyp< othesis that ecosystem functioning is subject to long-term constraints mediated by biodiversity effects and driven by past climate change and other historical factors. If supported, we will have to rethink ecosystem ecology, as traditionally ecosystem functioning is understood as the outcome of contemporary environmental drivers and their interplay with dominant species. I will employ an unconventional macroecological approach to ecosystem ecology to investigate this hypothesis for major organism groups and ecosystems across continents, modeling effects of historical factors such as past climate change. My specific objectives are to assess if and how (1) large-scale patterns in functional diversity of a key producer group, vascular plants, and (2) a key consumer group, mammals, are affected by historical factors; (3) if and how plant and mammal functional diversity are linked, and, if such links exist, how and to what extent they are shaped by historical factors; (4) if and how large-scale patterns in vegetation-related ecosystem functioning are shaped by historical factors; (5) if ecosystem functioning is linked to diversity of plants and mammals, and if such links exist, if they are shaped by historical factors; and finally (6) directly translate my findings into a novel framework for predicting spatiotemporal dynamics of ecosystem functioning that accounts for historical constraints. The project relies on extensive geospatial data now available on ecosystem functioning, species distributions, and functional traits as well as on paleodistributions, phylogenies, paleoclimate, environment, and human impacts, in combination with advanced statistical and mechanistic modeling./The Past, Present and Future of Neotropical BiodiversityThe 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 multidisciplinary 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.fThe Origin of Jawed Vertebrates and the Evolution of Morphology in Deep TimeJawed vertebrates account for more than 99% of modern vertebrate diversity. Collectively, they comprise chondrichthyans (sharks, rays, and chimaeras) and osteichthyans (bony fishes and terrestrial vertebrates, including humans). The anatomy of jawed vertebrates includes a series of complex traits such as jaws, teeth, paired appendages, and novel skeletal tissues such as bone. In spite of the intensive investigation of jawed vertebrate evolution in comparative morphology and molecular developmental evolution, the origin and early diversification of this important group remains mysterious. This project seeks to inject a large body of fresh data into the problem of early jawed vertebrate origins and evolution and develop modernized tools for morphological phylogenetics. We will use an integration of expeditionary fieldwork, modern digital imaging technology, and newly developed numerical methods in phylogenetics to address the problems of early jawed vertebrate origins. The work will focus on the morphology and relationships of fossil jawed vertebrates from the Palaeozoic Era (approx. 540-250 million years ago) which exhibit the earliest evidence of jaws, teeth, and paired appendages. Fieldwork in Mongolia will deliver new taxonomic and morphological data from poorly explored regions and attack a major geographic bias in existing fossil archives. The project will exploit computed tomography scanning to analyze existing fossil archives of extract species. This work will provide a detailed scheme of phylogenetic relationships inferring the relationships of early fossil forms to modern jawed vertebrate lineages and document the evolutionary assembly of complex morphological traits of jawed vertebrates. These results will yield refined timelines for jawed vertebrate evolution that can help calibrate molecular clock studies and deliver a rich comparative framework for evolutionary morphological and developmental studies.The role of de novo evolution in the emergence of new genesGene evoluti< on has long been thought to be driven primarily by duplication or transposition mechanisms, followed by divergence of the duplicated copy. However, every evolutionary lineage harbours also so-called orphan genes, which have no homologues in other evolutionary lineages i.e. which do not appear to have arisen via gene duplication mechanisms, or have diverged to a point where their origins can not be traced anymore. Orphan genes are generally thought to be important drivers of taxon specific adaptations and interactions with the environment. New insights from comparative genomics and phylogenetic analysis suggests now that orphan genes could indeed be created through de novo evolution and it is becoming increasingly clear that this mechanism might occur at high rates, which would provide a continuous source of material for new gene functions. However, only initial evidence is available for this so far and little is known about the evolutionary dynamics and mechanisms of de novo gene emergence. The present proposal will use experimental and functional approaches to study the role and the evolutionary potential of the emergence of completely new genes from random sequences. This will open up new perspectives in understanding the evolution of genomes and the molecular mechanisms of adaptation. Stress-Induced Plant Volatiles in Biosphere-Atmosphere SystemVegetation forms a key interface between Earth surface and atmosphere. The important role of vegetation carbon, water and energy exchanges is well established, but the overall impact of plant trace gas (VOC) emission for large-scale Earth processes is poorly understood. Although it is widely accepted that VOCs play major roles in the formation of ozone, secondary organic aerosols (SOA) and cloud condensation nuclei (CNN) with potentially profound impacts on air quality and Earth radiative balance, the research has so far focused only on constitutive emissions from species considered  emitters . However, differently from constitutive VOCs emitted only by certain species, all plant species can be triggered to emit induced VOCs under abiotic and biotic stress. So far, induced highreactivity VOCs are not considered in global VOC budget, and thus, this proposal tests the key assumption that VOC emissions worldwide have been vastly underestimated. As global change is resulting in higher level of stress in Earth ecosystems, the relevance of induced emissions is further expected to gain in importance. The current project has the overall objective to evaluate the effect of plant-generated VOC emissions on air composition and environment under global change, with particular emphasis on the role of VOCs induced in response to environmental stress. The study first quantifies the VOC production vs. stress severity relationships across species with differing stress tolerance and advances and parameterizes the qualitative induced VOC model developed by PI. The novel quantitative model is further verified by flux measurements and scaled up to regional and global scales to assess the contribution of induced emissions to overall VOC budget, and study the feedbacks between stress, ozone, SOA and CNN formation and the Earth climate using an hierarchy of available models. This highly cross-disciplinary project is expected to result in key contributions in two research fields of major significance: plant stress tolerance from molecules to globe and the role of vegetation component in atmospheric reactivity and Earth climate. The first part of the study provides fundamental insight into the stress responsiveness of plants with differing tolerance to environmental limitations, extending  leaf economics spectrum , a hotspot of current plant eco logy research. The second part provides quantitative information on large-scale importance of plant VOCs in globally changing climates with major relevance for understanding the role of plants in the Earth s large scale processes.GThe evolution of plant-fungal marketsThroughout the Earth s history, the mutualism between plants and their fungal partners has mediated nutrient cycles and energy flow in ecosystems. Underground, mycorrhizal fungi and plant roots form vast networks of connected individuals, in which sugars from roots are exchanged for nutrients from fungi. How is cooperation maintained in plant-fungal networks? Selfish individuals can potentially exploit the collaboration, reaping nutrient benefits while paying no costs. So, why cooperat< e at all? I recently demonstrated that plant and fungal partners are able to detect variation in nutrient provisioning by the other, and adjust their own strategy accordingly (Kiers et al. Science 2011). We argued that the partnership functions like an economic market: partners compete by trading resources, and those offering the best rate of exchange are rewarded. While this work suggests that plants and fungi can successfully negotiate conditions of trade, we have yet to conclusively demonstrate what drives  fair trade dynamics. In particular, we do not know how partner performance is evaluated, nor how trade strategies respond to changes in resource levels. I present an interdisciplinary program of research to address this problem by investigating four aspects critical to market regulation in nature: (1) Responses to external resources, (2) Partner decisions, (3) Network formation, (4) Conflict resolution within networks. Using a combination of gene-level characterization, microscale manipulation of nutrient landscapes, experimental evolution, and game theory, I will test: (1) how plant and fungal trading strategies respond to changing resource levels; (2) how hosts control fungal  behavior , stimulating them to collect specific nutrients; (3) the role of fungal fusion in network formation; (4) how genetic conflicts within a fungal network are resolved. This work opens up a new field of research into how markets evolve and are stabilized in non-animal systems.Physiological Reaction to Predation- A General Way to Link Individuals to EcosystemsThis proposal aims to advance a new general theory that links plasticity in prey responses to predation and biogeochemical processes to explain context-dependent variations in ecosystem functioning. The physiological reaction of prey to predation involves allocating resources from production to support emergency functions. An example of such a reaction is an increase in maintenance respiration concomitant with higher carbohydrate and lower N demand. Such changes in prey energy and elemental budget should alter the role prey play in regulating the quality of detrital inputs to soils. Nutrient content of detritus is an important determinant of the way soil communities regulate ecosystem processes. Thus, the physiological reaction of prey to predation can potentially explicate changes in ecosystem functioning. My first empirical examination of a few selected mechanisms of this theory has yielded very promising insights. The main objectives of this proposal are: (1) To systematically test whether prey reactions to predation are consistent with the proposed theory s predictions across species and ecosystems; (2) to examine the interface between stress physiology and anti-predatory behaviors in explaining predator induced diet shift, and (3) to evaluate how predator induced responses at the individual level regulate ecosystem processes. To address these objectives, I propose combining manipulative field experiments, highly controlled laboratory and garden experiments, and stable-isotopes pulse chase approaches. I will examine individual prey responses and the emerging patterns across five food-chains that represent phylogenetically distant taxa and disparate ecosystems. The proposed study is expected to revolutionize our understanding of the mechanisms by which aboveground predators regulate ecosystem processes. Promoting such a mechanistic understanding is crucial to predict how human-induced changes in biodiversity will affect life-supporting ecosystem services.Space use by bees radar tracking of spatial movement patterns of key pollinatorsCurrent radar tracking technology to monitor insect movements in space allows us to catch only glimpses of their spatial movements  it is severely constrained by the restricted range that can b< e covered, the fact that individuals can only be tracked one at a time, and the lack of a height dimension. Here we propose ground-breaking technology advances to make insect telemetry fit for the 21st century, to answer multiple fundamental questions in pollinator space use and its implications for the plants they pollinate. We will work towards transponder miniaturisation to make application to a large number of insect species viable; we will develop radar technology to allow coverage of areas of up to 10km2 and the exploration of the 3rd dimension of insect flight, and we will adapt the equipment so that multiple individuals can be traced simultaneously. We will identify the rules of bee movements at the landscape scale, and the extent to which they use familiar landmarks and learnt vectors to link multiple locations. We will explore whether speed-accuracy tradeoffs are relevant in landmark navigation. Natural resource exploration and exploitation will be monitored over the entire foraging career of select individuals, and we will quantify individual differences in space use. Tracking bees in three dimensions will allow us to ask whether looking at the landscape from above aids efficient navigation. The tracking of multiple bees simultaneously will allow us to monitor competitive interactions as well as the possibility of social learning in space use. For the first time we will also track the spatial movement strategies of queens and males to see how they interface the search for mates with the need to forage efficiently. Our findings will have wide-ranging applications not just for the understanding of pollinator space use, but also for the conservation, management, and the understanding of mating patterns in the plants they pollinate.Molecular inventions underlying the evolution of the nitrogen-fixing root nodule symbiosisCrop production worldwide is sustained through nitrogen fertilizer produced via the energy-demanding Haber-Bosch process. One group of closely related plants evolved to become independent of nitrogen from the soil by engaging in symbiosis with bacteria that convert atmospheric nitrogen to plant -usable ammonium and are hosted within specialized organs, the root nodules. Nodulation evolved several times independently but exclusively in four related orders, the Fabales, Fagales, Cucurbitales and Rosales (FaFaCuRo) based on a putative genetic predisposition to evolve root nodules acquired by a common ancestor of this clade. This project aims to identify the elusive genetic switches involved in the evolution of nodulation. It builds on the underlying idea that a succession of events co-opted preexisting developmental programs to be activated by symbiotic stimuli. We will systematically investigate and compare the prewired connections between signaling pathways and developmental modules present in non-nodulating and nodulating relatives, to identify components acquired by nodulators. The Rosaceae represent a particularly attractive family to test evolutionary hypotheses by transferring candidate switches from a nodulator into the genome of closely related sister genera to enable nitrogen fixing root nodule symbiosis. Most genera of the Rosaceae including economically valuable targets such as apple and strawberry are non-nodulating. A minority of Rosaceae form ancestral, lateral root related actinorhiza nodules with Frankia actinobacteria, which differs from the derived, more complex symbiosis of legumes with rhizobia. Frankia strains have a very broad host range and can fix nitrogen at ambient oxygen concentrations thus imposing minimal constraints on a host environment suitable for efficient symbiosis. Thus, by retracing small evolutionary steps within the Rosaceae we will take a huge leap towards nitrogen-fertilizer independent crops for sustainable agriculture.Pathogen Phylodynamics: Unifying Evolution, Infection and ImmunityGenetic sequences represent a rich source of information about evolutionary and ecological processes in natural populations. However the development of methods to recover this information is being outpaced by the explosion in sequence data, especially since the introduction of  next-generation sequencing. This problem is particularly acute for the inter-disciplinary field of pathogen phylodynamics. The rapid evolution of many pathogens means their ecological and evolutionary dynamics occur on the same timescale and therefore new analytical methods are required to study this joint behaviour. Further, the small genome sizes and medical importance of many viruses mean that hundreds of thousands of homologous sequences are already available, and sample sizes will continue to grow. The main goal of this proposal is to develop and apply multiple new frameworks of evolutionary analysis, to unlock the full potential of current data and to exploit new types of sequence data for which no rigorous analytical methods currently exist. Across four related themes I will use these novel methods to answer major unsolved questions about the evolutionary dynamics of viruses and their hosts: (i) How can we measure adaptation in data sets comprising many thousands of genomes? (ii) Can we reveal the adaptation of viral lineages to the genetic variation in immunity present in host populations? (iii) How can we combine mathematical ecological models with viral genomics to better predict the outcome of chronic HIV and hepatitis C virus infection, or the success of anti-viral drug therapy? (iv) Can we apply methods from ecology and evolution to analyse new data on immune receptor diversity, and use them to better understand the dynamics of leukaemia and viral infection? The suite of analytical methods created during this project will open fresh avenues of res< earch, creating opportunities to exploit the future growth in genetic data on biological diversityacross many disciplines.Water-walking insects: marrying evo-devo with ecology for a better understanding of morphological evolutionUnderstanding the origin of the remarkable biodiversity in nature is an important goal in biological studies. Despite recent advances in evolutionary developmental biology, our understanding of the interaction between developmental genetic processes and the ecological environment in shaping the phenotype remains largely fragmented. This is mainly because of the difficulty to transfer molecular genetic tools to natural systems where we have a good understanding of the ecology. In this proposal, we combine original natural systems, water-walking insects, with state of the art tools of functional and developmental genetics, to study the interplay between developmental genetic pathways and the ecol      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefgijklmnopqrstuvwxyz{|}~ogical environment, and how this interaction can shape adaptive phenotypic change. About 200 million years ago, the common ancestor of water-walking insects (Heteroptera, Gerromorpha) invaded water surface and radiated into a diverse array of niches, from shorelines to open oceans. This ecological transition and specialization is associated with an array of adaptive changes that enabled these insects to support their body weight and generate efficient propulsion on the water surface. In this project, we aim to develop a multilevel functional approach that combines developmental and evolutionary genetics, ecology, and comparative genomics and transcriptomics, to study a set of key morphological traits directly associated with the initial event of transition to water surface life, and the diversification that followed. To achieve this, we chose three water-walking insects, along with a terrestrial and under-water outgroups, based on their morphology, ecology, and amenability for laboratory culturing and functional experiments. We will identify the genes and genetic changes responsible for the development and evolution of the hydrophobic bristles  a key trait that was instrumental in the transition from terrestrial to water surface life. In addition, we will identify the genetiMultimodal functional neuroimaging techniques to probe the representation of pain in the human brainPain may be defined as a primarily aversive perception that is vital for survival, as it incites the individual to respond to stimuli constituting a real or potential menace. However, pain is also a major healthcare issue, undermining the health and welfare of millions of individuals and imposing a severe financial burden to our societies. How does the brain process noxious stimuli, and how does this lead to the perception of pain? In humans, using functional neuroimaging techniques such as electroencephalography (EEG) or functional magnetic resonance imaging (fMRI), a great number of studies have shown that noxious stimuli elicit activity within a widespread network of cortical regions, including the primary and secondary somatosensory cortices, the insula and the anterior cingulate cortex. However, recent studies have suggested that these responses are largely unspecific for pain and, instead, reflect attentional mechanisms that can be triggered by the occurrence of any salient sensory event, regardless of whether it elicits pain. Therefore, novel approaches are needed to progress in understanding the neural representation of pain in humans. This constitutes the main objective of this project in which we will develop a series of original experimental approaches to (1) explore how transient and sustained pain are respectively represented in the human brain, (2) characterize directly the functional connectivity, interdependency and hierarchical organization of the different brain regions involved in the perception of pain and (3) characterize the plastic changes in cortical excitability and functional connectivity induced by sustained experimental pain as well as chronic pathological pain. Each of these approaches has the potential to open a new line of research for basic and clinical pain neuroscience, with important development perspectives, such as the identification of novel human biomarkers for analgesic drug development and improved patient stratification.(The Evolution of Cognitive PerformanceI aim to determine how cognitive abilities evolve under natural selection; one of the most impo rtant, yet poorly understood issues in modern biology. Comparative studies inform us how species differ, and hence, one can infer selective pressures. However, studies of how heritable inter-individual cognitive differences determine fitness in the face of natural selection are absent. I will use methods and paradigms developed in comparative psychology, cognitive science and behavioural ecology, applying them to free-living animals, and so determine how cognition evolves. Pheasants (Phasianus colchicus) present an ideal system. Large numbers (100s) of individuals can be reared under controlled conditions and then exposed to natural selection pressures. Precocial chicks can be reared without differences in parental care. During rearing, chicks will complete a suite of automated cognitive training and testing, and their performance will be recorded. Conditions before and during rearing will be manipulated including maternal investment in eggs and diet complexity during rearing. Crucially, these captive reared birds will be released and exposed to natural selection. Surviving birds will be recaptured and bred from, producing l< arge broods so that heritability can be studied. Empirical work will describe how individuals vary in their performance across a suite of cognitive domains; how such performance links to their natural behaviours; how their performance contributes to their fitness; how variation in performance is inherited; and how variation in performance is influenced by early life maternal or environmental factors. These are all significant steps in themselves, but the real strength of this project is addressing them in synchrony in a single, free-living study system. This provides a robust framework to tackle the broad question of how cognitive performance evolves that can be applied across a wider suite of conditions and taxa, including humans./Recombination in Adaptive EvolutionMeiotic recombination is a key source of genetic diversity with considerable implications for the genomic landscape and evolutionary process. By shuffling parental alleles to produce novel haplotypes, recombination impacts the strength of selection on nearby polymorphisms, and can increase the rate of adaptation in natural populations. Recombination defects can have serious phenotypic consequences: inviable gametes, miscarriages and developmental abnormalities. Strikingly, recombination rate differs by orders of magnitude across the genome, among individuals, sexes, populations and species. Despite recent progress, we know little about how molecular constraints and evolutionary forces interact to shape recombination in natural populations. We will close this knowledge gap using threespine stickleback fish an exceptional evolutionary model system that bridges molecular genetic studies and adaptive evolution in the wild. This research program combines next-generation genomics with cutting-edge molecular biology and transgenics. We will 1) create kilobase-scale maps of the recombination landscape in adaptively diverging populations; 2) genetically dissect factors cis- and trans-acting factors that cause recombination variation; 3) characterize molecular mechanisms of recombination modifiers using cutting-edge techniques; and 4) test evolutionary theory that predicts natural selection favours recombination suppression in hybrids. This will significantly improve our understanding of recombination and introduce sophisticated genetic engineering techniques that further cement sticklebacks as an evolutionary model organism. Our ultimate goal is to understand how molecular mechanisms and natural selection shape and constrain recombination during adaptive divergence. This research connects a fundamental biological process that underlies severe human diseases with the tempo of adaptation in natural populations : 31/7/2019Phylogeography and somatic evolution of cancer tumor cellsBy far, most evolutionary research has focused on the changes that occur in the germline of individuals across generations, within and between species. For different reasons, much less attention has been given to the process of change within the somatic line of a multicellular individual. The formation of cancer tumors due to uncontrolled cell proliferation is one of the most prominent forms of somatic evolution. The evolution of cancer tumors in a body can be likened with the evolution of populations in more or less fragmented habitats. The tumor is usually a expanding population of clonal cells, which may differentiate to a bigger or lesser extent (population structure) and disperse to contiguous (range expansion) or more distant tissues (long distance colonization). During tumor progression, this population of cells is subject to distinct somatic evolutionary processes like mutation, drift, selection or migration, which can act at different points in time and geographical space. Very recently, the discovery of extensive intratumor heterogeneity, together with the rise of single cell genomics, has created an unique opportunity to study the phylogeography of cancer tumor cells. So far evolutionary inferences drawn from cancer genomes have been mostly qualitative. Here we propose to study a thousand single cell genomes from different regions in primary tumors and matched metastases. We will develop and apply state-of-the-art statistical and computational techniques from phylogenetics, phylogeography and population genomics to understand the tempo and mode of evolution of cell lineages within and between cancer tumors. By doing so we aim to construct a robust theoretical and methodological evolutionary framework that can contribute to a better understanding of the process of somatic evolution and shed light into the biology of cancer. : 30/9/2019Modelling lianas as key drivers of tropical forest responses to climate changeTropical forests are essential components of the earth system. Yet, much uncertainty exists about the exact role of this biome in the global carbon cycle. Our limited understanding of tropical forest functioning is reflected in uncertain global vegetation model projections. A large source of uncertainty in these models is their representation of ecosystem demographic processes. Interestingly, fieldwork has revealed lianas as important components of tropical forests, which are apparently increasing in abundance. Liana proliferation might be a key adaptation mechanism of tropical forests to climate change, which has potentially large impacts on the long term tropical forest biome carbon balance. Nevertheless, no single terrestrial ecosystem model currently includes lianas. TREECLIMBERS will generate important insights into the mechanisms by which lianas influence the carbon balance of tropical forests, by building the first vegetation model that includes lianas. We will make the first integrative study of (1) the contribution o< f lianas to instantaneous carbon and water fluxes, (2) liana contribution and influence on canopy structure, (3) their role for long term demographic processes, and (4) of their role in forest responses to drought events. TREECLIMBERS will develop the first liana plant functional type (PFT) by combining a unique global meta-analysis of existing data with innovative terrestrial LiDAR 3D measurements of the canopy to study the contribution of lianas to the canopy structure. New and available data will be integrated in the Ecosystem Demography (ED) model, a forerunner of the next generation of vegetation models. By using model-data fusion we will, for the first time, integrate the large amount of available and emerging liana data, leading to an integrated insight into the role of lianas in tropical forest functioning. This project aims to show that shifts in floristic composition due to global change may have important impacts in tropical forests.Origin and evolution of the sexes and reproductive systems: novel insights from a distant eukaryotic lineageSexual reproduction is an extraordinarily widespread phenomenon that assures the production of new genetic combinations in nearly all eukaryotic lineages. Although the core mechanisms of sexual reproduction (meiosis and syngamy) are highly conserved, the control mechanisms that determine whether an individual is male or female are remarkably labile across eukaryotes. In genetically controlled sexual systems, gender is determined by sex chromosomes, which have emerged independently and repeatedly during evolution. Sex chromosomes have been studied in only a handful of classical model organism, and empirical knowledge on the origin and evolution of the sexes is still surprisingly incomplete. The goal of our project is to exploit the remarkable richness of sexual characteristics of the brown algae to gain novel insights into the functional and evolutionary interactions between the sex chromosomes and key eukaryotic reproductive and life cycle features. First, we will use the model brown alga Ectocarpus to reveal the fundamental genetic mechanisms by which sex chromosomes control reproductive and life cycle traits of broad importance to all eukaryotes, including sex determination and asexual reproduction through parthenogenesis but also the control of gamete size and the regulation of developmental switches during the life cycle. Secondly, we will employ a combination of experimental and computational approaches on selected brown algal species exhibiting a range of reproductive and life cycle features to understand the long term evolutionary consequences of the variations in these traits to the structure of their sex chromosomes, in a phylogenetic context. These analyses will not only reveal fundamental forces that shape sex chromosome evolution in the scope of the tree of life, but will also uncover the mechanisms underlying important evolutionary transitions between major reproductive and life cycle modes and shed new light on the origin and evolution of the sexes.CEvolutionary origins of complex ecological adaptationsDuring evolution, organisms adapt to diverse environmental conditions by evolving new morphological and/or biochemical traits, some of which are of impressive complexity. This is for example the case of eyes, wings or complex biochemical pathways, which all involve multiple components. The evolution of such complex traits has always intrigued evolutionary biologists, including Charles Darwin, and is still only partially understood. How can natural selection on random mutations lead over time to novel complex ecological adaptations that allow organisms to thrive in diverse environments? This question will be addressed here by studying a species complex that presents exceptional variation in a key ecological adaptation, namely C4 photosynthesis. This trait results from multiple anatomical and biochemical components that function together to increase plant productivity in warm and dry environments. Capitalizing on a species complex of grasses that includes C4 as well as the ancestral C3 photosynthetic types and multiple intermediate states, the ComplEvol project will combine methods from different fields to infer (i) the history of mutations that generated components for C4 photosynthesis during the dispersal into different ecological conditions, (ii) the factors controlling the spread of these mutations among populations, (iii) the effects of these mutations on the properties of the encoded C4 enzymes, (iv) the effects of different anatomical and biochemical C4 components on the performance of the plants (fundamental niche), and (v) the relationships between these components and the distribution of individuals in contrasted environments (realised niche). The incorporation of these different dimensions of evolution and ecology will shed new lights on the processes that allow over time the emergence of major ecological novelties through the repeated action of natural selection on minor changes within populations.Honeybee communication: animal social learning at the height of social complexityLearning from others is fundamental to ecological success across the animal kingdom, but a key theme to emerge from recent research is that individuals respond differently to social information. Understanding this diversity is an imposing challenge, because it is hard to replicate the overwhelming complexity of free-living groups within controlled laboratory conditions. Yet here I propose that one of the most complex social models that we know of the sophisticated eusocial societies of honeybees offer unrivaled and yet unrecognized potential to study social information flow through a natural group. The honeybee  dance language is one of the most celebrated communication systems in the animal world, and central to a powerful information network that drives our most high-profile pollinator to food, but bee colonies are uniquely tractable for two reasons. Firstly, next-generation transcriptomics could allow us to delve deep into this complexity at the molecular level, on a scale that is simply not available in vertebrate social systems. I propose to track information flow through a natural group using brain gene expression profiles, to understand how dances elicit learning in the bee brain. Secondly, although bee foraging ranges are vast < and diverse, social learning takes place in one centralized location (the hive). The social sciences now offer powerful new tools to analyze social networks, and I will use a cutting-edge network-based modelling approach to understand how the importance of social learning mechanisms shifts with ecology. In the face of global pollinator decline, understanding the contribution of foraging drivers to colony success has never been more pressing, but the importance of the dance language reaches far beyond food security concerns. This research integrates proximate and ultimate perspectives to produce a comprehensive, multi -disciplinary program; a high-risk, high-gain journey into new territory for understanding animal communication.LGenetic Mapping of Evolutionary Developmental Variation using Hybrid Mouse in vitro CrossesDiscovering the genetic changes underlying species differences is a central goal in evolutionary genetics. Most evolutionarily important traits affecting fitness are complex or quantitative traits, whose genetic bases are elusive. In mammals, dissecting the genetic basis of complex trait variation is particularly challenging, because efficient genetic mapping requires enormous pedigrees or specialized genetic panels that are typically beyond the resources of individual groups. Using a radically novel method to circumvent breeding limitations by  breeding mice in vitro, I propose to dissect the genetic basis of evolutionary developmental variation. This ground-breaking approach will allow me to create large genetic mapping panels of potentially any size from mouse interspecific hybrids of increasing evolutionary divergence. In vitro crosses promise a breakthrough in evolutionary biology: by bypassing hybrid sterility and inviability, we will ask which genetic changes underlie species differences. The proposed experiments address how genetic changes accumulate during evolution of new species to shape gene regulatory networks and cause phenotypic changes at the gene expression, fitness and organismal level. This research has the potential to revolutionize genetic mapping. If realized, its impact on personalized medicine, agricultural science and evolutionary research cannot be understated.qNovel variation in plant breeding and the plant pan-genomesThe analysis of variation in plants has revealed that their genomes are characterised by high levels of structural variation, consisting of both smaller insertion/deletions, mostly due to recent insertions of transposable elements, and of larger insertion/deletion similar to those termed in humans Copy Number Variants (CNVs). These observations indicate that a single genome sequence might not reflect the entire genomic complement of a species, and prompted us to introduce the concept of the plant pan-genome, including core genomic features common to all individuals and a Dispensable Genome (DG) composed of partially shared and/or non shared DNA sequence elements. The very active transposable element systems present in many plant genomes may account for a large fraction of the DG. The mechanisms by which the CNV-like variants are generated and the direction of the mutational events are still unknown. Uncovering the intriguing nature of the DG, i.e. its composition, origin and function, represents a step forward towards an understanding of the processes generating genetic diversity and phenotypic variation. Additionally, since the DG clearly appears to be for the most part the youngest and most dynamic component of the pan genome, it is of great interest to understand whether it is a major contributor to the creation of new genetic variation in plant evolution and more specifically in the breeding process. We thus aim at: i) defining extent and composition of the pan genome in two plant species, maize and grapevine; ii) identifying the different mechanisms that generate and maintain the dispensable portion in these 2 species; iii) identifying the phenotypic effects of the DG; iv) estimating the rates and modes of creation of new genetic variation due to DG components and whether this could represent an important factor in the breeding process; v) extending our findings to other plant species for which the genome sequence in the meantime may have become available.Biotechnological optimization of light use efficiency in algae photobioreactorsNew renewable energy source are highly needed to compensate exhausting fossil fuels reserves and reduce greenhouse gases emissions. Some species of algae have an interesting potential as feedstock for the production of biodiesel thanks to their ability to accumulate large amount of lipids. Strong research efforts are however needed to fulfil this potential and address many issues involving optimization of cultivation systems, biomass harvesting and algae genetic improvement. This proposal aims to address one of these issues, the optimization of algae light use efficiency. Light, in fact, provides the energy supporting algae growth and must be exploited with the highest possible efficiency to achieve sufficient productivity. In a photobioreactor algae are highly concentrated and this cause a inhomogeneous light distribution with a large fraction of the cells exposed to very low light or even in the dark. Algae are also actively mixed and they can abruptly move from dark to full illumination and vice versa. This proposal aims to assess how alternation of dark/light cycles affect algae growth and functionality of photosynthetic apparatus both in batch and continuous cultures. In collaboration with the Chemical Engineering department, experimental data will be exploited to build a model describing the photobioreactor, a fundamental tool to improve its design. The other main scope of this proposal is the isolation of genetically improved strains more suitable to the artificial environment of a photobioreactor. A first part of the work of setting up protocols for transformation will be followed by a second phase for generation and selection of mutants with altered photosynthetic performances. Transcriptome analyses in different light conditions will also be instrumental to identify genes to be targeted by genetic engineering.\Metal transport in the tripar< tite symbiosis arbuscular mycorrhizal fungi-legume-rhizobiaPlant nutrition is essential to understand any physiological process in plant biology, as well as to improve crops, and agricultural practices. The root microbiome plays an important role in plant nutrition. The best characterized microbiome elements are two plant endosymbionts: arbuscular mycorrhizal fungi (AMF) and rhizobia. AMF are responsible for delivering most of the mineral nutrients required by the host plant. Similarly, rhizobia in legume nodules provide the vast majority of the nitrogen requirements. Given their importance for plant nutrition a significant effort in understanding macronutrient exchange among the symbionts has been made. However, very little is known about metal micronutrient exchange. This is in contrast to the role of metals as essential nutrients for life (30-50 % of the proteins are metalloproteins) and to the yield-limiting effect that low soil metal bioavailability has worldwide. AMF are a source of metals, transferring the incorporated metals to the host,. Nitrogen-fixing rhizobia in mature nodules act as metal sinks, since the main enzymes required are highly expressed metalloproteins. We hypothesize that by changing the expression levels of the metal transporters involved, we will increase nitrogen fixation rates and increase plant metal uptake, resulting in higher crop production and fruit metal biofortification. Towards this goal, we will answer: i) How are metals incorporated from the AMF into the plant?, ii) How are metals delivered to the nodule?, iii) How are metals recovered from senescent nodules?, and iv) How does the natural variation of symbiotic-specific metal transporters affect yields and metal content of the fruit? In this project, we will use a multidisciplinary approach that involves metallotranscriptomics, plant physiology and molecular biology, and state-of-the art synchrotron based X-ray fluorescence to study metal distributions.yEnzymology of oxidative sulfur transfersOxidative stress causes cancer, cardiovascular, neurodegenerative and infective disease. Much of cellular oxidative stress is mediated, communicated, mitigated or amplified by a complex system of sulphur containing small metabolites or protein based cysteines. Characterization of key players and reactions in this network is crucial for preventive and therapeutic interventions. I propose a new perspective on sulphur biochemistry. The reactivity of sulphur with the oxidative stressors superoxide, peroxides or hydroxyl radicals is well established, but far less is known about reactions between sulphur and molecular oxygen. I shall demonstrate that this reaction is fundamental to cellular life, and how advances in this field provide new options in medicine, biotechnology and the food industry. Assisted by a team of three PhD students and a postdoctoral researcher I intend to establish this new research field by identification, characterization and engineering of enzymatic activities which catalyse oxidative carbon-sulfur bond formation and cleavage. Specific systems in this study include the biosynthetic enzymes for ergothioneine, sparsomycine and alliin, all of which are sulphur containing secondary metabolites with potent activities on cellular functions.]Atlas of leaf growth regulatory networks in MAIZEUnderstanding how organisms regulate size is one of the most fascinating open questions in biology. The aim of the AMAIZE project is to unravel how growth of maize leaves is controlled. Maize leaf development offers great opportunities to study the dynamics of growth regulatory networks, essentially because leaf development is a linear system with cell division at the leaf basis followed by cell expansion and maturation. Furthermore, the growth zone is relatively large allowing easy access of tissues at different positions. Four different perturbations of maize leaf size will be analyzed with cellular resolution: wild-type and plants having larger leaves (as a consequence of GA20OX1 overexpression), both grown under either well-watered or mild drought conditions. Firstly, a 3D cellular map of the growth zone of the fourth leaf will be made. RNA-SEQ of three different tissues (adaxial- and abaxial epidermis; mesophyll) obtained by laser dissection with an interval of 2.5 mm along the growth zone will allow for the analysis of the transcriptome with high resolution. Additionally, the composition of fifty selected growth regulatory protein complexes and DNA targets of transcription factors will be determined with an interval of 5 mm along the growth zone. Computational methods will be used to construct comprehensive integrative maps of the cellular and molecular processes occurring along the growth zone. Finally, selected regulatory nodes of the growth regulatory networks will be further functionally analyzed using a transactivation system in maize. AMAIZE opens up new perspectives for the identification of optimal growth regulatory networks that can be selected for by advanced breeding or for which more robust variants (e.g. reduced susceptibility to drought) can be obtained through genetic engineering. The ability to improve the growth of maize and in analogy other cereals could have a high impact in providing food securityAdding Another Dimension  Arrays of 3D Bio-Responsive MaterialsThis proposal is focused in the areas of chemical medicine and chemical biology with the key drivers being the discovery and development of new materials that have practical functionality and application. The project will enable the fabrication of thousands of three-dimensional  smartpolymers that will allow: (i). The precise and controlled release of drugs upon the addition of either a small molecule trigger or in response to disease, (ii). The discovery of materials that control and manipulate cells with the identification of scaffolds that provide the necessary biochemical cues for directing cell fate and drive tissue regeneration and (iii). The development of new classes of  smartpolymers able, in real-time, to sense and report bacterial contamination. The newly discovered materials will find multiple biomedical applications in regenerative medicine and biotechnology ranging from 3D cell culture, bone repair and niche stabilisation to bacterial sensing/removal, while offering a new paradigm in drug delivery with biomarker triggered drug release. : 31/10/2019Development trajectories of temperate forest plant communities under global change: combining hindsight and forecasting (PASTFORWARD)The last decades are<  characterized by an upsurge of research on the impacts of global environmental changes on forests. Climate warming, atmospheric deposition of acidifying and eutrophying pollutants and land-use change are three of the most important threats to biodiversity in temperate forests. However, most studies focused on the effects of single factors over short time periods, such that our ability to predict the combined effects of multiple global change drivers over longer time periods remains rudimentary. The lack of knowledge on effects of global change drivers on forest herb layer communities is particularly striking, since the herb layer contains the largest part of vascular plant diversity in temperate forests and provides key ecosystem services. Therefore PASTFORWARD will build an integrative understanding of the interactive effects of land-use change, atmospheric deposition and climate warming on forest herb layer communities, starting from the insight that changes in herb layer communities are driven primarily by past land use, but can be modulated by atmospheric deposition, climate warming and forest management. Indeed, it is still largely ignored that sensible predictions of herb layer development trajectories under global change can only be made by taking the forest s land-use history into account, as legacies of past land use can leave century-long imprints on forest herb layer communities. Three complementary data sources (a database with resurveyed vegetation plots, field measurements in a pan-European network of resurvey plots, and a multi-factor experiment) combined with an ecosystem model will be used. Furthermore, concepts and tools from different disciplines, ranging from history over sylviculture to community and ecosystem ecology will be applied. The results of PASTFORWARD will help forest managers and policy makers in taking more informed decisions on how to combine resource extraction with biodiversity conservation.Peptide padlocks evolved towards infinite affinity for antibody nanoassembly and ultrasensitive cell captureOur ability to tailor individual proteins is now sophisticated, but our ability to assemble such proteins into larger structures is still primitive. Proteins are typically joined by reversible or non-specific linkages. We have designed a unique way to connect protein building blocks irreversibly and precisely, via spontaneous isopeptide bond formation. This involves modifying proteins with a short peptide tag (SpyTag) that is based upon remarkable chemistry used by pathogenic Gram-positive bacteria. Here we will develop this novel approach to address major challenges in synthetic biology. We will engineer SpyTag capture towards infinite affinity (defined as diffusion-limited on-rate and no off-rate), to transform the sensitivity of peptide detection in living systems. We will also apply SpyTag to create a new generation of protein polymers, irreversibly assembled with molecular precision and tailored branching. In parallel we will harness SpyTag to enhance circulating tumor cell (CTC) capture, one of the most promising ways to achieve early cancer diagnosis. In capturing CTCs and other rare cells from blood, the high forces mean that even the strongest non-covalent linkages fail. SpyTag covalent bridging, in concert with super-resolution live cell fluorescence microscopy, will give us the opportunity to answer key questions about the forces and membrane dynamics at the magnetic bead:cell synapse. We will exploit these insights and SpyTag-assembled antibody polymers to dramatically reduce the threshold of antigen expression for CTC capture. This comprehensive program of research will explore novel concepts in protein recognition and cellular response to force, while creating conceptually new tools, making it possible for biologists in a wide range of areas to step beyond existing barriers.The Power of Maternal Microbes on Infant HealthRecent reports suggest that early microbial colonization has an important role for in promoting health. This may contribute to reduce the risk of chronic diseases such as obesity, allergies and inflammatory conditions. Advances in understanding host-microbe interactions imply that maternal microbiota plays a crucial role on health programming. This process begins in utero and it is modulated by mode of delivery and diet. My research has shown that i) specific shifts in milk microbial composition are associated with lactation time and mode of delivery, ii) milk microbes drive the infant microbiota composition; iii) maternal microbiota dysbiosis may be transferred to the infant. However, factors defining maternal microbiota and its biological role upon infant s health are not yet fully understood. Hence, this project aims to characterize maternal microbes to be transferred to neonates a< nd determine their function in infant health programming. The specific aims are:(1) understanding how the maternal microbiome is influenced by host and environmental factors;(2) characterizing the microbial core and bioactive compounds transmitted to the offspring mainly via breastfeeding and their key roles in the microbial modulation and host response;(3) understanding the interactions among breast milk bioactive compounds and their role in infant health;(4) shedding light on how maternal microbes influence the infant immune system & (5)development of new dietary strategies and therapies based on microbial replacement and modulation. To achieve these objectives, a systems biology approach by means of state-of-the-art techniques and new methodologies based on subpopulation enrichment by flow cytometer-sorter to study host microbe interactions will be used. Results obtained will demonstrate the interaction between infant nutrition, microbes and host response in early life and its key role in health programming, enabling new applications in the field of personalized nutrition & medicine.mSensing soil processes for improved crop nitrogen bioavailabilityFood production is predicated on the application of nitrogen fertilisers, which can contribute significantly to the production of greenhouse gasses and eutrophication of agroecosystems. The use of nitrogen fertilisers must, therefore, be optimised. The recent development of transparent soils in my group gives great scope to unravel the processes involved in the reactive transport of nutrients in soil and their interaction with the soil biota. My team will combine principles of optics, chemical engineering, the physics, chemistry, and biology of soils, and plant biology to image and characterise nitrogen movement in soil at the micro-scale. We will develop a new generation of transparent soil analogues that measure the biological and chemical status of soils. This will enable, for the first time, to characterise transport at the surface of soil particles and to elucidate the role of root particle particle contacts, exudation and microbial transformation on the bioavailability of nitrate and ammonium. The legacy of the research will be knowledge, concepts, model soil systems and imaging approaches to understand and predict nutrient bioavailability in soil with an emphasis on nitrification as a model for nitrogen movement in soil. Transparent soils and imaging technologies will be patented and could pave the way for 3D chemical sensors, and have application in crop breeding and precision phenotyping. Understanding of nutrient movements in soil will lead to substantial progress in the development of more efficient fertilisers. New model soil systems could be used to better understand the spread of soil-borne diseases, the bio-remediation of contaminated soils and the mechanisms underlying soil biodiversity and activity.High-Definition TomographyIn computed tomography we mimic the brain s ability to synthesize an object s 3D structure from many projections by solving thousands of equations. Many efficient methods have been developed to do that, and the results can be impressive when the object is illuminated from many angles and the noise is negligible. However, one decisive factor behind the human brain's unrivalled success with 3D reconstruction remains to be incorporated into computed tomography: The ability to use prior information  an organized accumulation of experience with other objects in the world. The goal of the project is to accomplish this. The time is ripe to use the power of state-of-the-art mathematics and scientific computing to develop the enabling mathematical technology for next-generation tomographic reconstruction algorithms that are flexible enough to incorporate a variety of available prior information, and thus achieve major i< mprovements in the details and reliability of high-definition reconstructions  sharper images with reliable details. In contrast to existing approaches our goal is to make it possible to incorporate all available prior information in various forms, by replacing ad-hoc assumptions in the current tomography algorithms with prior-driven data representation models and reconstruction methods. We will look outside the world of classical tomography and incorporate elements and techniques from related areas, tuned to the particular problems that arise in tomography. While research in tomography is often performed either in the application areas or in specialized mathematical communities, we will create a unique research environment with tight collaborations between all the necessary activities as well as scientific and industrial users oftomography. For the first time we will be able to compute reliable high-definition 3D / 4D reconstructions based on the total amount of prior information, without the reconstructions being deteriorated by algorithmic limitations.Frontiers of Analytic Number Theory And Selected TopicsThis proposal sits at the interface of analytic number theory and selected topics, viewed through the prism of Diophantine equations defining higher-dimensional algebraic varieties. A core part of the proposal involves using analytic methods (such as complex analysis, Fourier analysis and additive combinatorics) to tackle a range of problems about Diophantine equations. These include such basic questions as precisely when families of equations admit integer or rational solutions and, furthermore, how ``dense'' these solutions are when they exist. In the reverse direction, a significant component of the proposal is dedicated to established problems in number theory (such as stable cohomology of moduli spaces and uniform spectral gaps for arithmetic lattices) which can be tackled via the successful analysis of intermediary Diophantine equations. : 30/11/2017tInverse Problems in Partial Differential Equations and GeometryInverse problems research concentrates on the mathematical theory and practical interpretation of indirect measurements. Applications are found in virtually every research field involving scientific, medical, or industrial imaging and mathematical modelling. Familiar examples include X-ray Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Inverse problems methods make it possible to employ important advances in modern mathematics in a vast number of application areas. Also, applications inspire new questions that are both mathematically deep and have a close connection to other sciences. This has made inverse problems research one of the most important and topical fields of modern applied mathematics. The research team proposes to study fundamental mathematical questions in the theory of inverse problems. Particular emphasis will be placed on questions involving the interplay of mathematical analysis, partial differential equations, and Riemannian geometry. A major topic in the research programme is the famous inverse conductivity problem due to Calder髇 forming the basis of Electrical Impedance Tomography (EIT), an imaging modality proposed for early breast cancer detection and nondestructive testing of industrial parts. The geometric version of the Calder髇 problem is among the outstanding unsolved questions in the field. The research team will attack this and other aspects of the problem field, partly based on substantial recent progress due to the PI and collaborators. The team will also work on integral geometry questions arising in Travel Time Tomography in seismic imaging and in differential geometry, building on the solution of the tensor tomography conjecture in two dimensions obtained by the PI and collaborators in 2011. The research will focus on fundamental theoretical issues, but the motivation comes from practical applications and thus there is potential for breakthroughs that may lead to important advances in medical and seismic imaging.Wall-crossing and Birational GeometryWe will use modern techniques in algebraic geometry, originating from string theory and mirror symmetry, to study fundamental problems of classical flavour. More concretely, we apply wallcrossing in the derived category to the birational geometry of moduli spaces. Bridgeland stability is a notion of stability for complexes in the derived category. Wall-crossing describes how moduli spaces of stable complexes change under deformation of the stability condition, often via a birational surgery occurring in its minimal model program (MMP). This relates wall-crossing to the most basic question of algebraic geometry, the classification of algebraic varieties. Our previous results additionally provide a very direct connection between Bridgeland stability conditions and positivity of divisors, the main tool of modern birational geometry. This makes the above link significantly more effective, precise and useful. We will exploit this in the following long-term projects: 1. Prove a Bogomolov-Gieseker type inequality for threefolds that we conjectured previously. This would provide a solution in dimension three to well-known open problems of seemingly completely different nature: the existence of Bridgeland stability conditions, Fujita's conjecture on very ampleness of adjoint line bundles, and projective normality of toric varieties. 2. Study the birational geometry of moduli space of sheaves via wall-crossing, adding more geometric meaning to their MMP. 3. Prove that the MMP for local CalabiYau threefolds is completely induced by deformation of Bridgeland stability conditions. The motivation is a derived version of the Kawamata-Morrison cone conjecture, classical questions on Chern classes of stable bundles, and mirror symmetry. 4. Answer major open questions on the birational geometry of the moduli space of genus zero curves (for example, the F-conjecture) using exceptional collections in the derived category and wall-crossing.Topological, Algebraic, Differential Methods in Classification and Moduli TheoryModuli of curves with symmetries:determine the stable irreducible components of the moduli space of curves of genus g with an action of a finite group G, using a new homological invariant. Stable means: for g sufficiently large, or for sufficiently large numerical branching function. Higher homological stabilization for these moduli spaces. Faithful actions of the absolute Galois group on moduli spaces of marked varieties, triangle curves, varieties isogenous to a product, Beauville surfaces. Change of fundamental group. Fields of definitions of < triangle curves and the scheme representing triangle curves. Uniformization: characterization of proj. var. whose universal cover is a given bounded symmetric domain (Catanese-Di Scala did the case of tube domains). Orbifold Uniformization: where we have a quotient of a non free action, or a noncompact such quotient. Classification of surfaces with genus 0 having the bidisk as universal cover. Symmetric differentials and fundamental groups of some ball quotients. Topological methods in Moduli Theory: strong, weak and pseudo rigidity for the Inoue type varieties of Bauer and Catanese (free quotients of ample divisors on projective varieties which are K(\pi, 1)). With Lonne and Wajnryb, using methods by Auroux and Katzarkov: study canonical symplectic structures and deformation types of some simply connected algebraic surfaces, determining braid group factorizations associated to subcanonical projections. More general bicoloured braid factorizations associated to general projections. Teichmueller space of certain algebraic surfaces. Classification and Moduli of surfaces with low invariants. Surfaces of geometric genus 0: new construction techniques, structure of fundamental groups, moduli spaces, existence questions for surfaces with certain invariants, for homotopy quadrics, structure of fake quadrics.Complex analysis and statistical physicsThe goal of this project is to achieve breakthroughs in a few fundamental questions in 2D statistical physics, using techniques from complex analysis, probability, dynamical systems, geometric measure theory and theoretical physics. Over the last decade, we significantly expanded our understanding of 2D lattice models of statistical physics, their conformally invariant scaling limits and related random geometries. However, there seem to be serious obstacles, preventing further development and requiring novel ideas. We plan to attack those, in particular we intend to: (A) Describe new scaling limits by Schramm s SLE curves and their generalizations, (B) Study discrete complex structures and use them to describe more 2D models, (C) Describe the scaling limits of random planar graphs by the Liouville Quantum Gravity, (D) Understand universality and lay framework for the Renormalization Group Formalism, (E) Go beyond the current setup of spin models and SLEs. These problems are known to be very difficult, but fundamental questions, which have the potential to lead to significant breakthroughs in our understanding of phase transitions, allowing for further progresses. In resolvingthem, we plan to exploit interactions of different subjects, and recent advances are encouraging.Variational Methods for Dynamic Inverse Problems in the Life SciencesThis project will develop novel techniques for solving inverse problems in life sciences, in particular related to dynamic imaging. Major challenges in this area are efficient four- dimensional image reconstruction under low SNR conditions and further the quantification of image series as obtained from molecular imaging or life microscopy techniques. We will tackle both of them in a rather unified framework as inverse problems for time-dependent (systems of) partial differential equations. In the solution of these inverse problems we will investigate novel approaches for the following aspects specific to the above-mentioned problems in the life sciences: 1. Solution of inverse problems for PDEs in complex time-varying geometries 2. Development of appropriate variational regularization models for dynamic images, including noise and motion models 3. Improved forward and inverse modelling of cellular and intracellular dynamics leading to novel inverse problems for nonlinear partial differential equations 4. Construction and implementation of efficient iterative solution methods for the arising 4D inverse problems and their variational formulation All tasks will be driven by concrete applications in biology and medicine and their success will be evaluated in applications to real problems and data. This is based on interdisciplinary work related to electrocardiology and developmental biology. The overall development of methods will however be carried out in a flexible and modular way, so that they become accessible for larger problem classes.63D Euler, Vortex Dynamics and PDEThis proposal deals with a collection of problems in PDE arising from fluid mechanics.The primary motivation is the understanding of the evolution of isolated vortex lines for 3D Euler. The importance of the evolution of vorticity in incompressible fluid mechanics is very well known. To date, only nonrigorous approaches are known to try to obtain an evolution equation for isolated vortex lines. Two desingularization procedures are carried out (including a time renormalization) to obtain an evolution equation (the binormal equation). While an isolated vortex line does not fit any known concept of solution (given the singularity of the velocity), and there has been significant recent activity on the nonuniqueness of solutions of Euler (De Lellis & Szekelyhidi, and recently Isett) it is expected that the geometric assumptions made about the solution will still make it possible to find a suitable concept of solution. In the proposal I describe an approach that should help to rigorously understand vortex lines. It is motivated by a programme developed for the Surface Quasi-Geostrophic (SQG) equation with C. Fefferman and for some related desingularized models with my student Zoe Atkins (Nov 2012 PhD). SQG has been of great interest in the PDE community due to the striking similarities it exhibits with 3D Euler. In particular, the evolution of sharp fronts for SQG corresponds to the evolution of vortex lines. In recent years I have developed an approach that overcomes the divergences known to exist for the velocity field (as in 3D Euler). The positive results obtained for SQG motivate the methodology and tools described in the proposal, including the construction of solutions with very large gradients and simple geometry and the use of a measure-theoretic approach to identify fundamental curves within these objects. Surprising connections with other equations motivate some other directions and linked projects, for example with Prandtl and boundary layer ther theory.Intermediate ChaosThe transition from order to chaos has been a central theme of investigation in dynamical systems in the last two decades. Structures that exhibit a mix of de< terministic and chaotic properties, for example, quasi-crystals, naturally arise in problems of geometry and mathematical physics. Despite intense study, key questions about these structures remain wide open.The proposed research is an investigation of intermediate chaos in ergodic theory of dynamical systems. Specific examples include systems of geometric origin such as interval exchange maps, translation and Hamiltonian flows on surfaces of higher genus, symbolic substitution systems important in the study of quasi-crystals as well as dynamical systems arising in asymptotic combinatorics and mathematical physics such as determinantal and Pfaffian point processes. Specific tasks include computation of the Hausdorff dimension for the spectral measure of interval exchange maps (problem posed by Ya. Sinai), limit theorems for Hamiltonian flows on surfaces of higher genus (question of A. Katok), development of entropy theory and functional limit theorems for determinantal point processes and a description of the ergodic decomposition for infinite orthogonally-invariant measures on the space of infinite real matrices (the real case of the problem, posed in 2000 by A. Borodin and G. Olshanski, of harmonic analysis on the infinite-dimensional analogue of the Grassmann manifold). The project consolidates the proposer's past work, in particular, his limit theorems for translation flows (Annals of Math. 2014), his proof of the 1985 Vershik-Kerov entropy conjecture (GAFA 2012) and his solution of the complex case of the Borodin-Olshanski problem (preprint 2013). The proposer is currently PI of project ANR-11-IDEX-0001-02 (1.11.2013--30.10.2015; budget 360000 euro) under the Programme "Investissements d'avenir" of the Government of the French Republic. : 31/12/2020Harmonic Analysis and Differential Equations: New ChallengesThis project sets forth cutting-edge challenges in the field of Mathematical Physics that will be solved within a common framework by making novel use of classical tools of Harmonic Analysis such as Oscillatory Integrals and Trigonometric Sums, the Cauchy operator, and the so-called Carleman estimates. Three aspects will be covered:1.Vortex Filament Equation (VFE)2.Relativistic and Nonrelativistic Critical Electromagnetic Hamiltonians 3.Uncertainty Principles (UPs) and ApplicationsThe interaction of vortex filaments is considered a key issue in order to understand turbulence which is seen by many as the most relevant unsolved problem of classical physics. VFE first appeared as an approximation of the dynamics of isolated vortex filaments. I want to understand what happens when at time zero the filament is a regular polygon. Preliminary theoretical arguments together with some numerical experiments suggest that the different corners behave like different vortex filaments that interact with each other in such a way that the dynamics seem chaotic. I will prove the so -called FrischParisi conjecture, showing that behind this chaotic behavior there is an underlying algebraic structure that controls the dynamics.The Dirac equation, despite being one of the basic equations of Mathematical Physics, is very poorly understood from an analytical point of view. I will use the classical Cauchy operator in a modern way to explain some key Hamiltonian systems such as the MIT bag model for quark confinement.UPs are at the heart of different fields like Quantum Mechanics, Harmonic Analysis, and Information Theory. We want to use a new approach to analyze modern versions of UPs that are not well understood. In order to do this, I will look at the problem from the point of view of partial differential equations making novel use of the Carleman estimates. This analysis will also be extended to the discrete setting where even classical UPs such the one by Hardy are not solved yetQuantifying aerosol-cloud-climate effects by regimeGlobal climate change is widely considered one of the main concerns of humankind. However, predictions are highly uncertain, with no substantial improvement since more than three decades. They are hampered by the huge uncertainty of climate forcing, which is dominated by the uncertainty in anthropogenic aerosol-cloud-climate effects ( aerosol indirect effects ). The goal of QUAERERE (Latin for researching) is a reliable, observations-based, global quantification of these effects, which would also imply a constraint on climate sensitivity and thus climate predictions. This goal is now reachable combining recent advances in different disciplines: (i) a decade-long satellite dataset involving retrievals of the relevant quantities is now available, complemented by a complete aerosol dataset from a new reanalysis; (ii) on the basis of high-resolved numerical weather pre-diction models, which include parameterisations of aerosol cycles and cloud-precipitation microphysics, cloud-system resolving simulations at a regional scale are now possible; reliable simulations beyond idealised cases are thus possible. These tools are complemented by comprehensive global climate models and reference ob-servations from ground-based sites. The problem in aerosol-cloud-climate effects is in its complexity: Various processes counteract each other, and large spatiotemporal variability of clouds buffers the forcing effects. QUAERERE proposes a two-fold  divide-and-conquer approach to this complex problem: (i) aerosol-cloud-climate effects will be investigated by regime; this allows to circumvent the problem of aerosol-cloud-climate ef-fects being buffered when averaging over different regimes; and (ii) by investigating individual terms con-tributing to the aerosol-cloud-climate effects separately; this allows to analyse individual statistical relation-ship in satellite obser< vations and model results consistently, and to perform model sensitivity studies for cause-effect attribution.Life beneath the ocean floor: The subsurface sink of carbon in the marine environmentOne prominent idea for mitigating global climate change is to remove CO2 from the atmosphere by storing it in fluids in the natural environment; for example dissolved within sediments below the ocean floor or in oceanic crust. This carbon sequestration is popular because it would allow us to place carbon into semi-permanent (on human timescales) storage,  buying time to wean us from our dependence on carbon-based energy sources. Application of such a mitigation technique presumes knowledge of what will happen to carbon when it is dissolved in various environments. Studies of naturally produced excess dissolved CO2 are, however, equivocal; this lack of knowledge represents a huge deficit in our comprehension of the global carbon cycle and specifically the processes removing carbon from the surface of the planet over geological timescales. This proposal will resolve the sink for CO2 within marine sediments and oceanic crust. Beneath much of the ocean floor exists the  deep biosphere , microbial populations living largely in the absence of oxygen, consuming organic carbon that has fallen to the sea floor, producing a large excess of dissolved inorganic carbon. This dissolved inorganic carbon can diffuse back to the ocean or can precipitate in situ as carbonate minerals. Previous attempts to quantify the flux of carbon through the deep biosphere focused mostly on studies of sulfur and carbon, and these studies cannot reveal the fate of the produced inorganic carbon. I propose a novel approach to constrain the fate of carbon through the study of the subsurface calcium cycle. Calcium is the element involved in precipitating carbon as in situ carbonate minerals and thus will directly provide the required mass balance to determine the fate of CO2 in the marine subsurface. This mass balance will be achieved through experiments, measurements, and numerical modeling, to achieve the primary objective of constraining the fate of carbon in submarine environments. Early Life Traces, Evolution, and Implications for AstrobiologyTracking the early traces of life preserved in very old rocks and reconstructing the major steps of its evolution is an exciting and most challenging domain of research. How amazing it is to have a cell that is 1.5 or 3.2 billion years old under a microscope! From these and other dissemi nated fragments of life preserved along the geological timescale, one can build the puzzle of biosphere evolution and rising biological complexity. The possibility that life may exist beyond Earth on other habitable planets lies yet at another scale of scientific debates and popular dreams. We have the chance now to live at a time when technology enable us to study in the finest details the very old record of life, or to land on planets with microscope and analytical tools, mimicking a geologist exploring extraterrestrial rocky outcrops to find traces of water and perhaps life. There is still a lot to be done however, to solve major questions of life evolution on Earth, and to look for unambiguous life traces, on Earth or beyond. The project ELiTE aims to provide key answers to some of these fundamental questions. Astrobiology studies the origin, evolution and distribution of life in the Universe, starting with life on Earth, the only biological planet known so far. The ambitious objectives of the project ELiTE are the following: 1) The identification of Early traces of life and their preservation conditions, in Precambrian rocks of established age 2) The characterization of their biological affinities, using innovative approaches comprising micro to nanoscale morphological, ultrastructural and chemical analyses of fossil and recent analog material 3) The determination of the timing of major steps in evolution. In particular, the project ELiTE aims to decipher two major and inter-related steps in early life evolution and the rise of biological complexity: the evolution of cyanobacteria, responsible for Earth oxygenation and ancestor of the chloroplast, influencing drastically the evolution of life and the planet Earth, and the evolution of the domain Eucarya since LECA (Last Eucaryotic Universal Ancestor). 4) The determination of causes of observed pattern of evolution in relation with the environmental context (oxygenation, impacts, glaciations, tectonics, nutrient availability in changing ocean chemistry) and biological innovations and interactions (ecosystems evolution). Objective 1 has implications for the search for unambiguous traces of life on Earth and beyond Earth. Objectives 2 to 4 have implications for the understanding of causes and patterns of biological evolution and rise of complexity in Earth life. Providing answers to these most fundamental questions will have major impact on our understanding of early life evolution, with implications for the search for life beyond Earth.Slip and Earthquake Nucleation in Experimental and Numerical Simulations: a Multi-scale, Integrated and Coupled ApproachEarthquakes represent one of the deadliest and costliest natural disasters affecting our planet  and one of the hardest to predict. To improve seismic hazard evaluation in earthquake-prone regions, an understanding of earthquake nucleation and of the underly< ing microphysical and chemical processes is crucial. A better understanding of the processes that control earthquake nucleation is also of rapidly growing importance for mitigation of induced seismicity, caused by activities such as gas and oil production, and geological storage of CO2 or gas. The SEISMIC project is a multi-scale study aimed at understanding the parameters that control slip (in)stability in experiments and models addressing earthquake nucleation. A central question to be tackled is what controls the velocity-dependence of fault friction and hence the potential for accelerating, seismogenic slip, and on what length scales the processes operate. A novel acoustic imaging technique will be developed and applied in experiments to obtain direct information on the internal microstructural evolution of fault slip zones during deformation, and on how this evolution leads to unstable slip. The SEISMIC project will link experiments with sophisticated numerical models of grain-scale frictional processes. Using both experiments and grain scale modelling, the SEISMIC project will in turn directly test boundary element models for large scale fault slip. The coupling of experiments with grain-scale numerical models, based on in-situ imaging, will provide the first, integrated, multiscale physical basis for extrapolation and upscaling of lab friction parameters to natural conditions. Ultimately, the SEISMIC project will test and validate the resulting models for fault slip by simulating and comparing patterns of seismicity for two natural-laboratory cases: a) for the l Aquila region of Central Italy, and b) for a reservoir-scale case study involving induced seismicity in the Netherlands.Pattern formation and mineral self-organization in highly alkaline natural environmentsThe precipitation of alkaline-earth carbonates in silica-rich alkaline solutions yields nanocrystalline aggregates that develop non-crystallographic morphologies. These purely inorganic hierarchical materials, discovered by the IP of this project, form under geochemically plausible conditions and closely resemble typical biologically induced mineral textures and shapes, thus the name  biomorphs . The existence of silica biomorphs has questioned the use morphology as an unambiguous criterion for detection of primitive life remnants. Beyond applications, the study of silica biomorphs has revealed a totally new morphogenetic mechanism capable of creating crystalline materials with positive or negative constant curvature and biomineral-like textures which lead to the design of new pathways towards concerted morphogenesis and bottom-up self-assembly created by a self-triggered chemical coupling mechanism. The potential interest of these fascinating structures in Earth Sciences has never been explored mostly because of their complexity and multidisciplinary nature. PROMETHEUS proposes an in depth investigation of the nature of mineral structures such as silica biomorphs and chemical gardens, and the role of mineral self-organization in extreme alkaline geological environments. The results will impact current understanding of the early geological and biological history of Earth by pushing forward the unexplored field of inorganic biomimetic pattern formation. PROMETHEUS will provide this discipline with much needed theoretical and experimental foundations for its quantitative application to Earth Sciences. The ambitious research program in PROMETHEUS will require the development of high-end methods and instruments for the non-intrusive in-situ characterization of geochemically important variables, including pH mapping with microscopic resolution, time resolved imaging of concentration gradients, microscopic fluid dynamics, and characterization of ultraslow growth rates.+The Greenhouse Earth SystemHuman activity is fundamentally changing the chemical composition of the atmosphere and warming the Earth. However, the impa< ct of these changes, especially on continental precipitation patterns and biogeochemical cycles, remains poorly understood. The study of ancient climates allows a mechanistic exploration of the Earth system and the opportunity to evaluate new generations of climate models. My proposed research will focus on three inter-related paleoclimatic themes, applied to the very warm climates of the Early Eocene, one of the most fascinating intervals in Earth history. First, I will generate new records of continental temperature using bacterial membrane lipid based proxies that have been recalibrated and critically evaluated for wetland environments. Second, I will assess how the global hydrological cycle responded to both transient and long-term warmth, including evaluating precipitation change and its impact on erosional and weathering regimes; this will entail the development of compound-specific hydrogen isotopic tools in modern contexts, doubling the number of such deep time records, and interpreting those data in the context of isotope-enabled climate models. Third, I will generate the first Paleogene records of terrestrial methane cycling using lipids derived from methanotrophs and methanogens, calibrated in modern settings and applied to Eocene lignites. These objectives are intrinsically linked via the feedbacks between pCO2, temperature, hydrology and carbon cycling. Each objective will comprise: the development of the proxies in modern settings in collaboration with world-leading biogeochemists; creation of unprecedented and globally widespread geochemical records for the Eocene; and quantitative interpretation of our findings using climate/biogeochemical models. Collectively, the work will exploit very recent discoveries to develop or create new proxies and apply them to a major challenge in understanding Earth history.aStardust to asteroids: Unravelling the formation and earliest evolution of a habitable solar systemAs far as we know, our solar system is unique. It could, in principle, be the only planetary system in the Universe to harbor intelligent life or, indeed, life at all. As such, attempting to reconstruct its history is one of the most fundamental pursuits in the natural sciences. Whereas astronomical observations of star- forming regions provide a framework for understanding the formation of low-mass stars and the early evolution of planetary systems in general, direct information about the earliest solar system can only come from primitive meteorites and their components and some differentiated meteorites that record the birth of the solar system. The main objective of this proposal is to investigate the timescales and processes  including the role of supernovas  leading to the formation of the solar system by measurement of isotopic variations in meteorites. To achieve our objectives, we will integrate longlived and short-lived radioisotope chronometers with the presence/absence of nucleosynthetic anomalies in various meteorites and meteoritic components. Our isotopic measurements will beobtained using state-of-the-art technologies such as second-generation mass spectrometers housed in laboratories directed by the PI and fully dedicated to cosmochemistry. This will allow us to: 1) define the mechanism and timescale for the collapse of the protosolar molecular cloud and emergence of the protoplanetary disk, 2) constrain the source and locale of chondrule-forming event(s) as well as the nature of the mechanism(s) required to transport chondrules to the accretion regions of chondrites, and 3) provide robust estimates of the timing and mechanism of asteroidal differentiation. We aim to understand how the variable initial conditions imposed by the range of possible stellar environments and protoplanetary disk properties regulated the formation and assemblage of disk solids into asteroidal and planetary bodies comprising our solar system.g375 Million Years of the Diversification of Life on Land: Shifting the Paradigm?Life on land today is spectacularly diverse, representing 75 95% of all species on Earth. However, it remains unclear how this extraordinary diversity has been acquired across deep geological time. This research project will address this major knowledge gap by reassessing the dominant paradigm of terrestrial diversification, an exponential increase in diversity over the last 375 million years, using the rich and well-studied fossil record of tetrapods (four-limbed vertebrates) as an exemplar group. Previous analyses of tetrapod diversification have been based on an outdated and problematic dataset that is likely to artificially inflate apparent diversity towards the present day. A major new dataset will be assembled, detailing the spatial and temporal distribution of terrestrial tetrapods across their entire fossil record in unprecedented detail. These data< will be analysed using the latest approaches to sampling-standardisation in order to generate completely novel, rigorous curves of diversification through time. These will be compared within a cutting-edge statistical framework to alternate diversification models, as well as to changes in rock record sampling, global environments (e.g. sea level and atmospheric composition) and marine diversity. These comparisons will allow us to address the following key questions: (i) Does terrestrial diversification follow an exponential pattern over the last 375 million years? (ii) Is the terrestrial fossil record as complete as the marine fossil record? (iii) Are long-term patterns of terrestrial diversification driven by physical changes in the Earth system such as climate change? (iv) Did marine and terrestrial biodiversity follow similar trajectories across geological time? (v) How severely did mass extinction events impact upon terrestrial tetrapod diversification? Our work will establish a new, rigorous paradigm for the long-term pattern of terrestrial diversification, and test and identify its drivers.Water-mass transformation and Pathways In The Weddell Sea: uncovering the dynamics of a global climate chokepoint from In-situ measurementsDeep water formed around the Antarctic continent drives the world ocean circulation. 50-70% of this deep water is formed within only about 10% of the Antarctic circumpolar band: the Weddell Sea. Subtle changes in the circulation of the Weddell Sea can lead to major changes in floating ice-shelves, with critical implications for global sea-level, the production of deep water and the global ocean overturning circulation. Despite these critical climate implications, the Antarctic shelf circulation remains poorly understood. I propose an ambitious project at the crossroads of experimental and numerical oceanography. By drawing on the strengths of each discipline I will explore the regional water-mass pathways in the Weddell Sea: an unchartered cornerstone for understanding the polar ocean circulation and its links to global climate. A key issue facing climate scientists will be addressed:  What sets the tridimensional water-mass structure and pathways in the Weddell Sea and modulates the flow of deep waters between the Antarctica ice-shelves and the global ocean circulation? To address this question I propose to investigate several key aspects of the Weddell Sea system: the dynamical forcing of the Weddell gyre and its response to atmospheric variability; the forcing and the circulation on the continental shelf and its interaction with the gyre; and the time-scale and mixing associated with bottom water sinking along the continental shelf. WAPITI approaches these objectives through a series of innovations, including (i) an ambitious field experiment to investigate the shelf circulation and processes, (ii) a powerful conceptual framework applied for the first time to a realistic eddy-resolving model of the Weddell gyre, and (iii) a novel instrument that will be developed to directly observe the sinking of deep water into the abyssal ocean for the first time. Collectively, the project will contribute a new insight into global climate feedbacks.Algal Lipids: the Key to Earth Now and aNcient EarthAlkenones are algal lipids that have been used for decades to reconstruct quantitative past sea surface temperature. Although alkenones are being discovered in an increasing number of lake sites worldwide, only two terrestrial temperature records have been reconstructed so far. The development of this research field is limited by the lack of interdisciplinary research that combines modern biological and ecological algal research with the organic geochemical techniques needed to develop a quantitative biomarker (or molecular fossil) for past lake temperatures. More research is needed for alkenones to become a widely used tool for reconstructing past terrestrial temperature change. The early career Principal Investigator has discovered a new lake alkenone-producing species of haptophyte algae that produces alkenones in high abundances both in the environment and in laboratory cultures. This makes the new species an ideal organism for developing a culture-based temperature calibration and exploring other potential environmental controls. In this project, alkenone production will be manipulated, and monitored using state-of-the-art photobioreactors with real-t< ime detectors for cell density, light, and temperature. The latest algal culture and isolation techniques that are used in microalgal biofuel development will be applied to developing the lake temperature proxy. The objectives will be achieved through the analysis of 90 new Canadian lakes to develop a core -top temperature calibration across a large latitudinal and temperature gradient ( latitude = 5,  spring surface temperature = 9C). The results will be used to assess how regional palaeo-temperature (Uk37), palaeo-moisture (Dwax) and palaeo-evaporation (Dalgal) respond during times of past global warmth (e.g., Medieval Warm Period, 900-1200 AD) to find an accurate analogue for assessing future drought risk in the interior of Canada.kExperiment to Unearth the Rheological Oceanic Lithosphere-Asthenosphere BoundaryPlate tectonics has been a fundamental tenet of Earth Science for nearly 50 years, but fundamental questions remain, such as where is the base of the plate and what makes a plate,  plate-like? A better understanding of the transition from the rigid lithospheric plate to the weaker mantle beneath  the rheological lithosphere-asthenosphere boundary (LAB) - has important implications for the driving forces of plate tectonics, natural hazard mitigation, mantle dynamics, the evolution of the planet, and climate change. There are many proxies used to estimate the depth and nature of the base of tectonic plates, but to date no consensus has been reached. For example, temperature is known to have a strong effect on the mechanical behaviour of rocks. However, it has also been suggested that the chemical composition of the plate provides additional strength or that melt weakens the mantle beneath the plate.We are at a critical juncture where large-scale efforts using geophysical, geochemical, and geological techniques are being launched to better understand the definition of the tectonic plate. The simple and short history of the ocean plate makes it the ideal location to advance our understanding. However, imaging the oceanic LAB has proved challenging given the remoteness of the oceans and associated difficulties in instrumentation. Most observations come from only one ocean, the Pacific, from indirect, remote observations, at different areas and scales.I propose a largescale effort to systematically image an oceanic plate beneath the Atlantic from birth at ridge to 40 My old seafloor. I will deploy ocean bottom seismometers (OBS) and magnetotelluric (MT) instruments, and I will image the plate at a range of resolution scales (laterally and in depth) and sensitivities to physical and chemical properties. This large, focused, interdisciplinary effort will finally determine the processes and properties that make a plate strongand define it. : 31/3/2021hSynchronisation to enhance reliability of climate predictionsClimate prediction is the next frontier in climate research. Prediction of climate on timescales from a season to a decade has shown progress, but beyond the ocean skill remains low. And while the historical evolution of climate at global scales can be reasonably simulated, agreement at a regional level is limited and large uncertainties exist in future climate change. These large uncertainties pose a major challenge to those providing climate services and to informing policy makers.This proposal aims to investigate the potential of an innovative technique to reduce model systematic error, and hence to improve climate prediction skill and reduce uncertainties in future climate projections. The current practice to account for model systematic error, as for example adopted by the Intergovernmental Panel on Climate Change, is to perform simulations with ensembles of different models. This leads to more reliable predictions, and to a better representation of climate. Instead of running models independently, we pro< pose to connect the different models in manner that they synchronise and errors compensate, thus leading to a model superior to any of the individual models  a super model. The concept stems from theoretical non-dynamics and relies on advanced machine learning algorithms. Its application to climate modelling has been rudimentary. Nevertheless, our initial results show it holds great promise for improving climate prediction. To achieve even greater gains, we will extend the approach to allow greater connectivity among multiple complex climate models to create a true super climate model. We will assess the approach s potential to enhance seasonal-to-decadal prediction, focusing on the Tropical Pacific and North Atlantic, and to reduce uncertainties in climate projections. Importantly, this work will improve our understanding of climate, as well as how systematic model errors impact prediction skill and contribute to climate change uncertainties.\Camera Observation and Modelling of 4D Tracer Dispersion in the AtmosphereCOMTESSA will push back the limits of our understanding of turbulence and plume dispersion in the atmosphere by bringing together full four-dimensional (space and time) observations of a (nearly) passive tracer (sulfur dioxide, SO2), with advanced data analysis and turbulence and dispersion modelling.Observations will be made with six cameras sensitive to ultraviolet (UV) radiation and three cameras sensitive to infrared (IR) radiation. The UV cameras will be built specifically for this project where high sensitivity and fast sampling is important. The accuracy of UV and IR retrievals will be improved by using a state-of-the art-3D radiative transfer model. Controlled puff and plume releases of SO2 will be made from a tower, which will be observed by all cameras, yielding multiple 2D images of SO2 integrated along the line of sight. The simultaneous observations will allow - for the first time - a tomographic reconstruction of the 3D tracer concentration distribution at high space (< 1 m) and time (>10 Hz) resolution. An optical flow code will be used to determine the eddy-resolved velocity vector field of the plume. Special turbulent phenomena (e.g. plume rise) will be studied using existing SO2 sources (e.g. smelters, power plants, volcanic fumaroles).Analysis of the novel campaign observations will deepen our understanding of turbulence and tracer dispersion in the atmosphere. For instance, for the first time we will be able to extensively measure the concentration probability density function (PDF) in a plume not only near the ground but also at high-er altitudes; quantify relative and absolute dispersion; estimate the value of the Richardson-Obukhov constant, etc. We will also use the data to evaluate state-of-the-art LES and Lagrangian dispersion models and revise their underlying parameterizations.COMTESSA s vision is that the project results will lead to large improvements of tracer transport in all atmospheric models.Quantum Optical Interfaces for Atoms and Nano-electro-mechanical SystemsQuantum interfaces capable of transferring quantum states and generating entanglement between fields and matter are set to play a growing role in the development of science and technology. Development of such interfaces has been a crucial component in quantum information processing and communication. In the past decade quantum interfaces between atoms and optical photons have been extensively explored by a number of leading groups. Quantum state transfer between light and atoms, such as quantum memory and quantum teleportation, entanglement of massive objects, as well as measurements and sensing beyond standard quantum limits have been demonstrated by the group of the PI. We propose to develop a robust, integrated and scalable atom-light interface and to incorporate it into a hybrid multi-facet quantum network with other relevant quantum systems, such as nano-mechanical oscillators and electronic circuits. Towards this ambitious goal we will develop room temperature atomic quantum memories in spin protecting micro-cells (mu-cells) and optomechanical and electromechanical strongly coupled systems. Interfacing atoms, electronic circuits and nano-mechanical oscillators we will perform ultrasensitive quantum limited field and force measurements and quantum teleportation of states across the range of these systems. In the fundamental sense, this research program will further broaden the horizons of quantum physics and quantum information processing by expanding it into new and unexplored macroscopic domains.jInterferometry beyond the Standard Quantum Limit using a Velocity Sensitive Sagnac InterferometerFrom the ver< y first Michelson Interferometer invented over 100 years ago to today s kilometre-scale gravitational wave detectors the sensitivity of interferometric length measurements has been improved by about 10 orders of magnitude and is now limited by the so-called Standard Quantum Limit (SQL), a manifestation of Heisenberg s Uncertainty Principle. The SQL is comprised of the inevitable combination of sensing noise (photon shot noise) and back action noise (photon radiation pressure noise) when repeatedly measuring the position of a test mass. However, by measuring a different var      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghiklmnopqrstuvwxyz{|}~iable, i.e. the test mass velocity (speedmeter) instead of its position (position-meter), it is possible to evade back action noise. The momentum of a free test mass can be measured continuously to arbitrary accuracy without being limited by the SQL. Since a Sagnac interferometer is sensitive only to the time-dependent part of the arm-length difference it is automatically a speed meter and therefore brings measurements beyond the SQL into our reach. Theoretical analyses have shown that the speedmeter approach is the most promising track towards wide-band sub-SQL measurements. An experimental test of this technique is urgently required! Therefore, my three main objectives of this proposal are: 1) Realisation of an ultra-low noise, quantum radiation pressure dominated speedmeter test bed. 2) Experimental demonstration of back action noise supression in a Sagnac speedmeter. 3) Development of speedmeter based sub-SQL interferometery for future gravitational wave detectors such as the Einstein Telescope. By the end of this project I will have demonstrated the sub-SQL potential of the Sagnac speedmeter configuration. A positive outcome of this project is expected to lead to the Sagnac speedmeter superseding the Michelson interferometer as state-of-the-art instrument for ultra-high sensitivity lengths measurements.The Structure of the Extra Dimensions of String TheoryString theory predicts the existence of several spatial dimensions in addition to the three of our everyday experience. The space spanned by these dimensions might be small enough to have escaped detection so far. The aim of this project is to characterize which spaces are allowed by the dynamics of the theory, and what physics they give rise to. A few years ago, I discovered a reformulation of supergravity in terms of differential forms, based on the so-called generalized complex geometry. This method was originally limited to string theory vacuum solutions, and over the years it has permitted to find many of them, often with applications to AdS/CFT. Recently, I was able to extend it to deal with any kind of spacetime dependence; this will allow to probe the choice of extra dimensions more extensively, for example by studying black hole solutions. It will help single out interesting geometries for the extra dimensions, even before one sets out to understand the effective four-dimensional Lagrangian that would result from compactifying string theory on it. Moreover, I plan to extend the method even further, to deal with controlled supersymmetry breaking. That would open the possibility of producing systematically vacuum solutions which have a positive cosmological constant. The vacua obtained in this way would be fully classical, and under better control than current models.3D-Quantum Integrated Optical SimulationQuantum information was born from the merging of classical information and quantum physics. Its main objective consists of understanding the quantum nature of information and learning how to process it by using physical systems which operate by following quantum mechanics laws. Quantum simulation is a fundamental instrument to investigate phenomena of quantum systems dynamics, such as quantum transport, particle localizations and energy transfer, quantum-to-classical transition, and even quantum improved computation, all tasks that are hard to simulate with classical approaches. Within this framework integrated photonic circuits have a strong potential to realize quantum information processing by optical systems. The aim of 3D-QUEST is to develop and implement quantum simulation by exploiting 3-dimensional integrated photonic circuits. 3D-QUEST is structured to demonstrate the potential of linear optics to implement a computational power beyond the one of a classical computer. Such "hard-to-simulate" scenario is disclosed when multiphoton-multimode platforms are realized. The 3D-QUEST research program will focus on three tasks of growing difficulty. A-1. To simulate bosonic-fermionic dynamics with integrated optical systems acting on 2 photon entangled states. A-2. To pave the way towards hard-to-simulate, scalable quantum linear optical circuits by investigating m-port interferometers acting on n-photon states with n>2. A-3. To exploit 3-dimensional integrated structures for the observation of new quantum optical phenomena and for the quantum simulation of more complex scenarios. 3D-QUEST will exploit the potential of the femtosecond laser writing integrated waveguides. This technique will be adopted to realize 3 -dimensional capabilities and high flexibility, bringing in this way the optical quantum simulation in to new regime.The strong interaction at neutron-rich extremesThe strong interaction at neutron-rich extremes (STRONGINT) will investigate the structure of matter at the neutron-rich frontier in the laboratory and in the cosmos based on chiral effective field theory (EFT) interactions. Chiral EFT opens up a systematic path to investigate many-body forces and provides unique constraints for three-neutron and four-neutron interactions. We will for the first time explore the predicted many-body forces in neutron matter and neutron-rich matter. One milestone will be set by the developmen< t of a systematic power counting for neutron-rich matter. This will enable us to carry out diagrammatic approaches, and to develop ground-breaking nonperturbative Monte-Carlo calculations. Our results will strongly constrain the nuclear equation of state at the extremes reached in core-collapse supernovae and neutron stars. Based on the developments for neutron-rich matter, we will investigate spin correlations and develop a systematic description of neutrino-matter interactions, which can set the new standard for supernova simulations. Our pioneering studies have revealed new facets of three-body forces in neutron-rich nuclei, such as their role in determining the location of the neutron dripline in oxygen and in elucidating the doubly-magic nature of calcium-48. We will investigate the impact of chiral three-nucleon forces on key regions in the r-process path and develop a chiral EFT for valence-shell interactions. This will open new horizons for understanding the shell structure of nuclei. Another milestone will be set by the first calculation of neutrino-less doublebeta decay based on chiral EFT interactions and consistent electroweak currents. The proposed interdisciplinary problems are essential for a successful and quantitative understanding of these bigscience questions.Spectroscopy of Trapped AntihydrogenAntihydrogen is the only stable, neutral antimatter system available for laboratory study. Recently, the ALPHA Collaboration at CERN has succeeded in synthesizing and trapping antihydrogen atoms, storing them for up to 1000 s, and performing the first resonant spectroscopy, using microwaves, on trapped antihydrogen. This last, historic result paves the way for precision microwave and laser spectroscopic measurements using small numbers of trapped antihydrogen atoms. Because of the breakthroughs made in our collaboration, it is now possible, for the first time, to design antimatter spectroscopicexperiments that have achievable milestones of precision. These measurements require a nextgeneration apparatus, known as ALPHA-2, which is the subject of this proposal. The items sought are hardware components and radiation sources to help us to test CPT (charge conjugation, parity, time reversal) symmetry invariance by comparing the spectrum of antihydrogen to that of hydrogen. More generally, we will address the very fundamental question: do matter and antimatter obey the same laws of physics? The Standard Model says that they must, but mystery continues to cloud our understanding of antimatter - as evidenced by the unexplained baryon asymmetry in the universe. ALPHA's experiments offer a unique, high precision, model-independent view into the internal workings of antimatter.Holography for realistic black holes and cosmologiesString theory provides with a consistent framework which combines quantum mechanics and gravity. Two grand challenges of fundamental physics - building realistic models of black holes and cosmologies evidence indicates that some black holes rotate extremely fast, as close as 98% to the extremality bound. No quantum gravity model for such black holes has been formulated so far. My first objective is building the first model in string theory of an extremal black hole. Taking on this challenge is made possible thanks to recent advances in a remarkable duality known as the gauge/gravity correspondence. If successful, this program will pave the way to a description of quantum gravity effects that have been conjectured to occur close to the horizon of very fast rotating black holes. Supernovae detection has established that our universe is starting a phase of accelerated expansion. This brings a pressing need to better understand still enigmatic features of de Sitter spacetime that models our universe at late times. My second objective is to derive new universal properties of the cosmological horizon of de Sitter spacetime using tools inspired from the gauge/gravity correspondence. These results will contribute to understand its remarkable entropy, which, according to the standard model of cosmology, bounds the entropy of our observable universe.1Parton Distributions in the Higgs Boson EraWith the recent discovery of a Higgs-like particle at the Large Hadron Collider (LHC), particle physics has entered a completely new era. The central goal for high energy physics in the following years will be the detailed determination of the properties of this new particle, in particular checking its consistency with the Standard Model Higgs boson hypothesis, and to further explore the highest energy domain in search for further new physics, like supersymmetry or extra dimensions, closely related to the Higgs-like boson properties and to dark matter and dark energy studies. It is thus of paramount importance to be able to provide accurate theoretical predictions for signal and background processes both for Higgs production and for hypothetical new particles, in order to optimize both the characterization of cross sections, couplings and branching fractions, but also to maxime the LHC discovery potential. A crucial ingredient of these theoretical predictions for an hadron collider as the LHC are the Parton Distribution Functions (PDFs) of the proton. This project aims to fully exploit the LHC potential to achieve the ultimate experimental and theoretical precision in the determination of PDFs to make essential contributions to our understanding of the structure of the nucleon, in particular in the regions more relevant for Higgs and BSM physics searches at the LH, the match between PDFs and NLO Monte Carlo event generators, a crucial tool for accurate exclusive event description at the LHC, and to propose new avenues in New Physics searches from precision LHC measurements, where PDFs are often the dominant systematic uncertainties.5Cryogenic wide-Area Light Detectors ?with Excellent ResolutionIn the comprehension of fundamental laws of nature, particle physics is now facing two important questions: 1) What is the nature of the neutrino, is it a standard (Dirac) particle or a Majorana particle? The nature of the neutrino plays a crucial role in the global framework of particle interactions and in cosmology. The only practicable way to answer this question is to search for a nuclear process called neutrinoless double beta decay (0nuDBD). 2) What is the so called "dark matter" made of? Astrophysical observations suggest that the largest part of the mass of the Universe is composed by a form of matter other than atoms and known matter constituents. We still do not know what dark matter is made of because its rate of interaction with ordinary matter is really low, thus making the direct experimental detection extremely difficult. Both 0nuDBD and dark matter interactions are rare processes and can be detected using the same experimental technique. Bolometers are promising devices and their combination with light detectors provides the identification of interacting particles, a powerful tool to reduce the background. ? The goal of CALDER is to realize a new type of light detectors to improve the upcoming generation of bolometric experiments. The detectors will be designed to feature unprecedented energy resolution and reliability, to ensure an almost complete particle identification. In case of success, CUORE, a 0nuDBD experiment in construction, would gain in sensitivity by up to a factor 6. LUCIFER, a 0nuDBD experiment already implementing the light detection, could be sensitive also to dark matter interactions, thus increasing its research potential. The light detectors will be based on Kinetic Inductance Detectors (KIDs), a new technology that proved< its potential in astrophysical applications but that is still new in the field of particle physics and rare event searches.XMesoscopic Fermi GasesThis proposal brings together the fields of ultracold Fermi gases and of mesoscopic systems. Starting with a two-dimensional (2D) Fermi gas, we will imprint small-scale potential structures onto the atoms. Thus, a mesoscopic system embedded in a 2D reservoir is produced. Specifically, we will imprint optical dipole potentials varying on a micrometre scale onto a 2D gas of 6Li atoms. Due to the widely different energy scales, the entropy of the atoms in the mesoscopic structures will be massively reduced as compared to the reservoir atoms. The atoms in the mesoscopic structures will be characterised by an innovative detection scheme with single atom sensitivity. The combination of mesoscopic potentials, single atom detection and entropy reduction will put us in a unique position to access new regimes of many-body physics. First, we will investigate a mesoscopic realisation of the 2D Hubbard model. Beyond the study of the fermionic Mott insulating phase and its excitations, the possibility to study staggered Hubbard models and create domain structures is a very attractive prospect. Most importantly, the massive entropy reduction inherent to the mesoscopic approach will enable us to observe antiferromagnetic ordering, the major milestone central to further progress in the field. Going beyond periodic structures, we will focus on the direct creation of mesoscopic model systems. In a bottom-up approach, we will realise a plaquette consisting of 2x2 sites, the essential building block for models of d-wave superconductivity. The creation of 1D structures with local defects will open the possibility to study phenomena such as spin-charge separation, Friedel oscillations and the rectification of atomic transport. Finally, the physics of open quantum systems will become accessible when studying the interaction between mesoscopic system and reservoir. In conclusion, I believe that the proposed research programme will bring a new level of functionality to the field.Quantum fields and knot homologiesThis project is concerned with fundamental problems arising at the interface of quantum field theory, knot theory, and the theory of random matrices. The main aim of the project is to understand two of the most profound phenomena in physics and mathematics, namely quantization and categorification, and to establish an explicit and rigorous framework where they come into play in an interrelated fashion. The project and its aims focus on the following areas: - Knot homologies and superpolynomials. The aim of the project in this area is to determine homological knot invariants and to derive an explicit form of colored superpolynomials for a large class of knots and links. - Super-Apolynomial. The aim of the project in this area is to develop a theory of the super-A-polynomial, to find an explicit form of the super-A-polynomial for a large class of knots, and to understand its properties. -Three-dimensional supersymmetric N=2 theories. This project aims to find and understand dualities between theories in this class, in particular theories related to knots by 3d-3d duality, and to generalize this duality to the level of homological knot invariants. - Topological recursion and quantization. The project aims to develop a quantization procedure based on the topological recursion, to demonstrate its consistency with knot-theoretic quantization of A-polynomials, and to generalize this quantization scheme to super-A-polynomials. All these research areas are connected via remarkable dualities unraveled very recently by physicists and mathematicians. The project is interdisciplinary and aims to reach the above goals by taking advantage of these dualities, and through simultaneous and complementary development in quantum field theory, knot theory, and random matrix theory, in collaboration with renowned experts in each of those fields.tMeeting Challenges in Computer ArchitectureComputer technology has doubled computational performance every 24 months, over the past several decades. This performance growth rate has been an enabler for the dramatic innovation in information technology that now embraces our society. Before 2004, application developers could exploit this performance growth rate with no effort. However, since 2004 power consumption of computer chips exceeded the allowable limits and from that point and onwards, parallel computer architectures became the norm. Currently, parallelism is completely exposed to application developers and managing it is difficult and time-consuming. This has a serious impact on software productivity that may stall progress in information technology. Technology forecasts predict that by 2020 there will be hundreds of processors on a computer chip. Apart from managing parallelism, keeping power consumption within allowable limits will remain a key roadblock for maintaining historical performancegrowth rates. Power efficiency must increase by an order of magnitude in the next ten years to not limit the growth rate. Finally, computer chips are also key components in embedded controllers, where stringent timing responses are mandatory. Delivering predictable and tight response times using parallel architectures is a challenging and unsolved problem. MECCA takes a novel, interdisciplinary and unconventional approach to address three important challenges facing computer architecture  the three Ps: Parallelism, Power, and Predictability in a unified framework. Unlike earlier, predominantly disciplinary approaches, MECCA bridges layers in computing systems from the programming language/model, to the compiler, to the run-time/OS, down to the architecture layer. This opens up for exchanging information across layers to manage paralleli< sm and architectural resources in a transparent way to application developers to meet challenging performance, power, and predictability requirements for future computers.CPhysics of Atoms with Attosecond Light PulsesThe field of attosecond science is now entering the second decade of its existence, with good prospects for breakthroughs in a number of areas. We want to take the next step in this development: from mastering the generation and control of attosecond pulses to breaking new marks starting with the simplest systems, atoms. The aim of the present application is to advance the emerging new research field  Ultrafast Atomic Physics , where one- or two-electron wave packets are created by absorption of attosecond pulse(s) and analyzed or controlled by another short pulse. Our project can be divided into three parts: 1. Interferometric measurements using tunable attosecond pulses How long time does it take for an electron to escape its potential? We will measure photoemission time delays for several atomic systems, using a tunable attosecond pulse source. This type of measurements will be extended to multiple ionization and excitation processes, using coincidence measurements to disentangle the different channels and infrared ionization for analysis. 2. XUV pump/XUV probe experiments using intense attosecond pulses How long does it take for an atom to become an ion once a hole has been created? Using intense attosecond pulses and the possibility to do XUV pump/ XUV probe experiments, we will study the transition between nonsequential double ionization, where the photons are absorbed simultaneously and all electrons emitted at the same time and sequential ionization where electrons are emitted one at a time. 3. "Complete" attosecond experiments using high-repetition rate attosecond pulses We foresee a paradigm shift in attosecond science with the new high repetition rate systems based on optical parametric chirped pulse amplification which are coming to age. We want to combine coincidence measurement with angular detection, allowing us to characterize (two-particle) electronic wave packets both in time and in momentum and to study their quantum-mechanical properties.Quantum-Degenerate Strontium:Mixtures, Molecules, and Many-Body PhysicsIn 2009 my research team created the first Bose-Einstein condensate of strontium. This breakthrough is the foundation of my research program, which will investigate quantum many-body phenomena with a focus on quantum magnetism and physics related to the quantum Hall effect. We are especially interested in studying unusual, strongly correlated quantum states, among them states with topological order. The unique properties of strontium make it ideally suited to follow four different approaches to this physics. 1) We will immerse our quantum gas into artificial gauge fields, which e.g. let neutral atoms behave as if they were charged particles in a strong magnetic field. These field s will allow us to study quantum Hall states or topological insulators. 2) We will study SU(N) magnetism, which is an unusual form of magnetism not found in condensed matter, but of high interest for theory. A high degree of frustration can lead to spin liquid behaviour. 3) We will use sympathetic Pomeranchuk cooling of a potassium spin mixture by fermionic strontium to reach low entropy quantum phases. Our goal is to study magnetically ordered states and frustrated antiferromagnetism. 4) We will create RbSr ground-state molecules, which are polar, open-shell molecules. They will allow us to engineer unique quantum-many body systems with long-range interactions, e.g. lattice-spin models that can support topological states. We will pursue this research not only on our existing Rb/Sr quantum gas mixture apparatus, but we will construct a new K/Sr quantum gas microscope. This machine will be very valuable to explore exotic quantum states. The properties of strontium will enable an innovative single-atom detection method based on shelving in a metastable state and quench cooling, which will allow us to take internal state-resolved, 3D, or super-resolution images of the lattice gas.fGenuine Quantumness in Cooperative PhenomenaThe proposed research programme addresses issues of fundamental and technological importance in quantum information science and its interplay with complexity. The main aim of this project is to provide a new paradigmatic foundation for the characterisation of quantumness in cooperative phenomena and to develop novel platforms for its practical utilisation in quantum technology applications.To reach its main goal, this programme will target five specific objectives:O1. Constructing a quantitative theory of quantumness in composite systems;O2. Benchmarking genuine quantumness in information and communication protocols;O3. Devising practical solutions for quantum -enhanced metrology in noisy conditions;O4. Developing quantum thermal engineering for refrigerators and heat engines;O5. Establishing a cybernetics framework for regulative phenomena in the quantum domain.This project is deeply driven by the scientific curiosity to explore the ultimate range of applicability of quantum mechanics. Along the route to satisfying such curiosity, this project will fulfill a crucial two-fold mission. On the fundamental side, it will lead to a radically new level of understanding of quantumness, in its various manifestations, and the functional role it plays for natural and artificial complex systems traditionally confined to a classical domain of investigation. On the practical side, it will deliver novel concrete recipes for communication, sensing and cooling technologies in realistic conditions, rigorously assessing in which ways and to which extent these can be enhanced by e< ngineering and harnessing quantumness.Along with a skillful team which this grant will allow to assemble, benefitting from the vivid research environment at Nottingham, and mainly thanks to his creativity, broad mathematical and physical preparation and relevant inter-disciplinary expertise, the applicant is in a unique position to accomplish this timely and ambitious mission.New frontiers in numerical general relativityIn recent years general relativity (GR) has become an increasingly important new tool in areas of physics beyond its traditional playground in astrophysics. The main motivation for this comes from the AdS/CFT correspondence which conjectures an equivalence between gravity in anti-de Sitter (AdS) spaces and certain conformal field theories (CFT s). Via this correspondence, GR now plays a key role in improving our understanding of non-gravitational physics at strong coupling. The AdS/CFT correspondence naturally leads to the study of GR in dimensions greater than four and/or in AdS spaces. Our current understanding of GR in these new settings is rather limited but it has been realized that the physics of gravity can be significantly different than in the 4d asymptotically flat case. Moreover, to access these new gravitational phenomena numerical methods have been and will be essential. However, the use of numerical GR beyond the traditional 4d asymptotically flat case is still in its infancy. The goal of this project is to improve our understanding of GR in higher dimensions and/or AdS spaces using numerical techniques. To achieve this goal, we will focus on the study of the following topics: 1. Develop stable codes for doing numerical GR in AdS and higher dimensions. We will use numerical GR and the AdS/CFT correspondence to study out of equilibrium phenomena in strongly coupled CFT s. We will also use numerical GR to understand the endpoint of the various black hole instabilities and thereby address long standing conjectures in GR. 2. New types of stationary black holes. We will use numerical GR to numerically construct new types of black holes in higher dimensions and in AdS, with novel topologies and fewer symmetries than the known ones. We shall apply them to the study of equilibrium configurations in strongly coupled gauge theories at finite temperature.Challenging the Standard Model using an extended Physics program in LHCbWe know that the Standard Model (SM) of Particle Physics is not the ultimate theory of Nature. It misses a quantum description of gravity, it does not offer any explanation to the composition of Dark Matter, and the matter-antimatter unbalance of the Universe is predicted to be significantly smaller than what we actually see. Those are fundamental questions that still need an answer. Alternative models to SM exist, based on ideas such as SuperSymmetry or extra dimensions, and are currently being tested at the Large Hadron Collider (LHC) at CERN. But after the first run of the LHC the SM is yet unbeaten at accelerators, which imposes severe constraints in Physics beyond the SM (BSM). From this point, I see two further working directions: on one side, we must increase our precision in the previous measurements in order to access smaller BSM effects. On the other hand; we should attack the SM with a new fleet of observables sensitive to different BSM scenarios, and make sure that we are making full use of what the LHC offers to us. I propose to create a team at Universidade de Santiago de Compostela that will expand the use of LHCb beyond its original design, while also reinforcing the core LHCb analyses in which I played a leading role so far. LHCb has up to now collected world-leading samples of decays of b and c quarks. My proposal implies to use LHCb for collecting and analysing also world-leading samples of rare s quarks complementary to those of NA62. In the rare s decays the SM sources of Flavour Violation have a stronger suppression than anywhere else, and therefore those decays are excellent places to search for new Flavour Viola< ting sources that otherwise would be hidden behind the SM contributions. It is very important to do this now, since we may not have a similar opportunity in years. In addition, the team will also exploit LHCb to search for  resonances predicted in models like NMSSM, and for which LHCb also offers a unique potential that must be used.Strategic Predictions for Quantum Field TheoriesAmbitious Questions: * How does the relatively calm macroscopic universe survive and emerge from the violent quantum fluctuations of its underlying microphysics? * How do classical notions of space and time emerge from fundamental principles, and what governs their evolution? These questions are difficult to answer---perhaps impossible given current ideas and frameworks---but I believe a strategic path forward is to thoroughly understand the quantum predictions of our Yang-Mills and Gravity theories, and unambiguously identify their non-perturbative UV completions. The first step forward, and the goal of this project, is to move towards the trivialization of perturbative calculations. Consider the notion of failure-point calculations -- calculations that push modern methods and worldclass technologies to their breaking-point. Such calculations, for their very success, engender the chance of cultivating and exploiting previously unappreciated structure. In doing so, such calculations advance the state of the art forward to some degree, dependent on the class of the problems and nature of the solution. With scattering amplitude calculations, we battle against (naive) combinatorial complexity as we go either higher in order of quantum correction ( loop order ), or higher in number of external particles scattering (multiplicity), so our advances must be revolutionary to lift us forward. Yet I and others have shown that the very complications of generalized gauge freedom promise a potential salvation at least as powerful as the complications that confront us. The potential reward is enormous, a rewriting of perturbative quantum field theory to make these principles manifest and calculation natural, an ambitious but now realistic goal. The path forward is optimized through strategic calculations.Stability Islands: Performance Revolution in MachiningCutting went through a revolution in the 1990s when high-speed milling (HSM) was introduced: the sculpture-like workpieces produced with high precision and efficiency resulted in one order of magnitude less parts in cars/aircrafts, which kept this traditional technology competitive at the turn of the century. This has been followed by an incremental development when not just the cutting speeds, but depths of cut and feed rates are pushed to limits, too. The limits are where harmful vibrations occur. Cutting is subject to a special one called chatter, which is originated in a time delay: the cutting edge interferes with its own past oscillation recorded on the wavy surface cut of the workpiece. In 1907, the 3rd president of ASME, Taylor wrote:  Chatter is the most obscure and delicate of all problems facing the machinist . In spite of the development of the theory of delay-differential equations and nonlinear dynamics, Taylor s statement remained valid 100 years later when HSM appeared together with a new kind of chatter. The applicant has been among those leading researchers who predicted these phenomena; the experimental/numerical techniques developed in his group are widely used to find parameters, e.g. where milling tools with serrated edges and/or with varying helix angles are advantageous. The SIREN project aims to find isolated parameter islands with 3-5 times increased cutting efficiency. The work-packages correspond to points of high risk: (1) validated, delay-based nonlinear modelling of the dynamic contact problem between chip and tool; (2) fixation of the tool that is compatible with a dynamically reliable mathematical model of the contact between tool and tool-holder; (3) up-to-date dynamic modelling of the spindle at varying speeds. High risk originates in the attempt of using distributed delay models, but high gain is expected with robust use of parameter islands where technology reaches a breakthrough in cutting efficiency for the 21st century.SMatter and strong-field gravity: New frontiers in Einstein s theoryGravity is the weakest but the most intriguing fundamental interaction in the Universe. In the last decades a formidable intellectual effort has shown that the full-fledged geometric nature of gravity offers much more than a beautiful description and understanding of all stellar and galactic. In the quest for the ultimate theory of gravity, new and spectacular connections between high-energy physics, astrophysics, cosmology and theoretical physics have emerged. Tr< iggered by breakthroughs at the observational, experimental and conceptual levels, strong gravity physics is experiencing a Golden Age, making it one of the most active fields of research of the 21st century. My group in Lisbon has been involved in groundbreaking research into the nature of strong-field effects in curved spacetime with applications in various fields, thus establishing international leadership in the field. This proposal aims at understanding, via perturbative techniques and full-blown nonlinear evolutions, the strong-field regime of gravity, and includes challenging nonlinear evolutions describing gravitational collapse, compact binary inspirals and collisions in the presence of fundamental fields. The proposed programme will significantly advance our knowledge of Einstein's field equations and their role in fundamental questions (e.g. cosmic censorship, hoop conjecture, spacetime stability, no hair theorems), but also its interplay with high energy, astro and particle physics (testing the precise nature of the interaction between compact objects and matter --such as dark matter candidates or accretion disks-- and its imprint on gravitational wave emission, understanding gravitational-led turbulence,etc).This is a cross-cutting and multidisciplinary program with an impact on our understanding of gravity at all scales, on our perception of black hole-powered phenomena and on gravitational-wave and particle physics.Loop amplitudes in quantum field theoryThe traditional formulation of relativistic quantum theory is ill-equipped to handle the range of difficult computations needed to describe particle collisions at the Large Hadron Collider (LHC) within a suitable time frame. Yet, recent work shows that probability amplitudes in quantum gauge field theories, such as those describing the Standard Model and its extensions, take surprisingly simple forms. The simplicity indicates deep structure in gauge theory that has already led to dramatic computational improvements, but remains to be fully understood. For precision calculations and investigations of the deep structure of gauge theory, a comprehensive method for computing multi-loop amplitudes systematically and efficiently must be found.The goal of this proposal is to construct a new and complete approach to computing amplitudes from a detailed understanding of their singularities, based on prior successes of so-called on-shell methods combined with the latest developments in the mathematics of Feynman integrals. Scattering processes relevant to the LHC and to formal investigations of quantum field theory will be computed within the new framework.Direct Visualization of Light-Driven Atomic-Scale Carrier Dynamics in Space and TimeElectronics is rapidly speeding up. Ultimately, miniaturization will reach atomic dimensions and the switching speed will reach optical frequencies. This ultimate regime of lightwave electronics, where atomic-scale charges are controlled by few-cycle laser fields, holds promise to advance information processing technology from today s microwave frequencies to the thousand times faster regime of optical light fields. All materials, including dielectrics, semiconductors and molecular crystals, react to such field oscillations with an intricate interplay between atomic-scale charge displacements (polarizations) and collective carrier motion on the nanometer scale (currents). This entanglement provides a rich set of potential mechanisms for switching and control. However, our ability to eventually realize lightwave electronics, or even to make first steps, will critically depend on our ability to actually measure electronic motion in the relevant environment: within/around atoms. The most fundamental approach would be a direct visualization in space and time. This project, if realized, will offer that: a spatiotemporal recording of electronic motion with sub-atomic spatial resolution and suboptical-cycle time resolution, i.e. picometers and few-femtoseconds/attoseconds. Drawing on our unique combination of expertise covering electron diffraction and few-cycle laser optics likewise, we will replace the photon pulses of conventional attosecond spectroscopy with freely propagating singleelectron pulses at picometer de Broglie wavelength, compressed in time by sculpted laser fields. Stroboscopic diffraction/microscopy will provide, after playback of the image sequence, a direct visualization of fundamental electronic activity in space and time. Profound study of atomic-scale lightmatter interaction in simple and complex materials will provide a comprehensive picture of the fundamental physics allowing or limiting the high-speed electronics of the future.BVery fast Imaging by Broadband coherent RAmanThe VIBRA project aims at developing an innovative microscope for real-time non-invasive imaging of cells and tissues, which promises to have a revolutionary impact on several fields of biology and medicine. Chemically specific vibrational signatures of molecules enable their direct structural characterization. Reliable and quantitative endogenous bio-markers can be established, e.g., to follow cell differentiation and to identify crucial properties of tissues (malignant vs benign phenotype of a tumour). In this way neoplasms can be located and their borders with normal tissue traced for surgery. Spontaneous Raman spectroscopy demonstrated this capability, but it is intrinsically too slow for imaging. Coherent Raman microscopy, on the other hand, can reach extremely high speed (up to the video rate) but at the expense of poor chemical selectivity, being < limited to a single vibrational frequency.The ground-breaking goal of VIBRA is to combine the most detailed molecular information over the entire vibrational spectrum with the highest acquisition speed. The PI will develop a complete coherent Raman microscope for near-video-rate broadband vibrational imaging. This high risk/high gain goal will be achieved by the combination of four key developments: improved pulsed laser source; optimized non-linear interaction, enhancing the signal; increase in acquisition speed, thanks to innovative spectrometers; parallel on-board data processing.In the final application phase, the VIBRA project will validate the performances of the novel vibrational imaging system studying two important bio-medical problems: cancerous cell differentiation and detection of neuronal tumours. This will pave the way towards future  virtual histopathology : intraoperative non-invasive evaluation of cancerous tissue. My vision is to allow researchers and doctors without a specific knowledge in lasers and optics to routinely visualize functional properties of cells and tissues in vivo.&Scalable Quantum Photonic NetworksIt is an outstanding challenge in quantum physics of today to scale small proof-of-concept experimental demonstrations into larger quantum networks. In the last decade, solid-state photonic systems have matured significantly, and an ambitious research project on such scaling seems viable. With the present proposal we intend to take up this challenge and exploit single quantum dots in photoniccrystal nanostructures as a deterministic photon-emitter interface for scalable quantum architectures. The project objectives are threefold. We will explore: 1) Deterministic single-photon sources for quantum simulations, 2) A giant photon nonlinearity for quantum-information processing, 3) The deterministic interfacing of multiple quantum dots.In 1) we will exploit our recently developed deterministic single-photon source to produce a spatially multiplexed array of single photons (prospectively of 10 photons or more). This source will be used for quantum simulations. Area 2) exploits a single quantum dot in a photonic-crystal waveguide as a giant nonlinearity. The quantum dot will be operated either as a passive nonlinear scatterer or actively controlled. The nonlinearity will enable constructing a deterministic CNOT gate for photons or a single-photon transistor. Finally, 3) concerns the coupling of two or more quantum dots by an extended dipole-dipole interaction that is mediated by the photonic-crystal waveguide. The fundamental limits for the size and complexity of such a quantum photonic network will be explored.The present project focus on overcoming the fundamental obstacles that photonic quantum-information processing applications have been sufferingfrom, i.e., probabilistic single-photon emission and weak nonlinearities. The successful accomplishment of the project could elevate quantum photonics to a frontrunner technology for scalable quantuminformation processing.Driven Glasses: from statistical physics to materials propertiesAmorphous systems form a large fraction of the solid materials that surround us, from polymer glasses to mineral or metallic glasses, from toothpaste (a colloidal paste) to granular materials. Still, a theoretical framework for describing the mechanical properties of such materials, comparable to t he dislocation theory that describes crystalline systems, is still missing. Our understanding of prominent experimental feature such as the heterogeneous character of deformation, or the temperature and rate dependence of the mechanical response, is very limited. These materials indeed combine several difficulties. In contrast to liquids or crystals, they are intrinsically out of equilibrium, and their microstructure presents a large statistical distribution of mechanically distinct local environments. Theimportance of the notion of heterogeneity in the mechanical behaviour of amorphous systems is being increasingly recognized, still there is no numerical or theoretical model that incorporates this microscopic feature into a macroscopic description of deformation and flow. The aim of the proposed research program is to build such models, within a multiscale approach seeking inspiration from dislocation dynamics, from the statistical physics of glasses and from the physics of dynamical critical phenomena. The proposed approach is based on a combination of intensive numerical simulations at the atomic scale and at a coarse grained scale, which will necessitate the development of efficient numerical schemes. The statistical analysis will allow us to understand the universal and non universal features of material behaviour in terms of the interactions between the atomic constituents, and to establish the validity and importance of new concepts such as mechanical activation or dynamical heterogeneities.Ab initio Dynamical Vertex ApproximationSome of the most fascinating physical phenomena are experimentally observed in strongly correlated electron systems and, on the theoretical side, only poorly understood hitherto. The aim of the ERC project AbinitioDGA is the development, implementation and application of a new, 21th century method for the ab initio calculation of materials with such strong electronic correlations. AbinitioDGA includes strong electronic correlations on all time and length scales and hence is a big step beyond the state-of-the-art methods, such as the local density approximation, dynamical mean field theory, and the GW approach (Green function G times screened interaction W). It has the potential for an extraordinary high impact not only in the field of computational materials science but also for a better understanding of quantum critical heavy fermion systems, high-temperature superconductors, and transport through nano- and heterostructures. These four physical problems and related materials will be studied within the ERC project, besides the methodological development. On the technical side, AbinitioDGA realizes Hedin's idea to include vertex corrections beyond the GW approximation. All vertex corrections which can be traced back to a fully irreducible local vertex and the bare non-local Coulomb interaction are included. This way, AbinitioDGA does not only contain the GW physics of screened exchange and the strong local correlations of dynamical mean field theory but also non-local correlations beyond on all length scales. Through the latter, AbinitioDGA can prospectively describe phenomena such as quantum criticality, spin-fluctuation mediated superconductivity, and weak localization corrections< to the conductivity. Nonetheless, the computational effort is still manageable even for realistic materials calculations, making the considerable effort to implement AbinitioDGA worthwhile.Statistical physics of dense particle systems in the absence of thermal fluctuationsFrontier research in statistical mechanics and soft condensed matter focuses on systems of everincreasing complexity. Among these are systems where microscopic dynamics are not controlled by thermal fluctuations, either because the sources of the fluctuations have not a thermal origin, or because  microscopic sources of fluctuations are altogether absent. Practical applications comprise everyday products such as paints or foodstuff which are soft solids composed of dense suspensions of particles that are too large for thermal fluctuations to play any role. Non-Brownian  active matter, obtained when particles internally produce motion, represents another growing field with applications in biophysics and soft matter. Because these systems all evolve far from equilibrium, there exists no general framework to tackle these problems theoretically from a fundamental perspective. I will develop a radically new approach to lay the foundations of a detailed theoretical understanding of the physics of a broad but coherent class of materials evolving far from equilibrium. To go beyond phenomenology, I will carry theoretical research to elucidate the physics of particle systems that are simultaneously Dense, Disordered, Driven and Dissipative D4PARTICLES. By combining numerical analysis of model systems to fully microscopic statistical mechanics analysis, my overall aim is to discover the general principles governing the physics of athermal particle systems far from equilibrium and to reach a complete theoretical understanding and obtain predictive tools regarding the phase behavior, structure and dynamics of D4PARTICLES. Reaching a new level of theoretical understanding of a broad range of materials will impact fundamental research by opening up statistical physics to a whole new class of complex systems and should foster experimental activity towards design and quantitative characterization of large class of disordered solids and soft materials.Unravelling the physical basis of morphogenesis in plantsMorphogenesis is the remarkable process by which a developing organism acquires its shape. While molecular and genetic studies have been highly successful in explaining the cellular basis of development and the role of biochemical gradients in coordinating cell fate, understanding morphogenesis remains a central challenge for both biophysics and developmental biology. Indeed, shape is imposed by structural elements, so that an investigation of morphogenesis must address how these elements are controlled at the cell level, and how the mechanical properties of these elements lead to specific growth patterns. Using plants as model systems, we will tackle the following questions: i. Does the genetic identity of a cell correspond to a mechanical identity? ii. Do the mechanical properties of the different cell domains predict shape changes? iii. How does the intrinsic stochasticity of cell mechanics and cell growth lead to reproducible shapes? To do so, we will develop a unique combination of physical and biological approaches. For instance, we will measure simultaneously physical properties and growth in specific cell groups by building a novel tool coupling atomic force microscopy and upright confocal microscopy; we will integrate the data within physical growth models; and we will validate our approaches using genetic and pharmacological alterations of cell mechanics. In plants, shape is entirely determined by the extracellular matrix (cell walls) and osmotic pressure. From that perspective, plants cells involve fewer mechanical parameters than animal cells and are thus perfectly suited to study the physical basis of morphogenesis. Therefore we propose such a study within the shoot apical meristem of Arabidopsis thaliana, a small population of stem cells that orchestrates the aerial architecture of the plant. This work will unravel the physical basis of morphogenesis and shed light on how stochastic cell behaviour can lead to robust shapes.Polariton condensates: from fundamental physics to quantum based devicesPolaritons are quantum superpositions of light and matter which combine appealing properties of both: the high coherence of photons and the strong interaction (non-linearities) of electrons. With the report of their Bose-Einstein condensation in 2006, they stand as one of the most exciting semiconductor-optical system of today. Given their peculiar character, they encompass different interdisciplinary areas of research which spans from the physics of phase transitions, critical phenomena and strongly-correlated systems (superfuidity, superconductivity, etc.) to various branches of quantum physics (quantum optics, quantum information, etc.), till the possibility of building polariton-based optical logics for implementation of optical circuits; all exciting realms yet to be explored. The majority of the outstanding findings reported have been realised in structureless samples with no, or random, potential barriers for polariton states. This proposal aims at developing the polariton physics in the presence of designed and controllable potential landscapes which will allow the observation and study of a new series of phenomena related to the system's reduced dimensionality and out-of-equilibrium character. Strong of several and complementary techni< ques to realize such potentials in microcavities, both in my institute and in partnership with leading growers worldwide, I will explore three phases of prospective physics in the framework where the polariton flow can be controlled, driven, localised and guided. First, I will study transport and interferometry. Then, these straightforward upgrades on the polariton state-of-the-art will be used to design elementary devices, such as polariton transistors (classical logic) or entangling devices (quantum logic). In a final phase, polariton lattices with controllable attributes will be used to study fundamental quantum phases from the superfluid to the Mott insulator, with prospects of realizing a polariton quantum simulator.XUNCONVENTIONAL SUPERCONDUCTIVITY FROM A MOTT INSULATING PARENT MATERIALThe mystery of unconventional superconductivity is one that is yet to be solved after decades of research. Better superconductors will have a crucial role in improved energy efficient applications such as power storage and transmission. While the highest temperature superconductors to date are the copper oxide family of antiferromagnetic Mott insulators, the origin of unconventional superconductivity in these materials remains mysterious. Furthermore, there are strikingly few other examples where unconventional superconductivity emerges from Mott insulating materials. In this project we adopt a two-pronged approach to find unconventional superconductivity and potentially novel quantum spin liquid phases in new classes of Mott insulating materials, and to understand the nature of the normal state out of which superconductivity develops in the family of copper oxide superconductors. In the first part of the project, multiple spin-orbit coupled Mott insulating materials will be tuned to induce superconductivity and / or an unconventional quantum spin liquid phase, and a roadmap relating materials properties to emergent unconventional superconductivity developed. In the second part of the project, we will aim to better understand the normal state out of which superconductivity emerges in cuprate superconductors by a study of the nature of Fermi surface evolution from a the small Fermi surface in the underdoped regime to a large Fermi surface in the overdoped regime, potentially via a quantum critical point underlying the superconducting dome. Our findings are anticipated to have important implications for the creation of newer and better superconductors. : 31/7/2018qDeveloping sequence controlled polymers for organization, templation and recognitionNature s toolbox for replication uses DNA and RNA which are nucleic acids capable of templating new copies of themselves. Nature s ability to replicate has led to the evolution of a wide variety of forms and functions for biological materials which cannot be achieved using current synthetic approaches. It seems likely that if we were able to teach plastics or other polymers how to template new copies of themselves that we would similarly be able to make new, impossible materials and hence further expand the potential function and properties of these materials. These new materials would provide enhanced properties and function (such as replication and evolution) that are not currently available to material chemists. This would allow for a best-of-both-worlds scenario with the development of robust synthetic materials, with tuneable properties including crystallinity, thermal properties, shape memory, and self-healing. Most importantly, by developing an empirical and perhaps even model-based connection between polymer sequence / composition and polymer properties it would be possible to begin to design new materials in a rational and knowledge-based way. Indeed, it could be argued that this advance would ultimately solve one of the major problems in materials science, multiscale modelling of polymer properties. It seems certain that achieving even a portion of these goals would open up a completely new area of material science. Hence, following the model of DNA, we propose developing a number of new routes for the preparation of sequence controlled polymers (SCPs) and specifically a new class of SCPs which are capable of replication and ultimately evolution. This will produce polymers and self-assembled structures with unprecedented physical properties and the ability to functionally interact and communicate with biological materials. Realizing this goal will allow us to bring new function to chemistry, through expanding chemical space to access new precision polymers*Nonequilibrium phenomena at femtosecond/nanometer scaleNanoscale objects like magnetic molecules and clusters, quantum dots, and graphene, bring us novel physical concepts. Recently, the temporal scale of the order of tens of femtoseconds (femtoscale) became available and new physical phenomena associated with this time scale, such as laser-induced electron and magnetic phase transitions, were discovered. The theoretical background for understanding this new physics is still rather poor. This temporal scale, like the spatial nanoscale is intermediate between micro- and macroworld making the standard approaches developed in microand macrophysics not suitable anymore. Essentially new theoretical ideas and methods are necessary for its description, especially in a combination with the spatial nanoscale. The aim of this project is to provide such a background via detailed studies of key problems, and open the way for new practical applications. Based on a combination of analytical and computational theoretical approaches (most of them were suggested by us), we plan to study systematically time-dependent many-body phenomena at the femto/nano scal< e. We will develop a theory of nonequilibrium magnetic interactions and spin dynamics of nanosystems and apply it to molecular magnets and clusters at metal surfaces and at graphene. We will study the physics of graphene and  artificial graphene (array of semiconducting quantum dots) in strongly time-dependent electric fields (laser-induced ultrafast dynamics). This list covers the crucial problems in this new field (nonequilibrium spin dynamics, calculation of response functions crucial for pump-probe experiments, new physics in highly excited graphene and graphenelike systems) and the success of the project will represent a breakthrough in our understanding of the nanoworld, with very important perspectives for applications, namely, for the drastic miniaturization of basic elements and enhancing speed of basic operations in electronics.Colloids with complex interactions: from model atoms to colloidal recognition and bio-inspired self assemblySelf-assembly is the key construction principle that nature uses so successfully to fabricate its molecular machinery and highly elaborate structures. In this project we will follow nature s strategies and make a concerted experimental and theoretical effort to study, understand and control selfassembly for a new generation of colloidal building blocks. Starting point will be recent advances in colloid synthesis strategies that have led to a spectacular array of colloids of different shapes, compositions, patterns and functionalities. These allow us to investigate the influence of anisotropy in shape and interactions on aggregation and self-assembly in colloidal suspensions and mixtures. Using responsive particles we will implement colloidal lock-and-key mechanisms and then assemble a library of  colloidal molecules with well-defined and externally tunable binding sites using microfluidicsbased and externally controlled fabrication and sorting principles. We will use them to explore the equilibrium phase behavior of particle systems interacting through a finite number of binding sites. In parallel, we will exploit them and investigate colloid self-assembly into well-defined nanostructures. Here we aim at achieving much more refined control than currently possible by implementing a protein-inspired approach to controlled self-assembly. We combine molecule-like colloidal building blocks that possess directional interactions and externally triggerable specific recognition sites with directed self-assembly where external fields not only facilitate assembly, but also allow fabricating novel structures. We will use the tunable combination of different contributions to the interaction potential between the colloidal building blocks and the ability to create chirality in the assembly to establish the requirements for the controlled formation of tubular shells and thus create a colloidbased minimal model of synthetic virus capsid proteins.[Multi-Dimensional Study of non Abelian Topological States of MatterNon-abelian topological states of matter are of great interest in condensed matter physics, both due to their extraordinary fundamental properties and to their possible use for quantum computation. The insensitivity of their topological characteristics to disorder, noise, and interaction with the environment may lead to realization of quantum computers with very long coherence times. The realization of a quantum computer ranks among the foremost outstanding problems in physics, particularly in light of the revolutionary rewards the achievement of this goal promises. The proposed theoretical study is multi-dimensional. On the methodological side the multi-dimensionality is in the breadth of the studies we discuss, ranging all the way from phenomenology to mathematical physics. We will aim at detailed understanding of present and future experimen< tal results. We will analyze experimental setups designed to identify, characterize and manipulate non-abelian states. And we will propose and classify novel non-abelian states. On the concrete side, the multi-dimensionality is literal. The systems we consider include quantum dots, one dimensional quantum wires, two dimensional planar systems, and surfaces of three dimensional systems. Our proposal starts with Majorana fermions in systems where spin-orbit coupling, Zeeman fields and proximity coupling to superconductivity are at play. It continues with  edge anyons , non-abelian quasiparticles residing on edges of abelian Quantum Hall states. It ends with open issues in the physics of the Quantum Hall Effect. We expect that this study will result in clear schemes for unquestionable experimental identification of Majorana fermions, new predictions for more of their measurable consequences, understanding of the feasibility of fractionalized phases in quantum wires, feasible experimental schemes for realizing and observing edge anyons, steps towards their classification, and better understanding of quantum Hall interferometry.GFrom Structure Property to Structure Process Property Relations in Soft Matter  a Computational Physics ApproachFrom cell biology to polymer photovoltaics, (self-)assembly processes that give rise to morphology and functionality result from non-equilibrium processes, which are driven by both, external forces, such as flow due to pressure gradients, inserting energy, or manipulation on a local molecular level, or internal forces, such as relaxation into a state of lower free energy. The resulting material is arrested in a metastable state. Most previous work has focused on the relationship between structure and properties, while insight into the guiding principles governing the formation of a (new) material, has been lacking. However, a comprehensive molecular level understanding of non-equilibrium assembly would allow for control and manipulation of material processes and their resulting properties. This lag of knowledge can be traced to the formidable challenge in obtaining a molecular picture of nonequilibrium assembly. Non-equilibrium processes have been studied extensively on a macroscopic level by non-equilibrium thermodynamics. We take a novel route approaching the challenge from a molecular point of view. Recent advances in experimental, but especially computational modeling, now allow to follow (supra-) molecular structural evolution across the range of length and time scales necessary to comprehend, and ultimately control and manipulate macroscopic functional properties of soft matter at the molecular level. Soft matter is particularly suited for that approach, as it is  slow and easy to manipulate. We take the computational physics route, based on simulations on different levels of resolution (all atom, coarse grained, continuum) in combination with recent multiscale and adaptive resolution techniques. This work will initiate the way towards a paradigm change from conventional Structure Property Relations (SPR) to molecularly based Structure Process Property Relations (SPPR).Plasmon-based Functional and Quantum NanophotonicsPlasmon-based nanophotnics, an explosively growing research field concerned with surface-plasmon waveguides and circuitry, is oriented towards exploiting unique perspectives opened for radiation guiding along metal surfaces: extreme mode confinement (i.e., far beyond the diffraction limit) and seamless interfacing of electronic and photonic circuits (that both utilize the same metal circuitry). At the same time, unavoidable radiation absorption by metals results in the fundamental trade-off between the mode confinement and propagation loss, so that the problem of making the most of the above unique features becomes of paramount importance. The proposal encompasses two groundbreaking research directions in plasmonics that explore and utilize extremely confined plasmonwaveguide modes for functional and quantum nanophotonics. These directions of in-depth investigations concentrate within two interrelated and largely unexplored research areas within plasmonics: development of ultra-compact plasmonic configurations exhibiting unique functionalities and realization of strong coupling between extremely confined plasmonic modes and individual quantum emitters. Fundamental studies of ultimate mode confinement and coupling to quantum emitters would evolve into investigations carried out within forefront topics including (i) dynamic control of plasmon-waveguide modes using the same metal circuitry for both radiation guiding and its control with el< ectrical signals; (ii) moulding the radiation flow by gradually varying waveguide cross sections in order to realize efficient nanofocusing of radiation, miniature ultra-dispersive wavelengthselective components and table-top models of plasmonic black holes, and (iii) quantum plasmonics with individual quantum emitters being strongly coupled to deep subwavelength surface plasmon modes, targeting the realization of a saturable waveguide mirror, single-photon transistor and longdistance entanglement of two remote quantum emitters.Circuit Quantum Electrodynamics with Single Electronic and Nuclear SpinsElectronic spins are usually detected by their interaction with electromagnetic fields at microwave frequencies. Since this interaction is very weak, only large ensembles of spins can be detected. In circuit quantum electrodynamics (cQED) on the other hand, artificial superconducting atoms are made to interact strongly with microwave fields at the single photon level, and quantum-limited detection of few-photon microwave signals has been developed. The goal of this project is to apply the concepts and techniques of cQED to the detection and manipulation of electronic and nuclear spins, in order to reach a novel regime in which a single electronic spin strongly interacts with single microwave photons. This will lead to 1) A considerable enhancement of the sensitivity of spin detection by microwave methods. We plan to detect resonantly single electronic spins in a few milliseconds. This could enable A) to perform electron spin resonance spectroscopy on few-molecule samples B) to measure the magnetization of various nano-objects at millikelvin temperatures, using the spin as a magnetic sensor with nanoscale resolution. 2) Applications in quantum information science. Strong interaction with microwave fields at the quantum level will enable the generation of entangled states of distant individual electronic and nuclear spins, using superconducting qubits, resonators and microwave photons, as  quantum data buses mediating the entanglement. Since spins can have coherence times in the seconds range, this could pave the way towards a scalable implementation of quantum information processing protocols. These ideas will be primarily implemented with NV centers in diamond, which are electronic spins with properties suitable for the project.Large Deviations and Non Equilibrium Phase Transitions for Turbulent Flows, Climate, and the Solar SystemThe aim of this project is to predict and compute extremely rare but essential trajectories in complex physical systems. We will compute rare transitions trajectories, first between two different turbulent attractors in models of planetary jet dynamics, and second between two configurations of ocean currents for a model of the thermohaline circulation. We will compute the dynamics and the probability for collisions between two planets in the solar system, on time scales of order of billions of years. We will evaluate rare events that lead to extremely large drags or torques on objects embedded in turbulent flows, directly from the dynamics. Because of the huge range of time scales, all those trajectories are not accessible through direct numerical simulations. The project's unity stems from the methodology based on large-deviations theory. Large deviation rate functions generalize the concept of entropy or free energy in non-equilibrium extended systems: they provide a global characterization of their most probable state, their large fluctuations and their phase transitions. Impressive explicit computations of large deviation rate functions have been recently performed in simple nonequilibrium systems. The main aim of this project is to bridge the gap between those extremely interesting new concepts and algorithms, and complex dynamical systems such as turbulent flows, semi-realistic models of fluids related to climate dynamics, or the long time behavior of the solar system. In order to achieve this goal, we will use macroscopic fluctuation theory, instanton theory, and other analytical methods in order to compute explicitly large deviation rate functions for essential macroscopic quantities (the velocity or density fields). We will also develop and use algorithms specifically dedicated at computing the statistics of extremely rare trajectories, based on the generalization of importance sampling implemented through cloning or multilevel splitting methods.vJosephson Junction Spectroscopy of Mesoscopic SystemsSpectroscopy is a powerful tool to probe matter. By measuring the spectrum of elementary excitations, one reveals the symmetries and interactions inherent in a physical system. Mesoscopic devices, which preserve quantum coherence over lengths larger than the atomic scale, offer a unique possibility to both engineer and investigate excitations at the single quanta level. Unfortunately, conventional spectroscopy techniques are inadequate for coupling radiation to mesoscopic systems and detecting their small absorption signals. I propose an on-chip, Josephson-junction based spectrometer which surpasses state-of-the-art instruments and is ideally suited for probing elementary excitations in mesoscopic systems. It has an original design providing uniform wideband coupling from 2-2000 GHz, low background noise, high sensitivity, and narrow linewidth.I describe the operating principle and design of the spectrometer, show preliminary results demonstrating proof-of-concept, and outline three experiments which exploit the spectrometer to address important issues in condensed matter physics. The experiments are: measuring the lifetime of single quasiparticle and excited Cooper pair states in superconductors, a topic relevant for quantum information processing; determining whether graphene has a bandgap, a fundamental yet unresolved question; and recording a clear spectros< copic signature of Majorana bound states in topological superconductor weak links.Various applications of the superconducting circuits developed for the spectrometer include a Josephson vector network analyzer, a cryogenic mixer, a THz camera, a detector for radioastronomy, and a scanning microwave impedance microscope. In itself the proposed JJ spectrometer is a general purpose tool that will benefit researchers studying mesoscopic systems. Ultimately, Josephson junction spectroscopy should not only be useful to detect existing elementary excitations but also to discover new ones.VTheory of statistical topological insulatorsTopological insulators (TI) are a novel class of materials with insulating bulk and conducting surface. The conduction of the surface is protected by the topological properties of the bulk, as long as a fundamental symmetry is present (for instance time-reversal symmetry). My goal is to investigate to what limits does the protection hold in cases where the protecting symmetry is broken, and only present in statistical sense, after averaging over the disordered ensemble. In a pilot study I showed that materials that are protected by such average symmetry, which I have called  statistical topological insulators (STI) significantly extend the classification of topological phases of matter and promise new methods to robustly control the conducting surface properties. I plan to develop a general theory of STI for physically relevant symmetries, describe the observable properties of their protected surface states, invent ways to predict whether materials are expected to be STI, and explore the generalization of STIs to strongly interacting topological phases of matter. I expect that the outcome of my research will significantly extend our understanding of topological phases of matter, and provide new ways to design materials with robust properties.jUnlocking new physics in controllably strained two-dimensional materialsWe will use strain engineering as an enabling tool to study previously inaccessible or hard-to-study phenomena in two-dimensional atomic crystals (2DACs: graphene, bilayer graphene, and monolayer transition metal dichalcogenides). In our first objective, we develop unique experimental tools to control and characterize mechanical strain in 2DACs. These are the distinguishing features of our approach: (i) The use of very low disorder suspended devices; (ii) Both uniform and controlled nonuniform strain will be induced; (iii) The level of strain will be precisely adjusted and determined in-situ during measurements. We will then use controllably-strained samples to study electrical, mechanical, thermal, and optical properties of 2DACs:Application of strain in suspended graphene will be shown to control amplitudes and dispersion relation of flexural out-of-plane phonons (FPs), a mode unique to 2D and quasi-2D materials. We will demonstrate, for the first time, that FPs dominate electrical, thermal, and mechanical of suspended graphene. Moreover, we will show dramatic mechanical softening of graphene in the regime of weak strain, similar to "entropic spring" behaviour seen in polymers.We will engineer strain distributions in high-mobility suspended graphene devices that translate into nearconstant "pseudomagnetic field" and observe Quantum Hall-like quantization at zero external magnetic field.Strain-induced changes in topology of the band structure of bilayer graphene will be shown to affect Quantum Hall states and the Berry phase.Through strain engineering, we will controllably adjust - and even make spatially dependent - the band gap energy and binding energies ofexcitons in monolayer transition metal dichalcogenides (TMDCs). We will study complex interplay between and direct and indirect excitons and look for emergence of a new phase of matter, an excitonic insulator, in strained narrow-bandgap TMDC.|Vibronic control of organic electronic devicesOrganic electronics (OE) is an expanding research field that exploits the electronic functionalities of organic molecules to make them robust and cost-efficient building blocks for future electronic devices. Due to the  soft character of organic materials, their electronic properties are defined by vibronic coupling (VC) phenomena which are a result of the interaction between electron and nuclear dynamics of the molecule. This research program aims to unlock a new direction of experimental studies investigating and exploiting VC in OE devices by using optical control of nuclear motion. The growing awareness that VC underlies diverse phenomena from physics to biology stimulates a broad interdisciplinary effort to address this issue. However, in the field of OE, the lack of synergy between device and optical studies holds the potential functionality offered by VC effects from being attained. In 2012, I proposed a direct route to control the performance of OE devices by optically switching the vibronic states of the molecules. Though this work came specifically in connection with organic photovoltaics, it provides the starting point for a more fundamental and broad reaching of VC phenomena. The proposed res< earch program will use this opportunity. I will apply state-of-the-art developments in infrared light shaping to create a well-defined coherent superposition of molecular vibrational motions inside devices and study their influence on electron dynamics with device-specific spectroscopic techniques. This approach combines recent advances in ultrafast spectroscopy and OE to extend our fundamental understanding of molecular charge transport. Our methodology will become a tool for elucidating current pathways in organic nanodevices and offer access to non-equilibrium phenomena down to the level of molecular junctions. This research will lead to the development of new design rules for OE materials serving future advances in molecular electronics, computing and sensing.Superconducting Diamond Quantum Nano-Electro-Mechanical SystemsIn this project, the fabrication and characterisation of all diamond superconducting Nano-ElectroMechanical Systems (NEMS) is proposed for the investigation of macroscopic quantum states. This involves state of the art Chemical Vapour Deposition (CVD) of diamond, doping, nanofabrication and modelling of devices. The fundamental properties of superconducting diamond, the associated mechanical properties of diamond NEMS and the characterisation of low temperature and low dimensional quantum effects will be investigated. Critically, the unprecedented resonant frequencies of diamond cantilevers allow the possibility of cooling cantilever devices down to the ground state. Coupled with its superconducting-based read out possibilities, this material offers new opportunities for challenging the Standard Quantum Limit, the study of quantum entanglement and the fabrication of superconducting diamond Qubits. This work is highly ambitious, as it aims to manipulate systems by exploiting fundamental quantum limits. However, the applicant has already demonstrated the individual constituents of this approach and thus it is not reckless to propose to integrate them.Interfacing spin waves with superconducting quantum circuits for single magnon creation and detectionThe proposed project will experimentally interface ferromagnets with superconducting quantum circuits to study dynamics within the magnet. To this end, magnonic elements made up by thin, structured magnetic films will be strongly coupled to the qubit. Superconducting qubits are ideal detectors due to their quantum limited back-action on the measured object and energy resolution. Spectroscopy and coherence measurements on the hybrid system will be made in order to address fundamental aspects such as spin wave generation, detection, coherence, or wave propagation down to mK temperatures and at ultra-low power (atto-watts). Amplitude and phase noise of spin wave resonators will be determined. At the final stage of the project, the quantum limited resolution of qubits will facilitate single magnon creation and detection. Quantum states are swapped between qubit and magnon, and superpositioned and entangled states will be explored. Monitoring the qubit response to its magnetic environment the low and high-frequency flux noise spectrum of spin waves will be inferred. The research methodology employs junctions, resonators, and qubits as research objects and detectors. The samples will be characterized at cryogenic temperatures by transport, magnetometry, resonator and qubit setups. Magnetic materials will be deposited and structured beneath or ontop the superconducting quantum circuits. Exploring spin wave dynamics in thin films by coupling to a superconducting qubit complements conventional measurement techniques based on photon, electron or neutron scattering methods, which require highly populated excitations. The project connects to and extends research objects of ground-breaking nature to open up new horizons for quantum, magnon and spin electronics. Magnetic material physics is enhanced by new research concepts such as quantum resolved spectroscopy and coherence measurements on intrinsic dynamic states.Many-body physics and superconductivity in 2D materialsThe goal of this project is to prepare and functionalize layered materials and then to characterize them in-situ using a novel combination of electrical transport, photoelectron and optical spectroscopy. This approach provides a solution to the intense research efforts in trying to engineer, probe and unravel many-body physics and the superconducting coupling mechanism in layered solids. The materials under investigation are based on the families of graphene, dichalcogenides and iron based superconductors. Chemical functionalization using dopants and strain allows for an unprecedented control over their physical properties. The proposed material systems provide a new arena to explore diverse condensed matter phenomena such as electron correlation, electron-phonon coupling and superconductivity. The groundbreaking aspects of this proposal are as follows: (1) development of a unique setup where electrical transport, angle-resolved photoemission (ARPES) and optical spectroscopy is measured in-situ on the same sample, (2) large-area deterministic layer-by-layer growth by chemical vapour deposition (CVD) and molecular beam epitaxy, (3) the effects of mechanical strain and hence large pseudomagnetic fields on the electronic band structure will be investigated using ARPES, (4) the effects of alkali metal doping on the superconducting transition temperature and the spectral function will be investigated using transport, ARPES and optical spectroscopies shining light onto the superconducting pairing mechanisms in different classes of materials. The proposal's feasibility is firmly grounded on the pioneering work of the PI s group on superconducting coupling in functionalized graphene and the in-situ ARPES measurements of a CVD grown graphene/BN heterost< ructure.lA nanophysics approach to synthetic cell divisionImagine building a living cell from basic components, a vesicle filled with biomolecules that can sustain itself and reproduce into similar offspring. Can this be done?This proposal addresses the most tantalizing aspect: synthetic cell division. We aim to build liposomes (lipid vesicles enclosing an aqueous solution with proteins and DNA) that can spontaneously divide through a contractile protein ring at the vesicle perimeter. To realize this, we employ an experimental biophysics approach that addresses both the actual division and the prerequisite spatial control, with:1. Cells in nanofabricated shapes. We will study cell-division proteins and DNA in live E.coli bacteria that are molded into userdefined arbitrary shapes and sizes. Clarifying the effects of cell shape will elucidate the guiding principles for the spatiotemporal organization of the cell-division machinery.2. Proteins and DNA in nanofabricated chambers. We will use a bottom up approach to study the basic divisome components in vitro exploiting the full control provided by nanochambers. This will resolve the spatial organization of the fascinating patterns of Min proteins and chromatin that dictate the localization of the division ring.3. Liposomes on chip. We will develop a chip-based technology to generate liposomes for exploring synthetic cell division. We will use both microfluidic constrictions and a biomimetic approach (encapsulation of divisome proteins such as FtsZ) to induce autonomous liposome splitting, thus enabling a simplified but tightly controlled form of synthetic cell division.To our knowledge, this nanofabrication-based approach to synthetic division is unique. We expect to be able to make important contributions to understanding cell division, and anticipate that on a 5-year scale we indeed can master synthetic division. We believe that our mix of nanophysics and synthetic biology is bound to yield deep insight into the biophysical underpinnings of cellular reproduction.Quantum devices in topological matter: carbon nanotubes, graphene, and novel superfluidsThe project addresses quantum devices in hybrid systems formed using carbon nanotubes, graphene, and 3He superfluid, all with particular topological characteristics. Topological properties of these nontrivial materials can be drastically modified by introducing defects or interfaces into them, like single layer graphene into superfluid helium, boron nitride between graphene sheets, carbon nanotubes in 3He superfluid, or misfit dislocation layers into HOPG graphite. We are particularly interested in graphene/3He systems where graphene acts as an interface/substrate of interacting atomic ensembles. The atomic interactions across graphene are expected to provide novel mesoscopic condensates. By studying the topological phases of thin 3He layers and graphene immersed into superfluid 3He, we will investigate pairing across the graphene interface, deduce the origin of supercurrents, and look for excitonic superfluidity in these systems.Single walled carbon nanotubes provide high-quality nanomechanical resonators with extraordinary properties. By using proximityinduced superconductivity, these objects will be integrated into circuit optomechanics in a way that facilitates strong coupling between the mechanical motion and the microwave cavity. By using adiabatic nuclear refrigeration, these non-linear quantum objects will be cooled below 1 mK, at the temperature of which the quantum ground state is reached. The cooling relies on immersion of the SWNT into superfluid 3He which, in the limit T -> 0, provides a quantum vacuum with unique topological properties. Intriguingly, the characteristics of this vacuum can be probed by ultrasensitive detectors provided by the suspended SWNTs.Finally, besides non-classical phonon states, e.g. Fock states in the mechanical resonator, reaching the ground state of such an anharmonic oscillator will allow studies of quantum tunnelling of a macroscopic object from its metastable minimum when biased with a large gate voltage.[Photo Induced Collective Properties of Hybrid Halide PerovskitesThe recent discovery of the organo-inorganic perovskite CH3NH3PbI3 as very efficient material in photoelectric conversion is multifaceted: it turns out that this compound is promising not only in photovoltaics, but it is lasing, it gives bright light emitting diodes, promising in water splitting and we are persuaded that it can play an important role in basic sciences, as well. We have recently realized that under white light illumination the photoelectrons, due to their very long recombination time, stay in the conduction band and the resistivity of a single crystal shows a metallic behavior. If the lifetime is sufficiently long and the density of these excited carrier is high enough they could condense into a Fermi sea. The project s goal is to realize this highly unusual state and to document its properties by magneto-transport and spectroscopic techniques. We will check in our model compound the longsought superconductivity of photo-excited carriers, extensively searched for in cuprates, if we could stabilize it by fine tuning the interactions by hydrostatic pressure under constant illumination. The availability of high quality samples is primordial for this program. It turns out that CH3NH3PbI3 is ideal compound, it seems to be almost free of charged defects (its room temperature resistance is 5 orders of magnitude higher than that of Phosphorus doped Silicon at 1013 cm-3 doping concentration) and we can grow excellent single crystals of it. Furthermore, it has a flexibility in material design: one can vary all the constituents, and even the dimensionality by making layered materials with the main chemical motifs. A special effort will be devoted to tune the spin-orbit coupling by different elements, since this could be < at the origin of the long recombination time of the photo-electrons. We suspect that the highly tunable, clean and disorder-free doping obtained by shining light on these ionic crystals opens a new era in material discovery.WBiomolecular Hydrogels  from Supramolecular Organization and Dynamics to Biological FunctionCertain proteins and glycans self-organize in vivo into soft and strongly hydrated, dynamic and gel-like supramolecular assembli      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijkmnopqrstuvwxyz{|}~es. Among such biomolecular hydrogels are the jelly-like matrix that is formed around the egg during ovulation, mucosal membranes, slimy coats produced by bacteria in biofilms, and the nuclear pore permeability barrier. Even though biomolecular hydrogels play crucial roles in many fundamental biological processes, there is still a very limited understanding about how they function. Our goal is to assess and to understand the relation between the organizational and dynamic features of such supramolecular assemblies, their physicochemical properties, and the resulting biological functions. We will investigate these relationships directly on the supramolecular level, a level that - for this type of assemblies - is hardly accessible with conventional approaches. To this end, we use purpose-designed in vitro model systems that are well-defined in the sense that their composition and supramolecular structure can be controlled and interrogated. These tailor-made models, together with a toolbox of surface-sensitive in situ analysis techniques, permit tightly controlled and quantitative experiments. Combined with polymer physics theory, the experimental data allow us to directly test existing hypotheses and to formulate new hypotheses that can be further tested in complementary molecular and cell-based assays. This project focuses on two types of biomolecular hydrogels: (i) the nuclear pore permeability barrier, a nanoscopic protein meshwork that regulates all macromolecular transport into and out of the nucleus of eukaryotic cells, and (ii) extracellular hydrogel-like matrices that are scaffolded by the polysaccharide hyaluronan and that are of prime importance in a wide range of physiological and pathological processes including inflammation, fertilization and osteoarthritis.Accelerated design and discovery of novel molecular materials via global lattice energy minimisationThe goal of crystal engineering is the design of functional crystalline materials in which the arrangement of basic structural building blocks imparts desired properties. The engineering of organic molecular crystals has, to date, relied largely on empirical rules governing the intermolecular association of functional groups in the solid state. However, many materials properties depend intricately on the complete crystal structure, i.e. the unit cell, space group and atomic positions, which cannot be predicted solely using such rules. Therefore, the development of computational methods for crystal structure prediction (CSP) from first principles has been a goal of computational chemistry that could significantly accelerate the design of new materials. It is only recently that the necessary advances in the modelling of intermolecular interactions and developments in algorithms for identifying all relevant crystal structures have come together to provide predictive methods that are becoming reliable and affordable on a timescale that could usefully complement an experimental research programme. The principle aim of the proposed work is to establish the use of state-of-the-art crystal structure prediction methods as a means of guiding the discovery and design of novel molecular materials. This research proposal both continues the development of the computational methods for CSP and, by developing a computational framework for screening of potential molecules, develops the application of these methods for materials design. The areas on which we will focus are organic molecular semiconductors with high charge carrier mobilities and, building on our recently published results in Nature [1], the development of porous organic molecular materials. The project will both deliver novel materials, as well as improvements in the reliability of computational methods that will find widespread applications in materials chemistry. [1] Nature 2011, 474, 367-371.yadvanced Light mIcroscopy for Green cHemisTryOptimization of catalytic materials and hence of chemical processes heavily relies on gaining detailed insight into the complex dynamics underlying the outcome of a catalytic process and using this information in the rational design of improved catalysts. So far, spectroscopic approaches have already contributed importantly; however a strong need for new and improved in situ spectroscopic methods with micro- and nanometer resolution still remains. This project aims to develop advanced light microscopy tools that will significantly contribute to this goal.4CHEMometric and High-throughput Omics Analytical Methods for Assessment of Global Change Effects on Environmental and Biological SystemsWe propose to develop new chemometric and high-throughput analytical methods to assess the effects of environmental and climate changes on target biological systems which are representative of ecosystems. This project will combine powerful chemometric and analytical high-throughput methodologies with toxicological tests to examine the effects of environmental stressors (like chemical pollution) and of climate change (like temperature, water scarcity or food shortage), on genomic and metabonomic profiles of target biological systems. The complex nature of experimental data produced by high-throughput analytical techniques, such as DNA microarrays, hyphenated chromatography-mass spectrometry or multi-dimensional nuclear ma< gnetic resonance spectroscopy, requires powerful data analysis tools to extract, summarize and interpret the large amount of information that such megavariate data sets may contain. There is a need to improve and automate every step in the analysis of the data generated from genomic and metabonomic studies using new chemometric and multi- and megavariate tools. The main purpose of this project is to develop such tools. As a result of the whole study, a detailed report on the effects of global change and chemical pollution on the genomic and metabonomic profiles of a selected set of representative target biological systems will be delivered and used for global risk assessment. The information acquired, data sets and computer software will be stored in public data bases using modern data compression and data management technologies. And all the methodologies developed in the project will be published.tDevelopment of a Research Environment for Advanced Modelling of Soft matterDREAMS aims at developing an integrated theoretical-computational approach for the efficient description of linear and non-linear spectroscopies of several classes of organic probes, dispersed in polymeric matrices that range in complexity from simple polyolefins all the way to large biomolecules (proteins and polysaccharides). In order to reach this objective, developments along the following lines are required: (i) elaboration of new theoretical models, to expand the scope of currently available treatments; (ii) definition of specific treatments for intermediate regions / regimes in the context of space- and time-multiscale descriptions; (iii) algorithmic implementation of the developed models / protocols in computational codes and, (iv) their efficient integration allowing for seamless flow of information and easy use by non-specialists. A crucial asset for the success of the planned theoreticalcomputational developments is represented by an extensive network of solid collaborations with leading experimental groups, that will be involved in the synthesis and characterization of the differentchromophore / matrix systems, as well as in the in-depth characterization of their spectroscopic responses. These interactions will thus allow for a stringent and exhaustive validation of the capabilities required of a general and versatile computational tool; at the same time, the experimental groups will make full use of advanced theoretical interpretations in the context of a real-world technological problem. In summary, DREAMS relies on a carefully planned combination of theoretical developments, computational implementations, and interactions with experimentalists, in order to achieve a novel and cutting-edge result, namely to provide the scientific community with a set of computational tools that will make possible the simulation and prediction of response and spectroscopic properties of multi-component materials.%Sequencing biological molecules with grapheneGraphene  a one atom thin material  has the potential to act as a sensor, primarily the surface and the edges of graphene. This proposal aims at exploring new biosensing routes by exploiting the unique surface and edge chemistry of graphene.7Excited state quantum dynamics in molecular aggregates: a unified description from biology to devicesThe coherent dynamics of excitons in systems of biological interest and in organic materials can now be studied with advanced experimental techniques, including two dimensional electronic spectroscopy, with time resolution of few femtoseconds. The theory of open quantum systems, that should support the interpretation of these new experiments, has been developed in different contexts over the past 60 years but seems now very inadequate for the problems of current interest. First of all, the systems under investigation are extremely complex and the most common approach, based on the development of phenomenological models, is often not very informative. Many different models yield results in agreement with the experiments and there is no systematic way to derive these models or to select the best model among many. Secondly, the quantum dynamics of excitons is so fast that one cannot assume that the dynamics of environment is much faster than the dynamics of the system, an assumption crucial for most theories. A remedy to the current limitation is proposed here through the following research objectives. (1) A general and automatic protocol will be developed to generate simple treatable models of the system from an accurate atomistic description of the same system based on computational chemistry methods. (2) A professionally-written software will be developed to study the quantum dynamics of model Hamiltonians for excitons in molecular aggregates. This software will incorporate different methodologies and will be designed to be usable also by nonspecialists in the theory of quantum open systems (e.g. spectroscopists, computational chemists). (3) A broad number of problems will be studied with this methodology including (i) exciton dynamics in light harvesting complexes and artificial proteins and (ii) exciton dynamics in molecular aggregates of relevance for organic electronics devices.]Next Generation Label-free Chemical Nanoscopy for Biomedical ApplicationsImagine if one could simply use an optical microscope and see whether a particular virus has infected a biological specimen or not! Or if a single disease causing molecular structure could be detected, 20 years before the disease manifests itself! Conventional microscopy simply does not have such spatial resolution! The challenge is to image endogenous molecules and structures composed of them specifically, in real-time, without tampering and sample destruction. Non-Linear optical techniques such as vibrational sum frequency generation (vSFG) and coherent Raman scattering (CRS), which use the intrinsic properties of molecules for selectively imaging them, provide a solution. They are noninvasive, label-free, chemically selective and non-destructive with capability for video-rate imaging of biomolecules and biochemical structures. However, they need to overcome the frontier of spatial resolution to be able to provide information at <100 nm level, which is much below the limit for these techniques and conventional microscopy. The proposal addre< sses this challenge by developing and implementing a generic, simple optical ultra-high resolution technology using a novel approach based on super-oscillatory modulation of light coupled with wavelength mixing. We will uniquely apply this approach to the chemically selective vSFG and CRS techniques. Ultra-high spatial resolution with these techniques will allow unprecedented new insight into many biochemical phenomena. To demonstrate the utility of  chemical nanoscopy developed in this proposal vesicular transport in axons of neurons will be studied, which is highly relevant to cognitive decline observed in ageing and neurodegenerative disorders. The project outcomes have the potential to revolutionize research and biomedical understanding by opening doors to  unseen biology , unravelling disease, viral infection and allergy mechanisms and ultimately, yielding better diagnostics and therapeutics.Structure-Property Relations in Aqueous Foam and Their Control on a Molecular LevelFoams are of enormous importance as we find them in many technological relevant applications and food products. Foams as hierarchical materials are dominated by the arrangement and distri-bution of gas bubbles on a macroscopic scale, as well as by thickness and composition of lamella on a mesoscopic scale. Liquid-gas interfaces are, however, the building block of foam with over-whelming importance as their molecular properties easily dominate hierarchical elements on larger length scales. In order to formulate foam with specific properties, its structure must be controlled at the molecular level of a liquid-gas interface. Here, the molecular composition, molecular order and interactions such as electrostatics dominate, and thus must be addressed with molecular level probes that can provide access to both interfacial solvent and solute molecules. Specifically, mo-lecular structures of aqueous interfaces can be modified by adding different mixtures of surface active molecules such as proteins, surfactants and polyelectrolytes, and by adjusting electrolyte properties. This is achieved by varying pH, introducing ions at different ionic strengths as well as by changing viscosities. Such model systems will be characterized with nonlinear optical spectroscopy amongst other surface sensitive probes. The gained information will be used to deduce properties of structures on larger length scales such as lamella, bubbles in a bulk liquid - as a precursor of foam - and finally macroscopic foam. For each length scale, experiments will be performed to gain access to molecular buildings blocks at liquid-gas interfaces and their effects on other hierarchical elements. These experiments thus provide essential information on foam stability and bubble coalescence, they can be used to verify structure -property relationships and to advance our understanding of foam on a molecular basis.=Structure of paramagnetic integral membrane metalloproteins by MAS-NMRIntegral membrane metalloproteins are involved in the transport and homeostasis of metal ions, as well as in key redox reactions that have a tremendous impact on many fields within life sciences, environment, energy, and industry. Most of our understanding of fine details of biochemical processes derives from atomic or molecular structures obtained by diffraction methods on single crystal samples. However, in the case of integral membrane systems, single crystals large enough for X-ray diffraction cannot be easily obtained, and the problem of structure elucidation is largely unsolved. We have recently pioneered a breakthrough approach using Magic-Angle Spinning Nuclear Magnetic Resonance (MAS-NMR) for the atomic-level characterization of paramagnetic materials and complex biological macromolecules. The proposed project aims to leverage these new advances through a series of new concepts i) to improve the resolution and sensitivity of MAS-NMR from nuclei surrounding a paramagnetic metal ion, such as e.g. cobalt, nickel and iron, and ii) to extend its applicability to large integral membrane proteins in lipid membrane environments. With these methods, we will enable the determination of structure-activity relationships in integral membrane metalloenzymes and transporters, by combining the calculation of global structure and dynamics with measurement of the electronic features of metal ions. These goals require a leap forward with respect to today s protocols, and we propose to achieve this through a combination of innovative NMR experiments and isotopic labeling, faster MAS rates and high magnetic fields. As outlined here, the approaches go well beyond the frontier of current research. The project will yield a broadly applicable method for the structural characterization of essential cellular processes and thereby will provide a powerful tool to solve challenges at the forefront of molecular and chemical sciences today.3D Model Catalysts to explore new routes to sustainable fuelsCurrently f< uels, plastics, and drugs are predominantly manufactured from oil. A transition towards renewable resources critically depends on new catalysts, for instance to convert small molecules (such as solar or biomass derived hydrogen, carbon monoxide, water and carbon dioxide) into more complex ones (such as oxygenates, containing oxygen atoms in their structure). Catalyst development now often depends on trial and error rather than rational design, as the heterogeneity of these composite systems hampers detailed understanding of the role of each of the components. I propose 3D model catalysts as a novel enabling tool to overcome this problem. Their well-defined nature allows unprecedented precision in the variation of structural parameters (morphology, spatial distribution) of the individual components, while at the same time they mimic real catalysts closely enough to allow testing under industrially relevant conditions. Using this approach I will address fundamental questions, such as:* What are the mechanisms (structural, electronic, chemical) by which non-metal promoters influence the functionality of copper-based catalysts?* Which nanoalloys can be formed, how does their composition influence the surface active sites and catalytic functionality under reaction conditions?* Which size and interface effects occur, and how can we use them to tune the actitivity and selectivity towards desired products?Our 3D model catalysts will be assembled from ordered mesoporous silica and carbon support materials and Cu-based promoted and bimetallic nanoparticles. The combination with high resolution characterization and testing under realistic conditions allows detailed insight into the role of the different components; critical for the rational design of novel catalysts for a future more sustainable production of chemicals and fuels from renewable resources.Computational Microscopy of Crowded MembranesCell membranes form a highly complex and heterogeneous mixture of membrane proteins and lipids. Understanding the protein-lipid interplay that gives rise to the lateral organisation principles of cell membranes is essential for life and health. Thus, investigations of these crowded membranes is emerging as a new and exceptionally exciting frontier at the crossroads of biology, life sciences, physics, and chemistry.However, our current understanding of the detailed organisation of cellular membranes remains rather elusive. Characterisation of the structural heterogeneity in-vivo remains very challenging, owing to the lack of experimental methods suitable for studying these fluctuating nanoscale assemblies of lipids and proteins with the required spatio-temporal resolution. In recent years, computer simulations have become a unique investigatory tool for understanding the driving forces governing the lateral organisation of cellular membrane components and this  computational microscopy has become indispensible as a complement to traditional microscopy methods.In this ERC project I will, using advanced computational microscopy, study the interaction of lipids and proteins in complex, crowded, membrane patches, to enable the driving forces of membrane protein sorting and clustering to be unravelled at conditions closely mimicking real cellular membranes. The specific objectives are:? To develop a novel computational microscopy framework for simulating biomolecular processes at multiple resolutions.? To use this new computational microscopy framework to investigate the driving forces of membrane protein sorting and clustering.? To provide a molecular view of realistic, crowded, biological membranes composed of hundreds of different lipids and proteins.The outcomes will enable subsequent studies of many different types of cell membranes based on forthcoming lipidomics studies and progress in structural characterisation of membrane proteins.uLewis Acidic Borocations: improving Suzuki couplings, Material synthesis, Alkylation and Radical TransformationsCarbon-carbon bond formation is arguably the most important reaction in synthetic chemistry, exemplified by the award of five noble prizes. The most recent Nobel prize was awarded for the development of palladium catalysed cross coupling, of which Suzuki cross coupling is the most widely applied version in industry and academia and utilizes organo-boronates (RB(OR)2) as the nucleophilic component. The aims of this project are; (i) to simplify the synthesis of organo-boron compounds that are utilized in (a) Suzuki cross coupling and (b) as boron containing materials for organic electronic applications. (ii) Reduce the dependency on expensive and toxic palladium by a) extending the Friedel Crafts C-C bond forming reaction to broad scope, electrophilic trifluoromethylat< ion and electrophilic arylation (b) generating and applying efficient iron catalysts in an iron analogue of the Suzuki Reaction. To achieve each of our aims we will utilise the unique properties of electrophilic borocations. Previously we have used boro-cations that combine a coordinatively unsaturated and electrophilic boron centre with a  masked form of a strong base to develop fundamentally new reactivity. These borocations enabled the sequential one pot activation of a substrate by a strong Lewis acid (the borocation) and then release of the masked Lewis base for a subsequent step (e.g., deprotonation). This concept of a boron reagent enabling sequential reactivity by subsequent dissociation of a group is a continual theme through this proposal. This property of borocations will be combined with appropriate leaving groups on the nucleophile to tackle the important challenges outlined above. Key to expanding the synthetic utility is design of the borocation to enable the release not only of a neutral Lewis base (for direct borylation, including the synthesis of RB(OR)2) but also an anionic group (for arylation/alkenylation) or a cationic moiety (for alkylation).NInnovative Polymers for Energy StorageiPes project aims to provide adequate support to Dr. David Mecerreyes (DM) who is at the stage of consolidating an independent research team. During his scientific career, DM has demonstrated creative thinking and excellent capacity to carry out research and going beyond the state of the art. His meritorious record of research, scientific publications (128 ISI articles, h index = 33), project conception, private sector experience, networking ability (participated in 10 European collaborative projects) and capacity for supervising and coordinating a research team are presented in detail in the initial part of the proposal. He recently moved from the private sector to create a new research group at the University of the Basque Country. He is now in an excellent academic position and research environment to commit and be devoted to an ERC frontier research project. DM s proposal passed to the second stage in the ERC starting grant call of last year. This year the research project has been rebuilt taking into account his group directions and the detected weak points of last year s proposal. This is his last opportunity for participating to the ERC starting-grant call. iPes proposes an innovative research programme at the forefront of polymer chemistry. The proposal goes in depth into the topic of energetic polymers. iPes activities will fully develop the field of polymers for energy storage by using an innovative macromolecular engineering approach generating the ground for future innovations. The main S&T goal is to obtain new polymeric materials, to get an insight into their unique electronic properties, to model the new energetic polymers and to investigate their application in innovative battery prototypes. These technologies are currently dominated by inorganic electrode materials. iPes aims at bringing polymer chemistry to a next level and developing basic knowledge about innovative polymeric materials which may open up new opportunities for Energy Storage.Sustainable Catalytic C-H Bond FunctionalizationThe impressive progress in synthetic organic chemistry during the past century has propelled this discipline to its current central place as the key enabling technology in the physical and life sciences. Despite these remarkable advances, our ability to construct molecules of even moderate structural complexity remains unsatisfactory, since these syntheses continue to be inefficient, rely on a high number of reaction steps, and generate undesired, often toxic waste. These features led to the general need for greener transformations that will stimulate the development of more sustainable chemical industries. Conventional approaches in synthetic org< anic chemistry make use of starting materials displaying specific functional groups, the installation of which results in costly reaction and purification steps. Therefore, an environmentally-sound and economically-attractive alternative is represented by the direct functionalization of ubiquitous carbon-hydrogen (C H) bonds. These transition-metalcatalyzed processes avoid prefunctionalization strategies, prevent the formation of undesired waste, and thus enable an overall streamlining of organic synthesis. While considerable recent progress has been accomplished in C H bond functionalizations, available methodologies continue to be limited in scope, and key challenges are still to be overcome. Establishing a full set of sustainable C H bond functionalization protocols will undeniably have a tremendous impact on various applied areas, such as drug discovery, chemical industries or material sciences.hMechanically Interlocked Carbon NanotubesWe present a plan to design, synthesize and exploit the properties of mechanically interlocked carbon nanotubes (MINTs). The scientific aim of the project is to introduce the mechanical bond as a new tool for the derivatization of carbon nanotubes. The mechanical link combines the advantages of covalent and supramolecular modifications, namely: kinetic stability (covalent) and conserved chemical structure (supramolecular). Besides this, its dynamic nature opens up unique opportunities for both fundamental studies and applications. From a technological point of view, MINTs should have a practical impact in the fields of molecular electronics and molecular machinery. A general modular approach to MINT-based materials for photovoltaic devices and electrochemical sensors is presented. We also expect to exploit the rigidity and low dimensionality of SWNTs to construct molecular machines that utilize them as tracks to move across long distances, which is not possible in smallmolecule molecular machines. To achieve these goals we will exploit the PI s expertise in the chemical modification of carbon nanostructures, in the self-assembly of electroactive materials and in the synthesis and characterization of mechanically interlocked molecules. Photo-Engineered Helices in Chiral Liquid CrystalsSupramolecular helices are a striking expression of chirality which is found at every level of biological materials, from plant cell walls to bones. Helical biomaterials formed out of equilibrium display multiple length scales, adaptation of structure to function and responsiveness to changing environments, a unique set of features that constitutes a fascinating source of inspiration for materials science. However, matching the complexity of these biological architectures by rational design of synthetic systems remains a major contemporary challenge. The aim of this project is to develop sophisticated helical materials with responsive architectures that are of interest in optical communication, energy management, photonic materials and mechanical actuation. The innovative and versatile approach proposed here consists in using light i) to engineer the period, handedness and orientation of the cholesteric helix, and ii) to stabilise the structures formed out of equilibrium by insitu formation of polymer networks. Three tasks will run concurrently: Task 1: Stimuli-responsive infrared super-reflectors Task 2: Dynamic templates for long range ordering of nano-objects Task 3: Photomechanical actuation of helicoids and spiral ribbons  Phelix will yield complex systems that reach beyond the state of the art in stimuli-responsive materials, push the frontiers of research on supramolecular helices and shed new light on transmission of chirality across length scales. Ultimately, the omnipresence of helical structures in nature means that biomedical applications could be envisioned< also. The proposal builds on my recent investigations on light-responsive helices in cholesteric liquid crystals. I have demonstrated the expertise in liquid crystals, photochemistry and microscopy required for this research and my leadership experience ensures its success.Nitride-based nanostructured novel thermoelectric thin-film materialsMy recent discovery of the anomalously high thermoelectric power factor of ScN thin films demonstrates that unexpected thermoelectric materials can be found among the early transition-metal and rare-earth nitrides. Corroborated by first-principles calculations, we have well-founded hypotheses that these properties stem from nitrogen vacancies, dopants, and alloying, which introduce controllable sharp features with a large slope at the Fermi level, causing a drastically increased Seebeck coefficient. In-depth fundamental studies are needed to enable property tuning and materials design in these systems, to timely exploit my discovery and break new ground. The project concernsfundamental, primarily experimental, studies on scandium nitride-based and related single-phase and nanostructured films. The overall goal is to understand the complex correlations between electronic, thermal and thermoelectric properties and structural features such as layering, orientation, epitaxy, dopants and lattice defects. Ab initio calculations of band structures, mixing thermodynamics, and properties are integrated with the experimental activities. Novel mechanisms are proposed for drastic reduction of the thermal conductivity with retained high power factor. This will be realized by intentionally introduced secondary phases and artificial nanolaminates; the layering causing discontinuities in the phonon distribution and thus reducing thermal conductivity. My expertise in thin-film processing and advanced materials characterization places me in a unique position to pursue this novel high-gain approach to thermoelectrics, and an ERC starting grant will be essential in achieving critical mass and consolidating an internationally leading research platform. The scientific impact and vision is in pioneering an understanding of a novel class of thermoelectric materials with potential for thermoelectric devices for widespread use in environmentally friendly energy applications.Orbital molecules' - self-organised states for orbitronics Orbital molecules are made up of coupled orbital states on several metal ions within an orbitallyordered (and sometimes also charge-ordered) solid such as a transition metal oxide. Spin-singlet dimers (a weak metal-metal bond) are known in several materials, but recent discoveries of more exotic species such as 18-electron heptamers in AlV2O4 and 3-atom trimerons in magnetite (Fe3O4) have shown that a general new class of quantum electronic states that we call  orbital molecules awaits exploration. The discovery of trimerons is particularly important as it provides the solution to the important and long-running problem of the low temperature Verwey phase of magnetite. This was discovered in 1939 but remained contentious as the complex superstructure was unknown. The applicant and co-workers recently used a synchrotron microcrystal technique to solve the structure. This showed that the Verwey transition is driven by Fe2+/3+ charge ordering in a first approximation, but with the formation of a self-organised network of trimeron orbital molecules that had not been predicted in over 70 years of previous study. To expand the magnetite discovery into a general breakthrough in understanding quantum matter, this project will explore chemical tuning of orbital molecule self-organisation, discovery of novel orbital molecule orders in frustrated networks, and investigations of trimeron glass and liquid phases in magnetite. Evidence for liquid phases is key to possible applications. The project will develop high resolution diffraction and total scattering methods to determine long range and local orbital molecule orders, with further characterisation from magnetisation and conductivity measurements. Samples will be synthesised at ambient and high pressures. This study will pioneer a new area of research in the electronic properties of solids, and may help to underpin future post-silicon orbitronic technologies based on the creation and manipulation of orbital states.Nanostructuring graphene and graphitic substrates for controlled and reproducible functionalizationGraphene is a new class of promising material with exceptional properties and thus warrants a plethora of potential applications in various domains of science and technology. However, due to intrinsic zero bandgap and inherently low solubility, a prerequisite for the use of graphene in several applications is its controlled and reproducible functionalization in a nanostructured fashion. Being a  surface-only nanomaterial, its properties are extremely sensitive not only to chemical modification but also < to noncovalent interactions with simple organic molecules. A systematic knowledge base for targeted functionalization of graphene still eludes the scientific community. The present experimental protocols suffer from important shortcomings. Firstly, graphene functionalization occurs randomly in solution based methods and there is scarcity of methods that can exert precise control over how and where the reactions/interactions occur. Secondly, due to random functionalization, producing reproducible samples of structurally uniform graphene and graphitic materials remains a major challenge. Lastly, a molecular level understanding of the functionalization process is still lacking which precludes systematic strategies for manipulation of graphene and graphitic materials. NANOGRAPH@LSI aims to develop systematic experimental protocols for controlled and reproducible (covalent, non-covalent as well as the combination of both) functionalization of graphene and graphitic materials in a nanostructured fashion at the liquid-solid interface (LSI), along with the implementation of new nanoscale characterisation tools, targeting a broad range of applications in the fields of electronics, i.e. graphene bandgap engineering, sensing, and separation. Supramolecular self-assembly of organic building blocks at the liquid-solid interface will be employed as a basic strategy. In view of the above mentioned applications, also upscaling protocols will be developed and implemented.Tuning Disorder in Chalcogenides to realize Advanced Functional DevicesBetter performance of future computers and communication equipment requires substantially higher speeds of switching devices at lower energy consumption. Those requirements can only be achieved by substantial improvement of the transport properties of the materials employed. The transport of charge and heat is strongly influenced by disorder. In recent years we have found a unique class of crystalline materials which combines an exceptionally high, yet tuneable degree of disorder with remarkable transport properties. This class includes the best phase change materials, superconductors with an unconventional coupling mechanism, good thermoelectrics, as well as known topological insulators. For these different phenomena disorder is either very beneficial or  if unconditioned -rather detrimental. Hence we need to be able to control disorder in these materials to tailor their properties. Exploring this concept requires the ability to understand, eliminate or harness the effects of disorder. Recently we have demonstrated an Anderson-type transition from insulating to metallic behaviour upon annealing. However, to fully utilize these ideas it is mandatory to realize devices with a more directly controllable degree of disorder. Within the framework of this project, we will develop a tuneable Anderson insulator to delocalize charge carriers. This allows us to address a) the transition from an insulator to a metal, the impact of disorder on superconductors (b) and topological insulators (c) and finally d) the ability to control thermoelectric properties by tuneable electronic disorder. From the results to be obtained we expect consequences for a wide range of materials listed in our  treasure map , with promising new technological applications in various devices.Advancing the Study of Chemical, Structural and Surface Transformations in Colloidal NanocrystalsColloidal inorganic nanocrystals (NCs) are among the most investigated nanomaterials in Nanoscience due to their high versatility. Research on NCs went through much advancement lately, especially on synthesis, assembly and on the study of their transformations, most notably via cation exchange (all fields in which the PI has contributed already). However, the integration of NCs with fabrication tools that employ conditions such as irradiation, etching and annealing is at a very early stage since we do not have a systematic knowledge of what transformations are triggered in the NCs under those conditions. Also, an issue related to the incorporation of NCs in materials/devices is whether, over time, the NCs will remain as they are, or they will transform into other structures. Plus, these transformations in NCs are poorly studied as they require fast recording techniques. This proposal will embark on an ambitious investigation of post-synthetic transformations in solution-grown NCs: by advancing the understanding of various aspects of chemical, structural and surface transformation of NCs, we will uncover new fabrication techniques that will employ such nanostructures as the key ingredients. This in turn will have a strong impact in opto -electronics, as several electronic components entirely made of NCs will be delivered. Four objectives are targeted: i) developing radically new sets of experimental tools for the investigation of chemical transformations in NCs, above all the ability to monitor in real time these transformations; ii) developing solution-grown nanostructures able to undergo programmed transformations under a defined stimulus; iii) understanding the role of irradiation on the fate of surface ligands and on cation exchange reactions in NCs; iv) combining chemical, structural and surface transformations towards NC-based opto-electronics. The success of the proposal hinges on the proven capabilities of the PI, with ample support from the host Institution.RIce-binding proteins: from antifreeze mechanism to resistant soft materialsCrystallization of water into ice is lethal to most organisms and detrimental to many soft materials. Freeze-tolerant fish living in polar seas evolved to tackle this problem with an unusual copi< ng strategy. They produce  antifreeze proteins that block the growth of nascent ice crystals within a narrow temperature range known as the  thermal hysteresis gap enabling survival under extreme conditions. Encoding this functionality into synthetic polymers would open up new avenues in biomedicine, agrifood and materials science for e.g. cryopreservation, crop hardiness, ice-templating, dispersion stability, and advanced coatings. Progress requires a profound understanding of the mechanism of non-colligative freezing point depression at the molecular level and allows for efficient strategies for the design and preparation of powerful macromolecular antifreezes.I propose to unravel how antifreeze proteins work and to build upon these insights to explore effective routes towards icebinding polymers aiming to make sensitive soft materials freeze-resistant. Within this challenge we first focus on single-molecule experiments to visualize bound proteins and study the strength of the noncovalent interaction with ice. We will study if and when adsorption on  foreign interfaces and solution assembly impact activity. These fundamental insights will guide our research towards synthetic antifreeze agents with superior functionality to achieve record supercooling in complex environments. This knowledge-based design of polymers with high affinity for crystalline interfaces holds great promise for many areas of science and technology in which crystallization plays a decisive role.Unravelling cross-presentation pathways using a chemical biology approachImmune therapies are therefore currently being pursued to reinvigorate the immune reaction against tumours. This is not trivial, as the right type of immune cells must be activated against a tumourspecific antigen. One method to achieve this is by targeting tumour antigens to certain crosspresentation-promoting receptors on antigen presenting cells. The most intriguing of these is the mannose receptor (MR) as the method by which it does this is unknown. This glycoprotein-binding receptor appears to have two functions on APCs: general uptake-enhancement and, in certain isolated cases, cross-presentation-enhancment. What ligand parameters are important in causing crosspresentation enhancement is not known. Current tools, such as anti-MR antibodies and randomly glycosylated ligands fail to selectively enhance cross-presentation. The main aim of this proposal is to determine what structural parameters of the glycoprotein antigen result in enhanced crosspresentation upon MR-ligation. I will synthesise a library of biologically traceable single glycoform ligands - with controlled variation in glycan nature, stoichiometry and positioning - for the MR and study differences in uptake, routing and antigen presentation. A 2nd aim is to uncover what happens to the antigen after uptake by the MR. I.e. whether changes in antigen routing and proteolysis are responsible for enhanced cross presentation of different glycoforms. A 3rd aim is to develop a new method to study the kinetics of surface appearance of epitopes without T-cell reagents to quantify differences between glycoforms. With this approach I aim to gain new insight into methods for enhancing cross-presentation resulting in improved immune therapies against cancer. My background in carbohydrate and protein modification chemistry will provide the toolkit to synthesise the relevant reagents and my background in immunology will ensure the successful immunological validation of the synthetic single glycoforms.LDynamics of Amorphous Semiconductors: Intrinsic Nature and Application in Neuromorphic HardwareAfter decades of perfecting the established way of computing, it is now evident that the fundamental logic of today s computers will prevent them from ever reaching the efficiency of neural networks as found in nature. Neuromorphic hardware promises a leap forward by following the inherent working principles of biological neural networks. In very-large-scale integrated neuromorphic circuits incorporating an immense number of artificial neurons, the even much larger number of synapses poses the challenge of imitating especially the synaptic functionality in a most compact way. Over the last years, various memristive devices have been proposed to represent the weight of a synapse, determining how well electrical spikes are transmitted from one neuron to another. Existing attempts to achieve spike-timing-dependent plasticity, however, possess inherent problems. The NEURAMORPH project aims to develop a simple and compact circuit element to regulate the access to the memristive device for weight modifications. The dynamics of electrical excitability intrinsic to the employed amorphous semiconductors will naturally be able to mimic spike-timing-dependent plasticity. For full control over the properties of these synaptic access elements, a < fundamental understanding of the relaxation processes in such amorphous materials is imperative. To this end, amorphization conditions will be systematically varied over a wide-range to create very distinct amorphous states. As a measure for relaxation the temporal evolution of their electrical properties will then be investigated. Based on experimental results for a variety of materials, molecular dynamics simulations will be employed to elucidate the relationship between elemental composition, structural dynamics and changing electrical excitability. Finally, as proof of concept, a prototype of a neuromorphic chip will be developed incorporating the new kind of synaptic device.ZRadical Solutions for Hysteresis in Single-Molecule MagnetsSingle-molecule magnets (SMMs) display magnetic hysteresis that is molecular in origin, and these materials have huge potential to be developed as nano-scale devices. The big challenge is to create SMMs that function without the need for liquid-helium cooling.This project will develop new SMMs that combine the strong magnetic anisotropy of lanthanide ions with a series of novel radical ligands. Our innovative SMMs will have controllable molecular and electronic structures, which will ultimately enable hysteresis at unprecedented temperatures.Highly unusual di- and tri-metallic Ln-SMMs are proposed in which the metals are bridged by radicals with heavy Group 15 (phosphorus-bismuth) and Group 16 (sulphur-tellurium) donor atoms. Trimetallic SMMs will also be based on hexaazatriphenylene (HAT) radicals, and dimetallic SMMs will also be based on nindigo radicals, both of which are nitrogen-donor ligands.The SMM field is dominated by systems with diamagnetic ligands. Our radical ligands have never been used in SMM studies: their diffuse unpaired spin provides a way of switching off the quantum tunnelling mechanisms that otherwise prevent hysteresis. We will exploit the rich electrochemistry of the target ligands: heavy p-block radicals have huge spin densities on the donor atoms; HAT radicals can have up to three unpaired electrons; reduced or oxidized nindigo radicals allow access to redox-switchable SMMs. In the HAT-bridged SMMs, the use of ligands with more than one unpaired electron is unprecedented. The heavy p-block ligands are themselves are novel.The PI s approach to SMMs has already established new directions in lanthanide chemistry and in molecular magnetism. He now proposes a new, radical approach to SMMs with potential to re-define the state of the art, and to extend the frontiers of a vibrant multi-disciplinary field. Achieving the aims will provide a major step towards using SMMs for applications at practical temperatures.HN2 as Chemical Feedstock  Synthetic Nitrogen Fixation beyond Haber-BoschThe chemical transformation of dinitrogen is one of the most important industrial processes. Thereby produced ammonia serves as nitrogen source for almost any synthetic nitrogen containing compound, such as fertilizers or many polymers and pharmaceuticals. However, despite forcing conditions associated with high energy consumption, the Haber-Bosch process gives low yields in NH3. Hence, homogeneous, bioinspired nitrogen fixation is a longstanding goal, yet with very limited success. In this proposal, we strive to circumvent the Haber-Bosch process for the synthesis of N-containing chemicals by direct N2 functionalization upon initial splitting into molecular nitrides at ambient conditions and subsequent C N bond formation. Catalytic platforms will be developed based on late, electron rich transition metal complexes with functional pincer ligands, which represents a fundamentally new approach for this purpose. The overall N2 functionalization effort will be broken down into three elementary steps, i.e. N2 splitting, de-/hydrogenation of metal bound N-species, and C N bond formation. These subprojects are examined individually with a combination of modern synthetic, physical inorganic, and computational methods. These results will finally enable the rational design of homogeneous catalysts. Hence, besides the primary goal to directly use N2 as chemical feedstock this project will also serve the secondary objectives of maki< ng important contributions to related timely and challenging topics, such as C N coupling by nitrenoid transfer or the use of nitrogen compounds, especially ammonia, as chemical fuels in energy storage applications. The previous record of my group in the chemistry of electron-rich transition metal complexes with functional pincer ligands, N2 splitting/coupling, and the activation of other N-containing small-molecules provide a strong basis for the feasibility of these challenging goals.lTracking the cognitive basis of social communication across the life-spanA vital part of successful everyday social interaction is the ability to infer information about others (e.g. their emotions, visual perspective, and language). Development of these social skills (termed Theory of Mind, ToM) has been linked to improvements in more general cognitive skills, called Executive Functions (EF). However, to date very little is known of how this link varies with advancing age, and no model exists to explain the relationship. Thus, the key aim of the proposed research is to systematically explore the cognitive basis of social communication and how this changes across the life-span. The research will address three complementary objectives: (1) to what degree can variations in ToM ability across the life-span be accounted for by changes in EF skills, (2) how do ToM ability and EF skill change over time in different age groups (using longitudinal methods, i.e. test-retest of the same participants), and (3) can ToM ability be enhanced through training specific EF skills, and how do these training effects differ across the life-span. Contrary to traditional studies of social communication, I will employ an interdisciplinary approach that links theory and practice from cognitive, social, developmental, and clinical (neuro)psychology to study the relationship between ToM and EF across a broad and dynamic age range (10 to 80+ yrs old). I will use cutting-edge combinations of techniques (eye-tracking and EEG) and paradigms, alongside sophisticated statistical methods to track the timecourse of social understanding, and model how it relates to EF and more general cognitive/social skills (eg. IQ, language) within and between individuals. This research will open up new horizons in ToM research by developing an intervention programme to enhance the quality of social communication in older adults (thus improving their mental health and well-being), which has the potential to be applied in other individuals with social communication deficits (eg. autism).*Tubular Supramolecular Polymers: A new class of therapeutic polymersThis research programme will establish a new class of materials and develop them into functional devices for biomedical applications. We will design tubular supramolecular polymers, supramolecular polymer brushes (SPBs), based on the self-assembly of cyclic peptide  polymer conjugates. The synergy between the cyclic peptide, which directs the formation of the SPBs and the polymer conjugate, which provides functionality, will open the route to a wealth of new functional structures. We will build on our initial work and expand our research to generate new synthetic routes for the ligation of polymers to peptides, develop new protocols for the characterisation of the materials, and establish the mechanism of supramolecular polymerisation. This research programme will open new horizons in the fundamental understanding and production of supramolecular polymers. In particular, beyond the generation of new materials, the functionality of these systems may allow the development of supramolecular living polymers, a long-standing goal in polymer chemistry that is still elusive. The functionality and versatility of the SPBs obtained in this work open the route to a wealth of applications, and we will focus on one specific target: the fabrication of drug delivery vectors. We will exploit the unique combination of features presented by this new class of polymer therapeutics, such as multiple attachment points for one or more drug(s) / targeting ligands / markers, the ability to selfdisassemble into smaller and easy-to-excrete components, and an elongated shape that enables diffusion and interaction with cells more efficiently than traditional globular delivery systems. We will study the pharmacology properties of the SPBs, including their stability, toxicity, mode of cell penetration and ability to deliver a single or a combination of bioactive agent(s) (in the case of concerted mechanisms).A preparative approach to geometric effects in innovative solar cell types based on a nanocylindrical structureThe ERC Consolidator Grant project SOLACYLIN aims at providing experimental insight into the function of 'third-generation' photovoltaic systems by generating materials stacks structured in a well-defined, accurately tunable, nanocylindrical geometry. To this goal, we will develop and exploit advanced preparative methods based on two fundamental ingredients: (a) ordered 'anodic' porous oxides and (b) atomic layer deposition (ALD). The former solids will be generated as templates providing ordered arrays of straight, cyclindrical pores, the diameter and length of which can be varied between 20 nm and 300 nm and between 0.5 microns and 50 microns, respectively. The latter method will be used to coat the inner pore w< alls with one or several layers of the photovoltaic stack, each with a thickness set to values chosen between 1 nm and 30 nm. We will invent and characterize novel surface reaction schemes for the deposition in ALD mode (from the gas phase and from solutions) of functional materials (doped semiconductors and intrinsic light absorbers) with tailored chemical and physical properties. We will investigate the experimental conditions in which they can be combined in a way that optimizes the quality of their interfaces. Finally, we will quantify the electrical and photovoltaic performance of p-i-n junctions prepared with our methods. We will have the unique capability of describing in a systematic, accurate manner how the experimental photovoltaic parameters depend on the individual thicknesses of the individual layers and on the length of the cylinders. This direct experimental handle on the amount of light absorbed, on the one hand, and the charge carrier transport distances to the electrical contacts, on the other hand, will be correlated with the relevant material parameters (absorption coefficients, carrier mobilities). This information will unveil the phenomena limiting the efficiency of each type of solar cell, and suggest avenues to remedy them.9Unconventional Bifunctional CatalystsThe development of sustainable chemical processes is one of the most important features in modern chemistry. It has become a key research area worldwide providing solutions to important societal demands by optimizing the use of natural resources and minimizing waste and environmental impact. Among the relevant methods for achieving this goal, catalysis represents a key and central approach. Both Organocatalysis and Metal Catalysis have emerged as solutions to the problems in this context. In this field, the progress of a novel bifunctional organocatalyst that could increase the number of different activations, and therefore the synthesis of valuable enantio-enriched molecules, would be highly desirable. Especially important, but still unknown, are the bifunctional-catalysts based on a Neutral Coordinate Organocatalyst and Photo-Organocatalysts. This proposal aims to develop two new unconventional approaches for the synthesis of bifunctional organocatalysts. The first one is based on the development of new Bifunctional Neutral Coordinate Organocatalyst and their application to the synthesis of biologically relevant compounds. I propose to use these bifunctional catalysts to promote the dual activation of silyl reagents and suitable electrophiles. This approach constitutes an unconventional way to synthesize asymmetric molecules and has no precedent in the literature. The second section of this proposal explores the photo-activation-bifunctional organocatalyst. I propose the design and application of new metal-free Bifunctional Photo-Organocatalysts which are able to chemically and photo-activate the substrate simultaneously in an asymmetric manner. This project has the potential to change the general view of asymmetric Neutral Coordinate Organocatalyst and Photo-catalysis as we know it today. These unconventional bifunctional would be incorporated into the privileged catalyst library for its applications in new asymmetric transformations.yTowards Artificial Enzymes: Bio-inspired Oxidations in Photoactive Metal-Organic FrameworksMetal-organic frameworks (MOFs) are key compounds related to energy storage and conversion, as their unprecedented surface areas make them promising materials for gas storage and catalysis purposes. We believe that their modular construction principles allow the replication of key features of natural enzymes thus demonstrating how cavity size, shape, charge and functional group availability influence the performances in catalytic reactions. This proposal addresses the question of how such novel, bio-inspired metallo-supramolecular systems can be prepared and exploited for sustainable energy applications. A scientific breakthrough that demonstrates the efficient conversion of light into chemical energy would be one of the greatest scientific achievements with unprecedented impact to future generations. We focus on the following key aspects:a) MOFs containing novel, catalytically active complexes with labile coordination sites will be synthesised using rigid organic ligands that allow us to control the topologies, cavity sizes and surface areas. We will incorporate photosensitizers to develop robust porous MOFs in which light-absorption initiates electron-transfer events that lead to the activation of a catalytic centre. In addition, photoactive molecules will serve as addressable ligands whereby reversible, photo-induced structural transformations impose changes to porosity and chemical attributes at the active sites. b) Catalytic studies will focus on important oxidations of alkenes and alcohols. These reactions are relevant to H2-based energy concepts as the anodic liberation of protons and electrons can be coupled to their cathodic recombination to produce H2. The studies will provide proof-of-concept for the development of photocatalytic systems for the highly endergonic H2O oxidation reaction that will be explored using most stable MOFs. Further, gas storage and magnetic properties that may also be influenced by light-irradiation will be analysed.Nanoencapsulation for Energy Storage and Controlled ReleaseThe main vision of the project ENERCAPSULE is the development of nanoencapsulation technologies based on switchable nanoscale barriers for novel generation of controlled energy storage and delivery systems. These systems will be based on the  smart nanocontainers (size below 200 nm) loaded with the energy-enriched active components: materials for thermal energy (both latent and based on chemical reactions) storage and substances for bioenergy (ATP or its components) storage for synthetic biology platforms. First novelty of the proposed project is the protection of the nanoscaled energyenriched materials against environment during storage and controlled release of the encapsulated energy on demand only using both inherent properties of nanocontainer shell or biomimetic nanovalves introduced as shell components. Another main objective of the project is to study the structure and surface-to-volume properties of the energy enriched materials dispersed and encapsulated on nanoscale. The questions of stability of energy nanomaterials, influence of the nanocontainer shell on their energy capacity, homogeneity and operation lifetime< will be investigated. Polymer organic nanocapsules with hollow interior and mesoporous carbon nanoparticles are chosen in the project as main types of the nanocontainer scaffolds for energy-enriched materials due to their high loading capacity and potential to design their shells to attain them controlled permeability properties. At the end of the project, developed novel energy storage and delivery systems will be combined within one network having several mechanisms for release and uptake of energy, which can be activated depending on type and intensity of the external impact (demand). The potential applications of such multienergy storage systems will be tested by industrial companies supporting the project.Modelling of MOF self-assembly, crystal growth and thin film formationMetal-organic frameworks (MOFs) constitute one of the most exciting developments in recent nanoporous material science. Synthesised in a self-assembly process from metal corners and organic linkers, a near infinite number of materials can be created by combining different building blocks allowing to fine tune host guest interactions. MOFs are therefore considered promising materials for many applications such as gas separation, drug delivery or sensors for which MOFs in form of nanoparticles, composite materials or thin films are required. For MOFs to realise their potential and to become more than just promising materials, a degree of predictability in the synthesis and the properties of the resulting material is paramount and the full multiscale pathway from molecular assembly to crystal growth and thin film formation needs to be better understood.Molecular simulation has greatly contributed to developing adsorption applications of MOFs and now works hand-in-hand with experimental methods to characterise MOFs, predict their performance and study molecular level phenomena. In contrast, hardly any simulation studies exist about the formation of MOFs, their crystal growth or the formation of thin films. Yet such studies are essential for understanding the fundamentals which will ultimately lead to a better control of the material properties. Building on my expertise in molecular modelling including the development of methods to model the synthesis of porous solids, we will develop new methods to study: 1. the self-assembly process of MOFs under synthesis conditions 2. the formation of nanoparticles 3. the integration of MOF nanoparticles into composite materials and the self-assembly into extended structures 4. the layer-by-layer growth of thin films At the end of the project we will have transformed our understanding of how MOFs form at a variety of length scales and opened up new research directions for the targeted synthesis of MOFs fit for applications.Boron-boron multiple bondingMultiple bonding between atoms is immensely important to chemistry, biology, physics and their associated industries; multiple bonds are both ubiquitous in everyday products and extremely useful functionalities for effecting chemical transformations. While very common with the elements carbon, nitrogen and oxygen, multiple bonding is in comparison extremely rare with other elements. Multiple bonding between heavier elements of the main group of the periodic table becomes less favourable the heavier the element becomes. However, this does not explain the relative paucity of multiple bonding with boron, which is immediately to carbon's left on the periodic table. In particular, isolable, stable compounds containing multiple bonds between two boron atoms are extremely rare, and until 2007 only a handful of charged examples existed.A revolution in this field has recently been witnessed with the syntheses of the first neutral compounds with boron-boron double bonds, diborenes, and the first compounds with boron-boron triple bonds, diborynes. The first neutral diborenes were prepared in 2007, however, we have recently developed a number of rational, selective and more general routes to these compounds. The first diboryne compounds were prepared by our group in 2012. The significance of these two families of molecules is not only their unusual multiple bonding but also the extremely high electron density on the boron atoms, an unusual situation for an element that is known for its electron-poor character. This high electron density leads to strong boron-based nucleophilicity and extremely high reduction potentials  both highly novel phenomena.This proposal aims to: (A) comprehensively explore the syntheses of these unique compounds and the limits thereof, and to (B) exploit the unusual reactivity of these electron-rich boron molecules in synthesis, small-molecule activation and materials science. : 30/4/2021Artificial-Intelligence Driven Discovery and Synthesis of Polyoxometalate ClustersWe outline a 5 year programme that introduces a new platform for the preparation, understanding, and exploitation of precisely defined nano-molecules / materials based upon the assembly of molecular metal oxide precursors (polyoxometalates) under non-equilibrium conditions with welldefined physical properties using automated intelligent feedback. We will elucidate the mechanism of assembly of these gigantic molecules and devise a set of rules similar to the magic numbers found in gold nanoclusters, using these to break the 10 nm size barrier for a single molecule. Targeted properties include photochemical and electrochemical sensors, bistable molecules, doped traditional oxides with polyoxometalates, and new catalysts including water oxidation via a Universal Building Block (UBB) approach that links properties of the building blocks with emergent properties of the resulting clusters and materials for the first time. The new approach includes the conversion of batch to flow synthesis not only for auto< mation, but to understand fundamental mechanistic aspects, and to use artificial intelligence algorithms to help move through the myriad of possible combinations (without needing to synthesise every possible molecule). The SMART-POM approach is therefore not merely automation of one-pot chemistry, but an entirely new paradigm building on our recent developments and will allow us to move through a vast combinatorial space effectively only locating areas of novelty via feedback control. This feedback will be used to discover, design, and develop complex, adaptive and functional metal oxide-based materials based upon sensory feedback from the physical properties measurements. Thus SMART-POM will open up a whole new synthetic space, give mechanistic understanding, and allow the discovery of molecules with potential real-world applications. Finally, we will aim to extend the SMART-POM paradigm to other areas of chemistry which will benefit from the search for novelty.gUnderstanding the Hardness of Theorem ProvingThis project aims to explore the fundamental question in computer science and mathematics regarding what computational problems can feasibly be solved on a computer. More specifically, we want to study algorithms for proving logic formulas as well as impossibility results for this problem. Proving formulas in propositional logic is a problem of immense importance both theoretically and practically. On the one hand, this computational task is believed to be intractable in general, and deciding whether this is so is one of the famous million dollar Millennium Problems (the P vs NP problem). On the other hand, today automated theorem provers, or so-called SAT solvers, are routinely used to solve largescale real-world problem instances with even millions of variables. This contrasts to that there are also known small example formulas with just hundreds of variables that cause even state-of-the-art SAT solvers to stumble. The main objectives of our project are as follows: (1) Understand what makes formulas hard or easy in practice by building and studying better theoretical models of the proof systems underlying SAT solvers, and testing the predictions of these models against empirical data. (2) Gain theoretical insights into other crucial issues in SAT solving such as memory management and parallelization. (3) Explore the possibility of basing SAT solvers on stronger proof systems than are currently being used. (4) Clarify the theoretical limitations of such enhanced SAT solvers by studying the corresponding proof systems, which are currently poorly understood. We see great opportunities for fruitful interplay between the fields of proof complexity and SAT solving in this area, as well as between theoretical results and practical implementations. We believe that resolving the questions posed by this project could potentially have a major impact in theoretical computer science, and in the longer term in more applied areas of computer science and mathematics.Self-Enforcing E-Voting System: Trustworthy Election in Presence of Corrupt AuthoritiesThis project aims to develop a new generation of e-voting called the  self-enforcing e-voting system . The new system does not depend on any trusted authorities, which is different from all currently existing or proposed e-voting schemes. This has several compelling advantages. First, voting security will be significantly improved. Second, the democratic process will be enforced as a whole. Third, the election management will be dramatically simplified. Fourth, the tallying process will become much faster. The idea of a  self-enforcing e-voting system has so far received little attention. Although several researchers have attempted to build such a system in the past decade, none were successful due to inefficiencies in computation, bandwidth and the number of rounds. My preliminary investigation indicates that a "self-enforcing e-voting system" is not only practically feasible, but has the potential to be the future of e-voting technology. I have identify several major research problems in the field, which need to be addressed urgently before a self-enforcing e-voting system can finally become viable for practical use. The problems span three disciplines: security, dependability and usability. My main hypothesis is:  a secure, dependable and usable self-enforcing e-voting system will trigger a paradigm shift in voting technology . I believe e-voting has great potential that has yet to be exploited, and this project is to develop that potential to the full. The work program involves six work packages: 1) to develop supportive security primitives to lay foundation for future e-voting; 2) to research the impact of  self-enforcing requirement on dependability; 3) to develop assistive technologies to improve the usability in voting; 4) to design system architectures suitable for different election scenarios; 5) to build open source prototypes; 6) to conduct real-world trial elections and evaluate the full technical, social, economic and political impacts.tDeformable Multiple-View Geometry and 3D Reconstruction, with Application to Minimally Invasive SurgeryProject FLEXABLE lies in the field of 3D Computer Vision, which seeks to recover depth or the 3D shape of the observed environment from images. One of the most successful and mature techniques in 3D Computer Vision is Shape-from-Motion which is based on the well-established theory of Multiple-View Geometry. This uses multiple images and assumes that the environment is rigid. The world is however made of objects which move and undergo deformations. Researchers have tried to extend Shape-fromMotion to a deformable environment for about a decade, yet with only< very limited success to date. We believe that there are two main reasons for this. Firstly there is still a lack of a solid theory for Deformable Shape-from-Motion. Fundamental questions, such as what kinds of deformation can facilitate unambiguous 3D reconstruction, are not yet answered. Secondly practical solutions have not yet come about: for accurate and dense 3D shape results, the Motion cue must be combined with other visual cues, since it is certainly weaker in the deformable case. It may require strong objectspecific priors, needing one to bridge the gap with object recognition. This project develops these two key areas. It includes three main lines of research: theory, its computational implementation, and its real-world application. Deformable Multiple-View Geometry will generalize the existing rigid theory and will provide researchers with a rigorous mathematical framework that underpins the use of Motion as a proper visual cue for Deformable 3D Reconstruction. Our theory will require us to introduce new mathematical tools from differentiable projective manifolds. Our implementation will study and develop new computational means for solving the difficult inverse problems formulated in our theory. Finally, we will develop cutting-edge applications of our framework specific to Minimally Invasive Surgery, for which there is a very high need for 3D computer vision.Life Long Learning for Visual Scene Understanding (L3ViSU)My goal in the project is to develop and analyze algorithms that use continuous, open-ended machine learning from visual input data (images and videos) in order to interpret visual scenes on a level comparable to humans. L3ViSU is based on the hypothesis that we can only significantly improve the state of the art in computer vision algorithms by giving them access to background and contextual knowledge about the visual world, and that the most feasible way to obtain such knowledge is by extracting it (semi-) automatically from incoming visual stimuli. Consequently, at the core of L3ViSU lies the idea of life-long visual learning. Sufficient data for such an effort is readily available, e.g. through digital TV-channels and media- sharing Internet platforms, but the question of how to use these resources for building better computer vision systems is wide open. In L3ViSU we will rely on modern machine learning concepts, representing task-independent prior knowledge as prior distributions and function regularizers. This functional form allows them to help solving specific tasks by guiding the solution to "reasonable" ones, and to suppress mistakes that violate "common sense". The result will not only be improved prediction quality, but also a reduction in the amount of manual supervision necessary, and the possibility to introduce more semantics into computer vision, which has recently been identified as one of the major tasks for the next decade. L3ViSU is a project on the interface between computer vision and machine learning. Solving it requires expertise in both areas, as it is represented in my research group at IST Austria. The life-long learning concepts developed within L3ViSU, however, will have impact outside of both areas, let it be as basis of life-long learning system with a different focus, such as in bioinformatics, or as a foundation for projects of commercial value, such as more intelligent driver assistance or video surveillance systems.bTowards Total Scene Understanding using Structured ModelsThis project is at the interface between computer vision and linguistics: the aim is to have an algorithm generate relevant sentences that describe a scene given one or more images. Scene understanding has been one of the central goals in computer vision for many decades. It involves various individual tasks, such as object recognition, action understanding and 3D scene recovery. One simple definition of this task is to say scene understanding is equivalent to being able to generate meaningful natural language descriptions of a scene, an important problem in computational linguistics. Whilst even a child can do this with ease, the solution of this fundamental problem has remained elusive. This is because there has been a large amount of research in computer vision that is very deep, but not broad, leading to an in depth understanding of edge and feature detectors, tracking, camera calibration, projective geometry, segmentation, denoising, stereo methods, object detection etc. However, there has been only a limited amount of research on a framework for integrating these functional elements into a method for scene understanding. Within this proposal I advocate a complete view of computer vision, in which the scene is dealt with as a whole, in which problems which are normally considered distinct by most researchers are unified into a common cost function or energy. I will discuss the form the energy should take and efficient algorithms for learning and inference. Our preliminary experiments indicate that such a unified treatment will lead to a paradigm shift in computer vision with a quantum leap in performance. We intend to build embodied demonstrators including a prosthetic vision aid to the visually impaired. The World Health Organization gives a figure of over 300 million such people world wide, which means that in addition to being transformative in the areas of linguistics, HCI, robotics, and computer vision, this work will have a massive impact world wideIntelligent systems' Holistic Evolving Analysis of Real-life Universal speaker characteristicsRecently, automatic speech and speaker recognition has matured to the degree that it entered the daily lives of thousands of Europe's citizens, e.g., on their smart phones or in call services. During the next years, speech processing technology will move to a new level of social awareness to make interaction more intuitive, speech retrieval more efficient, and lend additional competence to computer-mediated communication and speech-analysis services in the commercial, health, security, and further sectors. To reach this goal, rich speaker traits and states such as age, height, personality and physical and mental state as carried by the tone of the voice and the spoken words must be reliably identified by machines. In the iHEARu project, ground-breaking methodology including novel techniques for multi-task and semi-supervised learning will deliver for the first time intelligent holistic and evolving analysis in real-life condition of universal speaker characteristics which have been considered only in isolation so far. Today's sparseness of annotated realistic speech data will be overcome by large-scale speech and meta-data mining from public sources such as social media, crowd-sourcing for labelling and quality control, and shared semi-automatic annotation. All stages from pre-processing and feature extraction, to the statistical modelling will evolve in "life-long learning" according to new data, by utilising feedback, deep, and evolutionary learning methods. Human-in-theloop system validation and novel perception studies will analyse the self-organising systems and the relation of automatic signal processing to human interpretation in a previously unseen variety of speaker classification tasks. The project's work plan gives the unique opportunity to transfer current world-leading expertise in this field into a new de-facto standard of speaker characterisation methods and open-source tools ready for tomorrow's challenge of socially aware speech analysis.mFoundations for Temporal Retrieval, Exploration and Analytics in Web ArchivesSignificant parts of our cultural heritage are produced on the Web, yet only insufficient opportunities ex< ist for accessing and exploring the past of the Web. The ALEXANDRIA project aims to develop models, tools and techniques necessary to archive and index relevant parts of the Web, and to retrieve and explore this information in a meaningful way. While the easy accessibility to the current Web is a good baseline, optimal access to Web archives requires new models and algorithms for retrieval, exploration, and analytics which go far beyond what is needed to access the current state of the Web. This includes taking into account the unique temporal dimension of Web archives, structured semantic information already available on the Web, as well as social media and network information. Within ALEXANDRIA, we will significantly advance semantic and time-based indexing for Web archives using human-compiled knowledge available on the Web, to efficiently index, retrieve and explore information about entities and events from the past. In doing so, we will focus on the concurrent evolution of this knowledge and the Web content to be indexed, and take into account diversity and incompleteness of this knowledge. We will further investigate mixed crowd- and machine-based Web analytics to support long- running and collaborative retrieval and analysis processes on Web archives. Usage of implicit human feedback will be essential to provide better indexing through insights during the analysis process and to better focus harvesting of content. The ALEXANDRIA Testbed will provide an important context for research, exploration and evaluation of the concepts, methods and algorithms developed in this project, and will provide both relevant collections and algorithms that enable further research on and practical application of our research results to existing archives like the Internet Archive, the Internet Memory Foundation and Web archives maintained by European national libraries.uVision and Hearing in ActionThe objective of VHIA is to elaborate a holistic computational paradigm of perception and of perception-action loops. We plan to develop a completely novel twofold approach: (i) learn from mappings between auditory/visual inputs and structured outputs, and from sensorimotor contingencies, and (ii) execute perception-action interaction cycles in the real world with a humanoid robot. VHIA will achieve a unique fine coupling between methodological findings and proof-of-concept implementations using the consumer humanoid NAO manufactured in Europe. The proposed multimodal approach is in strong contrast with current computational paradigms influenced by unimodal biological theories. These theories have hypothesized a modular view, postulating quasiindependent and parallel perceptual pathways in the brain. VHIA will also take a radically different view than today's audiovisual fusion models that rely on clean-speech signals and on accurate frontalimages of faces; These models assume that videos and sounds are recorded with hand-held or headmounted sensors, and hence there is a human in the loop who intentionally supervises perception and interaction. Our approach deeply contradicts the belief that complex and expensive humanoids (often manufactured in Japan) are required to implement research ideas. VHIA's methodological program addresses extremely difficult issues: how to build a joint audiovisual space from heterogeneous, noisy, ambiguous and physically different visual and auditory stimuli, how to model seamless interaction, how to deal with high-dimensional input data, and how to achieve robust and efficient humanhumanoid communication tasks through a well-thought tradeoff between offline training and online execution. VHIA bets on the high-risk idea that in the next decades, social robots will have a considerable economical impact, and there will be millions of humanoids, in our homes, schools and offices, which will be able to naturally communicate with us.Scalable Similarity SearchSimilarity search is the task of identifying, in a collection of items, the ones that are  similar to a given query item. This task has a range of important applications (e.g. in information retrieval, pattern recognition, statistics, and machine learning) where data sets are often big, high dimensional, and possibly noisy. State-of-the-art methods for similarity search offer only weak guarantees when faced with big data. Either the space overhead is excessive (1000s of times larger than the space for the data itself), or the work needed to report the similar items may be comparable to the work needed to go through all items (even if just a tiny fraction of the items are similar). As a result, many a pplications have to resort to the use of ad-hoc solutions with only weak theoretical guarantees. This proposal aims at strengthening the theoretical foundation of scalable similarity search, and developing novel practical similarity search methods backed by theory. In particular we will: - Leverage new types of embeddings that are kernelized, asymmetric, and complex-valued. - Consider statistical models of noise in data, and design similarity search data structures whose performance guarantees are phrased in statistical terms. - Build a new theory of the communication complexity of distributed, dynamic similarity search, emphasizing the communication bottleneck present in modern computing infrastructures. The objective is to produce new methods for similarity search that are: 1) Provably robust, 2) scalable to large and high-dimensional data sets, 3) substantially more resource efficient than current state-oftheart solutions, and 4) able to provide statistical guarantees on query answers. The study of similarity search has been an incubator for techniques (e.g. locality-sensitive hashing and random projections) that have wide-ranging applications. The new techniques developed in this project are likely to have significant impacts b< eyond similarity search.Efficient Resource Constrained Cryptography      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmopqrstuvwxyz{|}~Traditionally, cryptographic protocols were run on servers or personal computers which have large and easily scalable computational resources. For these applications there exist a large variety of wellestablished cryptographic systems. Right now, we are in the midst of the shift toward ubiquitous computing on resource constrained devices (RCDs): small devices with severe constraints in terms of computing power, code size, and network capacities. RCDs are used virtually everywhere: smart phones, bank cards, electronic ID-cards, medical implants, cars, RFIDs as bar code replacement, etc. Due to their computational constraints, many current cryptographic security solutions are no longer applicable to RCDs. Existing solutions are often  ad-hoc and do not come with a formal security treatment. The central objective of the ERCC project is to initiate an overarching formal treatment of cryptographic solutions for RCDs, particularly focusing on efficiency. The main conceptual novelty is to follow the concept of provable security. We intend to design new cryptographic protocols that have a mathematical proof of security (assuming the hardness of some mathematical problem) and are still competitive with constructions currently used on RCDs. While we certainly cannot hope that all our new provably secure constructions will be superior to existing ad-hoc constructions, recent preliminary research results give rise to optimism. Concretely, we will base our new protocols on hard problems in ideal and structures lattices and we will study weaker (yet still realistic) security models for RCDs allowing for efficient instantiations.wFormalizing Subjective Interestingness in Exploratory Data MiningThe rate at which research labs, enterprises and governments accumulate data is high and fast increasing. Often, these data are collected for no specific purpose, or they turn out to be useful for unanticipated purposes: Companies constantly look for new ways to monetize their customer databases; Governments mine various databases to detect tax fraud; Security agencies mine and crossassociate numerous heterogeneous information streams from publicly accessible and classified databases to understand and detect security threats. The objective in such Exploratory Data Mining (EDM) tasks is typically ill-defined, i.e. it is unclear how to formalize how interesting a pattern extracted from the data is. As a result, EDM is often a slow process of trial and error. During this fellowship we aim to develop the mathematical principles of what makes a pattern interesting in a very subjective sense. Crucial in this endeavour will be research into automatic mechanisms to model and duly consider the prior beliefs and expectations of the user for whom the EDM patterns are intended, thus relieving the users of the complex task to attempt to formalize themselves what makes a pattern interesting to them. This project will represent a radical change in how EDM research is done. Currently, researchers typically imagine a specific purpose for the patterns, try to formalize interestingness of such patterns given that purpose, and design an algorithm to mine them. However, given the variety of users, this strategy has led to a multitude of algorithms. As a result, users need to be data mining experts to understand which algorithm applies to their situation. To resolve this, we will develop a theoretically solid framework for the design of EDM systems that model the user's beliefs and expectations as much as the data itself, so as to maximize the amount of useful information transmitted to the user. This will ultimately bring the power of EDM within reach of the non-expert.NNext Generation Causal Analysis: Inspired by the Induction of Biological Pathways from Cytometry DataDiscovering the causal mechanisms of a complex system of interacting components is necessary in order to control it. Computational Causal Discovery (CD) is a field that offers the potential to discover causal relations under certain conditions from observational data alone or with a limited number of interventions/manipulations. An important, challenging biological problem that may take decades of experimental work is the induction of biological cellular pathways; pathways are informal causal models indispensable in biological research and drug design. Recent exciting advances in flow/mass cytometry biotechnology allow the generation of large-sample datasets containing measurements on single cells, thus setting the problem of pathway learning suitable for CD methods. CAUSALPATH builds upon and further advances recent breakthrough developments in CD methods to enable the induction of biological pathways from cytometry and other omics data. As a testbed problem we focus on the differentiation of human T-cells; these are involved in autoimmune and inflammatory diseases,<  as well as cancer and thus, are targets of new drug development for a range of chronic diseases. The biological problem acts as our campus for general novel formalisms, practical algorithms, and useful tools development, pointing to fundamental CD problems: presence of feedback cycles, presence of latent confounding variables, CD from time-course data, Integrative Causal Analysis (INCA) of heterogeneous datasets and others. Three features complement CAUSALPATH s approach: (A) methods development will co-evolve with biological wet-lab experiments periodically testing the algorithmic postulates, (B) Open-source tools will be developed for the non-expert, and (C) Commercial exploitation of the results will be sought out. CAUSALPATH brings together an interdisciplinary team, committed to this vision. It builds upon the PI s group recent important results on INCA algorithms.Virtualization of Real Flows for Animation and SimulationBesides their application in a very broad range of engineering disciplines, physically-based simulations have become a prevalent tool for all forms of computer-generated environments. Simulations of fluids are a particularly important area that has applications ranging from the design of aerodynamic bodies to the realization of impressive visual effects in movies. However, despite their extremely wide-spread use there are fundamental problems: a lack of practical flow capturing technologies and the inherent difficulties of resolving crucial features such as turbulence. These issues are show-stoppers preventing the area from realizing its full potential for animations and interactive environments.The goal of this research is to address these central problems: 1) by designing novel data-centric approaches for fluid simulations to enable re-use, and 2) by establishing an innovative pipeline for capturing flow motions yielding details that were previously unachievable. To this end, I plan to design algorithms that tightly integrate accurate physics solvers with methods for the reconstruction of motion from volumetric images. At the same time, I will work on novel structured representations that decompose complex flows into hierarchical space-time structures. These structured virtual counter-parts will not only enable powerful avenues for intuitive editing, but will also serve as a basis for robust and efficient datadriven fluid simulations. This virtualization of flows opens the door for interactive design tools and medical applications, allowing to incorporate complex physical constraints. In addition, this research could radically change the way we work with synthetic and captured flow data, and has significant potential to break new ground in terms of data-centric work-flows for fluid simulations.jFormal lexically informed logics for searching the webSemantic search engines use structured knowledge to improve traditional web search, e.g. by directly answering questions from users. Current approaches to semantic search rely on the unrealistic assumption that all true facts about a given domain are explicitly stated in their knowledge base or on the web. To reach their full potential, semantic search engines need the ability to reason about known facts. However, existing logics cannot adequately deal with the imperfect nature of knowledge from the web. One problem is that relevant information tends to be distributed over several heterogeneous knowledge bases that are inconsistent with each other. Moreover, domain theories are seldom complete, which means that a form of so-called plausible reasoning is needed. Finally, as relevant logical theories do not exist for many domains, reasoning may need to rely on imperfect probabilistic theories that have been learned from the web. To overcome these challenges, FLEXILOG will introduce a family of logics for robust reasoning with messy real-world knowledge, based on vector-space representations of natural language terms (i.e. of lexical knowledge). In particular, we will use lexical knowledge to estimate the plausibility of logical models, using conceptual simplicity as a proxy for plausibility (i.e. Occam s razor). This will enable us to implement various forms of commonsense reasoning, equipping classical logic with the ability to draw plausible conclusions based on regularities that are observed in a knowledge base. We will then generalise our approach to probabilistic logics, and show how we can use the resulting lexically informed probabilistic logics to learn accurate and comprehensive domain theories from the web. This project will enable a robust data-driven approach to logic-based semantic search, and more generally lead to fundamental progress in a variety of knowledge-intensive applications for which logical inference has traditionally been too brittle.Robots with animal-like resilienceDespite over 50 years of research in robotics, most existing robots are far from being as resilient as the simpl< est animals: they are fragile machines that easily stop functioning in difficult conditions. The goalof this proposal is to radically change this situation by providing the algorithmic foundations for lowcost robots that can autonomously recover from unforeseen damages in a few minutes. The current approach to fault tolerance is inherited from safety-critical systems (e.g. spaceships or nuclear plants). It is inappropriate for low-cost autonomous robots because it relies on diagnostic procedures, which require expensive proprioceptive sensors, and contingency plans, which cannot cover all the possible situations that an autonomous robot can encounter. It is here contended that trial-and-error learning algorithms provide an alternate approach that does not require diagnostic, nor pre-defined contingency plans. In this project, we will develop and study a novel family of such learning algorithms that make it possible for autonomous robots to quickly discover compensatory behaviors. We will thus shed a new light on one of the most fundamental questions of robotics: how can a robot be as adaptive as an animal? The techniques developed in this project will substantially increase the lifespan of robots without increasing their cost and open new research avenues for adaptive machines.iSynthesis Technologies for Reactive Systems Software EngineersThe design and development of open reactive systems, which compute by reacting to ongoing stimuli from their environment, and include, for example, mobile applications running on smart phone devices, web-based applications, industrial robotic systems, embedded software running on chips inside cars and aircraft, etc., is a complex and challenging task. Despite advancement from low-level assembly languages to higher-level languages with powerful abstraction mechanisms, and the use of automated testing and formal verification, reactive systems software development is still a mostly manual and error-prone iterative activity of coding and debugging.A fundamentally different alternative approach to reactive systems development is synthesis, the automatic creation of correctby-construction software from its specification. Synthesis has the potential to transform the way open reactive systems software is developed, making the process more effective and productive, and making its results more reliable and usable. However, while important advancements have been recently made on the algorithmic aspects of synthesis, no work has yet taken advantage of these achievements to change software engineering practices from  program centric to  specification centric . No effective end-to-end means to use synthesis are available to engineers, and the potential revolutionary impact of synthesis on the engineering of reactive systems software is far from being fully explored. The proposal targets four objectives: a new, rich specification language, tailored for synthesis and for use by software engineers; a set of new methods for specification centric development; tool implementations in  killer app application domains; and systematic evaluation with engineers. The research aims to unleash and evaluate the potential of synthesis to revolutionize reactive systems software development and to open the way for new directions in software engineering research and practice.jHolistic Integration of Emerging Supercomputing TechnologiesHi-EST aims to address a new class of placement problem, a challenge for computational sciences that consists in mapping workloads on top of hardware resources with the goal to maximise the performance of workloads and the utilization of resources. The objective of the placement problem is to perform a more efficient management of the computing infrastructure by continuously adjusting the number and type of resources allocated to each workload. Placement, in this context, is well known for being NP-hard, and resembles the multi-dimensional knapsack problem. Heuristics have been used in the past for different domains, providing vertical solutions that cannot be generalised. When the workload mix is heterogeneous and the infrastructure hybrid, the problem becomes even more challenging. This is the problem that Hi-EST plans to address. The approach followed will build on top of four research pillars: supervised learning of the placement properties, placement algorithms for tasks, placement algorithms for data, and software defined environments for placement enforcement.Hi-EST plans to advance research frontiers in four different areas: 1) Adaptive Learning Algorithms: by proposing the first known use of Deep Learning techniques for guiding task and data placement decisions; 2) Task Placement: by proposing the first known algorithm to map heterogeneous sets of tasks on top of systems enabled with Active Storage capabilities, and by extending unifying performance models for heterogeneous workloads to cover and unprecedented number of workload types; 3) Data Placement: by proposing the first known algorithm used to map data on top of heterogeneous sets of key/value stores connected to Active Storage technologies; and 4) Software Defined Environments (SDE): by extending SDE description languages with a still inexistent vocabulary to describe Supercomputing workloads that will be leveraged to combine data and task placement into one single decision-making process.GLeveraging Binary Analysis to Secure the Internet of ThingsWe are in the midst of the shift towards the Internet of Things (IoT), where more and more (legacy) devices are connected to the Internet and communicate with each other. This paradigm shift brings new security challenges and unfortunately many current security solutions are not applicable anymore, e.g., because of a lack of clear network boundaries or resource-constrained devices. H< owever, security plays a central role: In addition to its classical function in protecting against manipulation and fraud, it also enables novel applications and innovative business models. We propose a research program that leverages binary analysis techniques to improve the security within the IoT. We concentrate on the software level since this enables us to both analyze a given device for potential security vulnerabilities and add security features to harden the device against future attacks. More specifically, we concentrate on the firmware (i.e., the combination of persistent memory together with program code and data that powers such devices) and develop novel mechanism for binary analysis of such software. We design an intermediate language to abstract away from the concrete assembly level and this enables an analysis of many different platforms within a unified analysis framework. We transfer and extend program analysis techniques such as control-/data-flow analysis or symbolic execution and apply them to our IL. Given this novel toolset, we can analyze security properties of a given firmware image (e.g., uncovering undocumented functionality and detecting memory corruption or logical vulnerabilities,). We also explore how to harden a firmware by retrofitting security mechanisms (e.g., adding control-flow integrity or automatically eliminating unnecessary functionality). This research will deepen our fundamental understanding of binary analysis methods and apply it to a novel area as it lays the foundations of performing this analysis on the level of intermediate languages.+Domain Adaptation for Statistical Machine TranslationRapid translation between European languages is a cornerstone of good governance in the EU, and of great academic and commercial interest. Statistical approaches to machine translation constitute the state-of-the-art. The basic knowledge source is a parallel corpus, texts and their translations. For domains where large parallel corpora are available, such as the proceedings of the European Parliament, a high level of translation quality is reached. However, in countless other domains where large parallel corpora are not available, such as medical literature or legal decisions, translation quality is unacceptably poor. Domain adaptation as a problem of statistical machine translation (SMT) is a relatively new research area, and there are no standard solutions. The literature contains inconsistent results and heuristics are widely used. We will solve the problem of domain adaptation for SMT on a larger scale than has been previously attempted, and base our results on standardized corpora and open source translation systems. We will solve two basic problems. The first problem is determining how to benefit from large out-of-domain parallel corpora in domain-specific translation systems. This is an unsolved problem. The second problem is mining and appropriately weighting knowledge available from in-domain texts which are not parallel. While there is initial promising work on mining, weighting is not well studied, an omission which we will correct. We will scale mining by first using Wikipedia, and then mining from the entire web. Our work will lead to a break-through in translation quality for the vast number of domains with less parallel text available, and have a direct impact on SMEs providing translation services. The academic impact of our work will be large because solutions to the challenge of domain adaptation apply to all natural language processing systems and in numerous other areas of artificial intelligence research based on machine learning approaches.Automated Program Analysis for Advanced Web ApplicationsWeb applications that execute in the user's web browser constitute a substantial part of modern software. JavaScript is the main programming language of the web, although alternatives are emerging, in particular, TypeScript and Dart. Despite the advances in design of languages and libraries, it is difficult to prevent errors when programming such web applications. Although the basic principles of software verification have been known for decades and researchers have developed an abundance of techniques for formal reasoning about programs, modern software has lots of errors, as everyday users can testify. The PAW project will create novel automated program analysis algorithms for preventing errors and improving performance of advanced web applications. The project hypothesis is that a scientific breakthrough is within reach, due to recent results in static and dynamic program analysis for JavaScript. The central idea is to combine static and dynamic analysis in new ways. In addition, the project will make program analysis algorithms and infrastructure available in a form that embraces reusability.Small Summaries for Big DataA fundamental challenge in processing the massive quantities of information generated by modern applications is in extracting suitable representations of the data that can be stored, manipulated and interrogated on a single machine. A promising approach is in the design and analysis of compact summaries: data structures which capture key features of the data, and which can be created effectively over distributed data sets. Popular summary structures include the Bloom filter, which compactly represents a set of items, and sketches which allow vector norms and products to be estimated. These are very attractive, since they can be computed in parallel and combined to yield a single, compact summary of the data. Yet the full potential of summaries is far from being fully realized. The Principal Investigator will lead a team, working on important problems around creating Small Summaries for Big Data. The goal is to substantially advance the state of the art in data summarization, to the point where accurate and effective summaries are available for a wide array of problems, and can be used seamlessly in applications that process big data. Several directions will be pursued, including: designing and evaluating new summaries for fundamental computations such as tracking the data distribution; summary techniques for complex structures, such as massive matrices, massive graphs, and beyond; and summaries that allow the verification of outsourced computation over big data. Success in any one of these areas could lead to substantial impact on practice, as evidenced by the influence of existing summary techniques. Support in the form of a five-year research grant will allow the PI to consolidate his research in this area, and build an expert team to focus on these challenging algorithmic questions.Taming non convexity?In many important areas and applications of science one has to solve non convex optimization problems and ideally and ultimately one would like to find the global optimum. However in most cases one is faced with NP-hard problems and therefore in practice one has been often satisfied with only a local optimum obtained with some ad-hoc (local) optimization algorithm. TAMING intends to provide a systematic methodology for solving hard non convex polynomial optimization problems in all areas of science. Indeed the last decade has witnessed the emergence of Polynomial Optimization as a new field in which powerful positivity certificates from real algebraic geometry have permitted to develop an original and systematic approach to solve (at global optimality) optimization problems with polynomial (and even semi-algebraic) data. The backbone of this powerful methodology is the ? moment-SOS ? approach also known as ? Lasserre hierarchy ? which has attracted a lot of attention in many areas (e.g., optimization, applied mathematics, quantum computing, engineering, theoretical computer science) with important p< otential applications. It is now a basic tool for analyzing hardness of approximation in combinatorial optimization and the best candidate algorithm to prove/disprove the famous Unique Games Conjecture. Recently it has also become a promising new method for solving the important Optimal Power Flow Problem in the strategic domain of Energy Networks (as the only method that could solve to optimality certain types of such problems). However in its present form this promising methodology inherits a high computational cost and a (too) severe problem size limitation which precludes from its application many important real life problems of significant size. Proving that indeed this methodology can fulfill its promises and solve important practical problems in various areas poses major theoretical & practical challenges.Better MPC Protocols in Theory and in PracticeMultiparty computation (MPC) is a cryptographic technique allowing us to build distributed computer systems for handling confidential data. We can control exactly what information is released from the system, and privacy of the input data is maintained, even if an adversary breaks into several of the machines in the system. The efficiency of MPC protocols has been significantly improved in recent years. There are countless applications and the techniques are just now entering the commercial domain. However, the theory of the area has in several respects failed to keep up with this development, and we are still very far from being able to apply MPC to large-scale applications. In this project, we propose that state of the art for MPC protocols can be dramatically advanced by 1) Developing a completely new theory for the performance of MPC protocols based on a more detailed model that better reflects what happens when protocols are executed on real platforms.2) Use the new theory to guide development and implementation of new MPC protocols that will perform much better in practice. 3) Explore the limits of what we can achieve by showing new lower bounds for MPC protocols, attacking a number of long-standing open problems. This will enable us to focus our attention to where improvements are possible.[Middle Infrared Broadly Tunable Compact Cavity-Less Source based on Parametric ConversionThe middle-infrared (Mid-IR) is a core band for molecular detection and identification as nearly every molecule strongly absorbs in this wavelength range. Hence, it hosts critical applications ranging from spectroscopy, health monitoring, sensing as well as free space communication. Unfortunately, the advantages of this wavelength range have not been fully exploited due to the lack of Mid-IR sources that can simultaneously satisfy stringent requirements these diverse applications impose. To this end, MATISSE seeks to transfigure light generation in the Mid-IR spectral band by designing new classes of nonlinear frequency mixers. We aim at overturning the limitations of conventional resonant (cavity) processes by simultaneously enabling mode-hop free tuning, narrow linewidth and wide tunable range operation. In addition, we also plan in developing the first modulation-capable source across a wide range of Mid-IR frequencies. To overcome these challenges, MATISSE will leverage the cavity-less nature and parametric origin of the proposed source. The project will cascade two distinct compact nonlinear platforms to enable the efficient wavelength conversion from NIR to Mid-IR. This two-step approach takes advantage of attributes each distinct platform has to offer by 1) utilizing the advanced technology available at the NIR wavelengths and 2) exploiting the Mid-IR capabilities of non-silica platforms. We believe only an approach such as ours can provide a compact, freely tunable Mid-IR source without resorting to conventional cavity (resonant) physics. The MATISSE project therefore promises substantial impact in spectroscopy, sensing and free space communication by providing presently non-existing tools that will not only improve the sensitivity of absolute and relative spectroscopic methods, but also introduce free space sensing/communication using emitted powers that are considered non-viable in conventional systems.wBlack holes and their host galaxies: coevolution across cosmic timeGalaxy formation is one of the most fascinating yet challenging fields of astrophysics. The desire to understandgalaxy formation has led to the design of ever more sophisticated telescopes which show a bewildering varietyof galaxies in the Universe. However, the degree to which an interpretation of this wealth of data can succeeddepends critically on having accurate and realistic theoretical models of galaxy formation. While cosmologicalsimulations of galaxy formation provide the most powerful technique for calculating the non-linear evolution ofcosmic structures, the enormous dynamic range and poorly understood baryonic physics are main uncertaintiesof present simulations. This impacts on their predictive power and is the major obstacle to our understanding ofobservational data. The objective of this proposal is to drastically improve upon the current state-of-the-art by i)including more realistic physical processes, such as those occurring at the sphere of influence of a galaxy s centralblack hole and ii) greatly extending spatial dynamical range with the aid of a novel technique I have developed.With this technique I want to address one of the major unsolved issues of galaxy formation:  How do galaxies andtheir central black holes coevolve? Specifically, I want to focus on three crucial areas of galaxy formation: a) Howand where the very first black holes form, what are their observational signatures, and when is the coevolution withhost galaxies established? b) Is black hole heating solely responsible for the morphological transformation andquenching of massive galaxies, or are other processes important as well? c) What is the impact of supermassiveblack holes on galaxy clusters and ca< n we calibrate baryonic physics in clusters to use them as high precisioncosmological probes? The requested funding is for 50% of the PI s time and three postdoctoral researchers toestablish an independent research group at the KICC and IoA, Cambridge.Surface Plasmon-Based Wifi for Nanoscale Optical Information Transport - SWIFTThis proposal focuses on the design, fabrication, characterization and optimization of novel groundbreaking communication nano-devices. SWIFT proposes resolutely innovative concepts adopting metal-based optical nano-antennas as a disruptive technological vehicle. Nanoscale electronics and photonics exploit novel fascinating physical phenomena and are among the most promising research areas for providing functional nano-components for data transfer and processing. The aim of this proposal is to interface these two device-generating technologies to create the first electrically-driven nanoscale optical antenna transceiver. The concept will enable electron/photon transduction at the nanoscale by a unique surface plasmon-assisted metal-based design, a significant leap at the forefront of research in nanoelectronics and nanophotonics. SWIFT proposes a series of fundamental advances motivated by application-driven perspectives that will push the burgeoning field of optical antenna to a new area. Deploying optical antenna transceivers enables a paradigm shift in optical interconnects and communication at ultimate device densities through the following innovations: ? Development a whole new class of plasmon-assisted transducing optical functional nanodevices.This unique concept addresses the development for ultracompact nanocomponents. ? Prototyping self-sustained plasmonic in/out electrical ports on SPP waveguiding platforms, removing thus complex optical interfacing that cannot be miniaturized. ? Pioneering a technological breakthrough enabling nanoscale wireless broadcasting of optical information. ? Using these functionalities, we will prospect new research directions by proviing a unique ground for (i) generating ultrafast electron surges in an integrated electronic layout enabling ultrafast transport studies in molecular electronics and (ii) for realizing ultrasmall THz sources enabling thus penetration of THz technology at the nanometer-scale.Networked Pico-Satellite Distributed System ControlA paradigm shift is emerging in spacecraft engineering from single, large, and multifunctional satellites towards cooperating groups of small satellites. This will enable innovative applications in areas like Earth observation or telecommunication. Related interdisciplinary research in the field of formation control and networked satellites are key challenges of this proposal. Modern miniaturization techniques allow realization of satellites of continuously smaller masses, thus enabling cost-efficient implementation of distributed multi-satellite systems. In preparation my team has already realized two satellites at only 1 kg mass in the University Wrzburg s Ex?perimental satellite (UWE) program, emphasizing crucial components for formation flying, like communication (UWE-1, launched 2005), attitude determination (UWE-2, launched 2009), and attitude control (UWE-3, launched 2013). My vision for the proposed project is to demonstrate formation control of four pico-satellites in-orbit for the first time worldwide. To realize this objective, innovative multi-satellite networked orbit control based on relative position and attitude of each satellite is to be implemented in order to enable Earth observations based on multipoint measurements. Related sensor systems used in my laboratory in research for advanced characterization of teams of mobile robots will be transferred to the space environment. Breakthroughs are expected by combining optimal control strategies for coordination of relative motion with a robust flow of information in the network of satellites and ground stations, implemented via innovative use of ad-hoc networks in space. Based on my team s expertise in implementing very small satellites, first time a system composed of four satellites will be launched to demonstrate autonomous distributed formation control in orbit. This research evaluation in space is expected to open up significant application potential for future distributed satellite system services in Earth observation.From Radio-Frequency to Giga-BitOptical- and Quantum-WirelessThe majority of the globe's population carries a mobile phone, but with the increasing proliferation of smart phones and tablet-computers the tele-traffic is predicted to grow 1000-fold over the next decade, especially, when aiming for creating the impression of ubiquitous and flawless 'tele -presence' based on crisp, three-dimensional (3D) video with its sense of joy and wonder. For tele-presence to become a reality requires a further quantum-leap from the popular 3G/4G smart phones and tabletcomputers. This project will create the link-level enabling techniques of this transformational quantum leap to immersive Giga-bit 3D video communications, relying on Optical Wireless (OW) hotspots and their ad hoc networking. As a result, the Beam-Me-Up project will contribute to job- and wealthcreation in numeorus ways, as exemplified by the often-quoted economic benefits of 3G/4G phones on bu< sinesses. From an environmental perspective, flawless tele-presence has the potential of eliminating millions of flights/trips and hence will considerably reduce CO2 emissions, whilst reducing the related business-costs as well as saving precious time for the work-force. However, the transfiguration of the voice-only phone into today's intelligent smart phone was facilitated by a 1000-fold transmission-rate increase, which would result in a proportionally increased power consumption, CO2 emissions and in a soaring energy-bill. Tele-presence based on crisp Avatar-style 3D video has even higher bitrates and energy consumption. These radically new high-rate 3D tele-presence services can no longer be accommodated in the severely congested Radio Frequency (RF) band. Hence the project will create a suite of new OW system components, operating in the visible-light domain and will conceive lowpower, low-complexity OW solutions to enable immersive Giga-bit 3D wireless video communications over heterogeneous networks.Harmonic identification, mitigation and control in power electronics based power systemsGlobal electrical energy consumption is still increasing which demands that power capacity and power transmission capabilities must be doubled within 20 years. Today 40 % of the global energy consumption is processed by electricity in 2040 this may be up to 70 %. Electrical power production is changing from conventional, fossil based sources to renewable power resources. Highly efficient and sustainable power electronics in power generation, power transmission/distribution and end-user applications are introduced to ensure more efficient use of electricity. Traditional centralized electricity production with unidirectional power flows in transmission and distribution system will be replaced by the operation and control of intelligent distribution systems which are much more based on power electronics systems and having bidirectional power flow. Such large scale expansion of power electronics usage will change the characteristic of the power system by introducing more harmonics from generation, from the efficient load systems all resulting in a larger risk of instability and more losses in the future power system. The projects goal is to obtain  Harmony between the renewable energy sources, the future power system and the loads in order to keep stability at all levels seen from a harmonic point of view. The project establishes the necessary theories, models and methods to identify harmonic problems in a power electronic based power system, a theoretical and hardware platform to enable control of harmonics and mitigate them, and develops on-line methods to monitor the harmonic state of the power system. The outcomes are new tools for identifying stability problems in power electronics based power systems and new control methods for reducing the harmonic presence and reduce the overall instability risks. Further, new design methods for active and passive filters in renewable energy systems, in the power system and in the power electronics based loads will be developedxHigh-speed chip-based nanoscopy to discover real-time sub-cellular dynamicsOptical nanoscopy has given a glimpse of the impact it may have on medical care in the future. Slow imaging speed and the complexity of the current nanoscope limits its use for living cells. The imaging speed is limited by the bulk optics that is used in present nanoscopy. In this project, I propose a paradigm-shift in the field of advanced microscopy by developing optical nanoscopy based on a photonic integrated circuit. The project will take advantage of nanotechnology to fabricate an advance waveguide-chip, while fast telecom optical devices will provide switching of light to the chip, enhancing the speed of imaging. This unconventional route will change the field of optical microscopy, as a simple chip-based system can be added to a normal microscope. In this project, I will build a waveguide-based structured-illumination microscope (W-SIM) to acquire fast images (25 Hz or better) from a living cell with an optical resolution of 50-100 nm. I will use W-SIM to discover the dynamics (opening and closing) of fenestrations (100 nm) present in the membrane of a living liver sinusoidal scavenger endothelial cell. It is believed among the Hepatology community that these fenestrations open and close dynamically, however there is no scientific evidence to support this hypothesis because of the lack of suitable tools. The successful imaging of fenestration kinetics in a live cell during this project will provide new fundamental knowledge and benefit human health with improved diagnoses and drug discovery for liver. Chip-based nanoscopy is a new research field, inherently making this a high-risk project, but the possible gains are also high. The W-SIM will be the first of its kind, which may open a new era of simple, integrated nanoscopy. The proposed multiple-disciplinary project requires a nearunique expertise in the field of laser physics, integrated optics, advanced microscopy and cell-biology that I have acquired at leading research centers on three continents.WNanodevice Engineering for a Better Chemical Gas Sensing TechnologyBetterSense aims to solve the two main problems in current gas sensor technologies: the high power consumption and the poor selectivity. For the former, we propose a radically new approach: to integrate the sensing components and the energy sources intimately, at the nanoscale, in order to achieve a new kind of sensor concept featuring zero power consumption. For the latter, we will mimic the biological receptors designing a kit of gas-specific molecular organic functionalizations to reach ultra-h< igh gas selectivity figures, comparable to those of biological processes. Both cutting-edge concepts will be developed in parallel an integrated together to render a totally new gas sensing technology that surpasses the state-of-the-art. As a matter of fact, the project will enable, for the first time, the integration of gas detectors in energetically autonomous sensors networks. Additionally, BetterSense will provide an integral solution to the gas sensing challenge by producing a full set of gasspecific sensors over the same platform to ease their integration in multi-analyte systems. Moreover, the project approach will certainly open opportunities in adjacent fields in which power consumption, specificity and nano/micro integration are a concern, such as liquid chemical and biological sensing. In spite of the promising evidences that demonstrate the feasibility of this proposal, there are still many scientific and technological issues to solve, most of them in the edge of what is known and what is possible today in nano-fabrication and nano/micro integration. For this reason, BetterSense also aims to contribute to the global challenge of making nanodevices compatible with scalable, cost-effective, microelectronic technologies. For all this, addressing this challenging proposal in full requires a funding scheme compatible with a high-risk/high-gain vision to finance the full dedication of a highly motivated research team with multidisciplinary skillDAtacommunications based on NanophotoniC ResonatorsA key challenge for the 21st century is, therefore to provide billions of people with the means to access, move and manipulate, what has become, huge volumes of information. The environmental and economic implications becoming serious, making energy efficient data communications key to the operation of today s society. In this project, the Principal Investigator will develop a new framework for optical interconnects and provide a common platform that spans Fibre-to-the-home to chip-to-chip links, even as far as global on-chip interconnects. The project is based on the efficient coupling of the Photonic Crystal resonators with the outside world. These provide the ultimate confinement of light in both space and time allowing orders of magnitude improvements in performance relative to the state of the art, yet in a simpler simple system- the innovator s dream. New versions of the key components of optical links- light sources, modulators and photo-detectors- will be realised in this new framework providing a new paradigm for energy efficient communication.aEvolving Internet Routing: A Paradigm Shift to Foster InnovationAlthough the Internet is a great technological achievement, more than 40 years after its creation some of its original security and reliability problems remain unsolved. The root cause of these problems is the rigidity of the Internet architecture or in other words the Internet ossification problem, i.e., the basic architectural components of the Internet are set to stone and cannot be changed. The most ossified component of the Internet architecture is the inter-domain routing system. In this project, ourgoal is to address this challenge and to introduce a new Internet routing architecture that 1) enables innovation at the inter-domain level, 2) is backward-compatible with the present Internet architecture, and 3) provides concrete economic incentives for adopting it. We propose a new Internet routing paradigm based on a novel techno-economic framework, which exploits emerging technologies and meets these three goals. Our novel idea is that the combination of routing control logic outsourcing with Software Defined Networking (SDN) principles enables to innovate at the inter-domain level and therefore has the potential for a major break-through in the architecture of the Internet routing system. SDN is a rapidly emerging new computer networking architecture that makes the routing control plane of a network programmable. Based on our framework, we propose to design, build, and verify a better inter-domain routing system, which solves fundamental security, reliability, and manageability problems of the Internet architecture. Our work will be organized in four core topics 1) build a mutli-domain centralized routing control platform, 2) improve the reliability and security of the current inter-domain routing system, 3) design techniques for resolving tussles between competing network domains, 4) introduce advanced network monitoring and security techniques that intelligently correlate data from multiple domain to diagnose routing outages and attacks.HComputational Foundations of Anthropomorphic ActionActanthrope intends to promote a neuro-robotics perspective to explore original models of anthropomorphic action. The project targets contributions to humanoid robot autonomy (for rescue and service robotics), to advanced human body simulation (for applications in ergonomics), and to a new theory of embodied intelligence (by promoting a motion-based semiotics of the human action). Actions take place in the physical space while they originate in the  robot or human sensory-motor space. Geometry is the core abstraction that makes the link between these spaces. Considering that the structure of actions inherits from that of the body, the underlying intuition is that actions can be segmented within discrete sub-spaces lying in the entire continuous posture space. Such sub-spaces are viewed as symbols bridging deliberative reasoning and reactive control. Actanthrope argues that geometric approaches to motion segmentation and generation as promising and innovative routes to explore embodied intelligence: - Motion segmen< tation: what are the sub-manifolds that define the structure of a given action? - Motion generation: among all the solution paths within a given submanifold, what is the underlying law that makes the selection? In Robotics these questions are related to the competition between abstract symbol manipulation and physical signal processing. In Computational Neuroscience the questions refer to the quest of motion invariants. The ambition of the project is to promote a dual perspective: exploring the computational foundations of human action to make better robots, while simultaneously doing better robotics to better understand human action. A unique  Anthropomorphic Action Factory supports the methodology. It aims at attracting to a single lab, researchers with complementary know-how and solid mathematical background. All of them will benefit from unique equipments, while being stimulated by four challenges dealing with locomotion and manipulation actions.Wearable Augmented Reality 3D DisplaysWearable displays have advanced rapidly over the past few decades but they are limited in field-ofview due to optical constraints. Likewise, 3D displays have several technological and viewing discomfort limitations. These limitations result from the missing 3D depth cues in stereoscopic displays, which are essential for real 3D and for interactive augmented reality (AR) applications. Wear3D proposal aims to overcome the two fundamental scientific challenges of wearable displays and make them as natural as wearing a pair of eyeglasses: (i) Eliminate the relay lenses. We need to overcome the focusing problem of the eyes in order to completely eliminate the large relay lenses. As a result, miniaturization of wearable displays will be possible by taking full advantage of the advancements in micro-technologies; (ii) Provide all the essential 3D depth cues to avoid perceptual errors and viewing discomfort. We need to enable the two eyes to fixate at the correct depth of the objects rather than the display panel without losing resolution. Thereby, eliminating the conflict between the accommodation and convergence. Overcoming these challenges would enable a display which can provide natural looking and interactive 3D and very wide field-of-view (>100deg) in an eyeglasses form factor. Such a display goes far beyond the state-of-the art in wearable displays and open new research directions for intelligent human-computer interfaces and AR.QMICROMACHINED OPTOMECHANICAL DEVICES: looking at cells, tissues, and organs ... with a gentle touch.Every time we grab an object to look at its geometrical details or to feel if it is hard or soft, we are ineluctably confronted with the limits of our senses. Behind its appearances, the o bject may still hide information that, encrypted in its microscopic features, remains undetected to our macroscopic assessment. In life sciences, those limits are more than just frustrating: they are an obstacle to study and detect life threatening conditions. Many different instruments may overcome those limits, but the vast majority of them rely either on  sight (optics) or  touch (mechanics) separately. On the contrary, I believe that it is from the combination of those two  senses that we have more c hances to tackle the future challenges of cell biology, tissue engineering, and medical diagnosis. Inspired by this tantalizing perspective, and supported by a technology that I have brought from blackboard to market, I have now designed a scientific program to breach into the microscopic scale via an unbeaten path. The program develops along three projects addressing the three most relevant scales in life sciences: cells, tissues, and organs. In the first project, I will design and test a new optomechanical probe to investigate how a prolonged mechanical load on a brain cell of a living animal may trigger alterations in its Central Nervous System. With the second project, I will develop an optomechanical tactile instrument that can assess how subsurface tissues deform in response to a mechanical stroke  a study that may change the way physicians look at tissue classification. For the third project, I will deliver an acousto-optical gas trace sensors so compact that can penetrate inside the lungs of an adult patient, where it could be used for early detection of pulmonary life threatening diseases. Each project represents an opportunity to open an entire new field, where optics and micromechanics are combined to extend our senses well beyond their natural limits.DEtermination of Orphan Receptor PHysiological Agonists and sigNalsG protein-coupled receptors make up both the largest membrane protein and drug target families. DEORPHAN aims to determine the close functional context; specifically physiological agonists and signaling pathways; and provide the first research tool compounds, of orphan peptide receptors. Determination of physiological agonis< ts (aka de-orphanization), by high-throughput screening has largely failed. We will introduce a new research strategy: 1) developing highly innovative bioinformatics methods for handpicking of all orphan receptor targets and candidate ligand screening libraries; and 2) employing a screening technique that can measure all signaling pathways simultaneously. The first potent and selective pharmacological tool compounds will be identified by chemoinformatic design of focused screening libraries. We will establish the ligands structure-activity relationships important for biological activity and further optimization towards drugs. The first potent and selective Gs- and G12/13 protein inhibitors will be designed by structure-based re-optimization from a recent crystal structure of a Gq-inhibitor complex, and applied to determine orphan receptor signaling pathways and ligand pathway-bias. They will open up for efficient dissection of important signaling networks and development of drugs with fewer side effects. DE-ORPHANs design hypotheses are based on unique computational methods to analyze protein and ligand similarities and are founded on genomic and protein sequences, structural data and ligands. The interdisciplinary research strategy applies multiple ligands acting independently but in concert to provide complementary receptor characterization. The results will allow the research field to advance into studies of receptor functions and exploitation of druggable targets, ligands and mechanisms. Which physiological insights and therapeutic breakthroughs will we witness when these receptors find their place in human pharmacology and medicine?\A new communication paradigm for future very high speed wireless networksDue to the tremendous growth in mobile devices such as smartphones, tablet PCs, and laptops over the past years, a larger and larger fraction of Internet traffic is delivered wirelessly. Dealing with this vast increase in traffic is one of the most important challenges for future wireless networks. State-ofthe-art wireless communication already operates close to Shannon capacity. The only viable option to further increase data rates is to use high bandwidth channels in the very high frequency part of the radio spectrum. However, this spectrum suffers from high attenuation and signal absorption, restricting communication primarily to line-of-sight (LOS) scenarios. This in turn requires a radical rethinking of wireless networking. We envision that future wireless networks will consist of many highly directional LOS channels for communication between access points (APs) and end devices. Such an environment is extremely dynamic, in particular for mobile devices. At the same time, such channels experience very little interference and resources that would otherwise be used to handle interference can now be used to further increase achievable data rates. We propose to build a wireless network architecture that maintains directional LOS channels between several APs and (mobile) end devices. Data is transmitted via all of these channels and end device uses multiple antennas to receive and decode several such data streams simultaneously. The main complexity of the design lies in the selection of APs as well as the beamforming directions of their antennas, given the large number of end devices that future wireless networks will have to support. To speed up this decision process, the system maintains a map of the radio environment and learns likely sequences of beamforming patterns and APs. This further allows to intelligently switch off APs to improve energy efficiency. We believe that such a design is the key element for the scalability of future wireless networks.NControl of contact interactions for robots acting in the worldWhat are the algorithmic principles that would allow a robot to run through a rocky terrain, lift a couch while reaching for an object that rolled under it or manipulate a screwdriver while balancing on top of a ladder? Answering this seemingly na?ve question resorts to understanding the fundamental principles for robot locomotion and manipulation, which is very challenging. However, it is a necessary step towards ubiquitous robots capable of helping humans in an uncountable number of tasks. The fundamental aspect of both locomotion and manipulation is that the dynamic interaction of the robot with its environment through the creation of physical contacts is at the heart of the tasks. The planning of such interactions in a general manner is an unsolved problem. Moreover, it is not clear how sensory information (e.g. tactile and force sensors) can be included to improve the robustness of robot behaviors. Most of the time, it is simply discarded. CONT-ACT has the ambition to develop a consistent theoretical framework for motion generation and control where contact interaction is at the core of the approach and an efficient use of sensory information drives the development of high performance, adaptive and robust planning and control methods. CONT-ACT develops an architecture based on realtime predictive controllers that fully exploit contact interactions. In addition, the structure of sensory information during contact interactions is experimentally analyzed to create sensor repres entations adapted for control. It is then possible to learn predictive models in sensor space that are used to create very reactive controllers. The robot constantly improves its performance as it learns better sensory models. It is a step towards a general theory for robot movement that can be used to control any robot with legs and arms for both manipulation and locomotion tasks and that allows robots to constantly improve their performances as they experience the world.uHigh-frequency printed and direct-written Organic-hybrid Integrated CircuitsThe HEROIC project aims at filling the gap between the currently low operation frequencies of printed, organic flexible electronics and the high-frequency regime, by demonstrating polymer-based fieldeffect transistors with maximum operation frequencies of 1 GHz and complementary integrated logic circuits switching in the 10-100 MHz range, fabrica< ted by means of printing and direct-writing scalable processes in order to retain low temperature manufacturability of cost-effective large area electronics on plastic. The recent development of semiconducting polymers with mobilities in the range of 1 to 10 cm^2/Vs, and even higher in the case of aligned films, suggests that suitably downscaled printed polymer transistors with operation frequencies in the GHz regime, at least three orders of magnitude higher than current printed polymer devices, are achievable, by addressing in a holistic approach the specific challenges set in the HEROIC trans-disciplinary research programme: (i)development of scalable high resolution processes for the patterning of functional inks, where printing will be combined with direct-writing techniques such as fs-laser machining, both in an additive and subtractive approach; (ii)development of printable nanoscale hybrid dielectrics with high specific capacitance, where low-k polymer buffer materials will be combined with solution processable high-k dielectrics, such as insulating metal oxides; (iii)improvement of the control of charge injection and transport in printed polymer and hybrid semiconductors, where high-mobility 1-D and 2-D structures are included in polymer films; (iv)development of advanced printed and direct-written transistors architectures with low parasitic capacitances for high-speed operation. HEROIC will radically advance and expand the applicability of polymer-based printed electronics, thus making it suitable for next generation portable and wearable short-range wireless communicating devices with low power consumption.}Distributed Optimization Methods for Smart Cyber-Physical NetworksThe combination of embedded electronics and communication capability in almost any mobile or portable device has turned this century into the age of cyber-physical networks. Smart communicating devices with their sensing, computing and control capabilities promise to make our cities, transportation systems, factories and living environments more intelligent, energy-efficient, safe and secure. This extremely complex system has raised a number of new challenges involving ICT disciplines. In particular, a novel peer-to-peer distributed computational model is appearing as a new opportunity in which a service is built-up cooperatively by peers, rather than by a unique provider that knows and owns all data. The interdisciplinary  Optimization Community is facing this revolution sharing a common need: to find new theories, methodologies and tools to optimize over this complex network system. With this in mind, OPT4SMART has a twofold objective. First, to provide a comprehensive theoretical framework to solve distributed optimization problems over peer-to-peer networks. Second, to develop effective numerical tools, based on this framework, to solve estimation, learning, decision and control problems in cyber-physical networks. To achieve this twofold objective, we will take a systems-theory perspective. Specific problems from these four areas will be abstracted to a common mathematical set-up, and addressed by means of interdisciplinary methodologies arising from a synergic combination of optimization, controls, and graph theories. In particular, OPT4SMART will face the challenge of solving optimization problems under severe communication limitations, very-largescale problem and data size, and real-time computational constraints. The expected result will be a combination of strong theoretical methods and effective numerical toolboxes available to people in Engineering, Computer Science, Mathematics and other areas, who are facing optimization in cyberphysical networks.Functional 2D metamaterials at visible wavelengthsFor the last 15 years, optics has undergone a remarkable evolution towards ever decreasing sizes, better integration in complex systems, and more compact devices readily available to mass markets. Whereas traditional optics is at the centimeter scale, newly developed techniques use nanoscale objects to control, guide, and focus light. From the capability to shape metallic and dielectric nanostructures has emerged the field of nanophotonics. Advances in nanophotonics offer the possibility to control the material s optical properties to create artificial materials with electromagnetic properties not found in nature. Man-made 3D metamaterials have interesting fundamental aspects and present many advantages with respect to conventional devices. Unexpected effects have led to the development of interesting applications like high resolution lenses and cloaking devices. Inspired by this new technology, we have developed new 2D metamaterial< s. Our flat metamaterials (metasurfaces) are much simpler to manufacture than their 3D counterparts. By depositing a set of nanostructures at an interface, we can immediately control the light properties; unlike refractive optical components, the wavefront is modified without propagation. As of today, these interfaces are created using metallic nanostructures and work in the infrared. In this ERC, we plan to extend the concept of optical metasurfaces in the visible which is the most important wavelength range for applications. By combining with optically active semiconductors such as InGaAlN, we will add optical gain and modulation capability to the system to create new, efficient optoelectronic devices. The response of the metasurfaces is tunable by changing the environment surrounding the nanostructures. We will use this property to create ultrathin reconfigurable flat devices. Metasurfaces will be integrated with AlN/GaN to modulate light at high frequencies and further exploited to control polariton gases in solid state metasystems.rQuantum Photonic EngineeringBy harnessing the unique properties of quantum mechanics (superposition and entanglement) to encode, transmit and process information, quantum information science offers significant opportunities to revolutionise information and communication technologies. The far-reaching goal of this project is to build quantum technology demonstrators that can outperform conventional technologies in communications and computation. For quantum information technologies (QITs) to have as big an impact on society as anticipated, a practical and scalable approach is needed. One promising approach to QITs is the photonics implementation, where single particles of light (photons) are used to encode, transmit and process quantum information  in the form of photonic quantum-bits (qubits). Currently, state-of-the-art experiments are limited to the  few-photon regime, occupying many metres of space on an optical table, constructed from bulk optical elements, with no routes to scalability and far from outperforming conventional technologies. Integrated quantum photonics has recently emerged as a new approach to address these challenges. This research programme will take an engineering approach to QITs and draw upon rapidly growing field of silicon photonics. We will develop a silicon-based quantum technology platform where single-photon sources, circuits and detectors will be integrated into miniature microchip circuits containing thousands of discrete components, enabling breakthroughs in quantum communications and computation, and developing a scalable approach to quantum technologies.There are no new physics breakthroughs required to achieve the goals of this project, however, there are hard engineering challenges that need to be addressed.ZMultiscale Modelling of the Neuromuscular System for Closed Loop Deep Brain StimulationDeep brain stimulation (DBS) is an effective therapy for treating the symptoms of Parkinson s disease (PD). Despite its success, the mechanisms of DBS are not understood and there is a need to improve DBS to improve long-term stimulation in a wider patient population, limit side-effects, and extend battery life. Currently DBS operates in  open-loop , with stimulus parameters empirically set. Closedloop DBS, which adjusts parameters based on the state of the system, has the potential to overcome current limitations to increase therapeutic efficacy while reducing side-effects, costs and energy. Several key questions need to be addressed before closed loop DBS can be implemented clinically. This research will develop a new multiscale model of the neuromuscular system for closed-loop DBS. The model will simulate neural sensing and stimulation on a scale not previously considered, encompassing the electric field around the electrode, the effect on individual neurons and neural networks, and generation of muscle force. This will involve integration across multiple temporal and spatial scales, in a complex system with incomplete knowledge of system variables. Experiments will be conducted to validate the model, and identify new biomarkers of neural activity that can used with signals from the brain to enable continuous symptom monitoring. The model will be used to design a new control strategy for closed-loop DBS that can accommodate the nonlinear nature of the system, and short - an< d long-term changes in system behavior. Though challenging, this research will provide new insights into the changes that take place in PD and the mechanisms by which DBS exerts its therapeutic influence. This knowledge will be used to design a new strategy for closed-loop DBS, ready for testing in patients, with the potential to significantly improve patient outcomes in PD and fundamentally change the way in which implanted devices utilise electrical stimulation to modulate neural activity.Quantum Metamaterials: A Theoretical and Computational Approach Towards Seamlessly Integrated Hybrid Classical/Quantum Nano-structuresThe overarching aim of this proposal is to initiate and advance an integrated theoretical and computational research programme in an emerging area of metamaterials research, namely Quantum Metamaterials. Thus, it is commonly believed that one of the most noteworthy developments witnessed in the last decade in physical sciences and engineering is the emergence of metamaterials. Unlike ordinary materials, which are assembled at the atomic level, metamaterials are composite materials built up from artificially engineered meta-atoms and meta-molecules. The fundamental idea in this area of research is that remarkable physical properties beyond those available in naturally occurring materials can be achieved by designing the meta-constituents of the metamaterial and structuring it at a scale comparable or smaller than the optical wavelength. In this context, a new paradigm in metamaterials research emerges when the building blocks of metamaterials are quantum resonators, e.g., quantum dots (QDs), QD molecules, graphene disks coupled to interacting QDs, and quantum nanowires, case in which the macroscopic properties of quantum metamaterials are determined by the quantum properties of their basic constituents. We have organised this research programme along three broad, synergistically integrated themes. The first will focus on the development of a general theory of the effective, macroscopic properties of quantum metamaterials. The key challenge is to build a theoretical framework in which the macroscopic properties of quantum metamaterials are derived directly from those of their quantum building blocks. The second theme will be geared towards developing a set of numerical methods and software tools for ab initio simulations of fundamental physical properties quantum metamaterials. The foundational work pertaining to the first two themes will enable us to pursue the main objective of the third theme, which is the exploration of new science and novel applications.REsistive-Switch CompUting bEyond CMOSDigital computers rely today on CMOS (complementary metal-oxide-semiconductor) technology, which improves its performance every generation thanks to the Moore s law of downscaling. As CMOS transistor size approaches few nm, alternative logic switches with better scaling capability must be identified to prolong Moore s law beyond CMOS. Among the emerging switching concepts, resistive switching (RS) devices can change their resistance by electrically-induced redox reactions. RS provides the basis for the resistive memory (ReRAM) technology which is currently investigated as future computer memory and storage technology. The objective of this project is to design, develop and demonstrate a novel computing paradigm based on RS devices. The project will pursue this objective at 3 levels of increasing complexity, namely the device fabrication, the design of new logic gates and the demonstration of computing circuits. RS logic will be finally compared to CMOS and other approaches to identify the strength and the potential applications of RS logic in the computing scenario.Plasma penetration into porous materials for biomedical, textile and filtration applications.My group will explore the undeveloped field of penetration of non-thermal plasma into porous structures. Porous materials are an exciting class of materials with a wide range of applications. However, given the narrow dimensions of the porous network, modifying in a homogeneous way an entire porous material is a challenging task. This project is based on the use of non-thermal atmospheric pressure plasmas for an effective internal surface modification of 3D porous structures. To make plasma technology reach this desired level of controlled penetration into porous structures, a far better understanding of the penetration of chemical active species into porous structures is required. Therefore, my project envisages a thorough study of the interactions between a non-thermal plasma and a second phase, the second phase being a porous substrate. Through diagnostics of the processrelevant plasma parameters and a quantitative analysis of the plasma-induced effects, the knowledge on the physics and chemistry of such hybrid plasma systems will be enhanced and, in most cases, newly founded. My group will start exploring this exciting field by focussing on three cornerstone research lines. Firstly, I will develop new plasma reactor concepts enabling effective plasma penetration. Secondly, these newly developed plasma reactors will be employed for the internal surface modification of porous biodegradable polyester scaffolds used in tissue engineering. Thirdly, besides the development of biomedical implants, the possibilities for the design of functional porous textiles and advanced filter materials will also be explored. Realisation of these three cornerstones would result in a major breakthrough in their specific field which makes this proposal inherently a relatively high risk/very high gain proposal. I therefore strongly believe that my research program will open a whole new window of opportunities for porous materials with a large impact on science and society.Secure Computation on Encrypted DataRecent trends in computing have prompted users and organizations to store an increasingly large amount of sensitive data at third party locations in the cloud outside of their direct control. Storing data remotely poses an acute security threat as these data are outside our control and could potentially be accessed by untrusted parties. Indeed, the reality of these threats have been borne out by the Snowden leaks and hundreds of data breaches each year. In order to protect our data, we will need to encrypt it.Functional encryption is a novel paradigm for public-key encryption that enables both fine-grained access control and selective computation on encrypted data, as is necessary to protect big, complex data in the cloud. Functional encryption also enables sear< ches on encrypted travel records and surveillance video as well as medical studies on encrypted medical records in a privacypreserving manner; we can give out restricted secret keys that reveal only the outcome of specific searches and tests. These mechanisms allow us to maintain public safety without compromising on civil liberties, and to facilitate medical break-throughs without compromising on individual privacy.The goals of the aSCEND project are (i) to design pairing and lattice-based functional encryption that are more efficient and ultimately viable in practice; and (ii) to obtain a richer understanding of expressive functional encryption schemes and to push the boundaries from encrypting data to encrypting software. My long-term vision is the ubiquitous use of functional encryption to secure our data and our computation, just as public-key encryption is widely used today to secure our communication. Realizing this vision requires new advances in the foundations of functional encryption, which is the target of this project.aActive Wind Farms: Optimization and Control of Atmospheric Energy Extraction in Gigawatt Wind FarmsWith the recognition that wind energy will become an important contributor to the world s energy portfolio, several wind farms with a capacity of over 1 gigawatt are in planning phase. In the past, engineering of wind farms focused on a bottom-up approach, in which atmospheric wind availability was considered to be fixed by climate and weather. However, farms of gigawatt size slow down the Atmospheric Boundary Layer (ABL) as a whole, reducing the availability of wind at turbine hub height. In Denmark s large off-shore farms, this leads to underperformance of turbines which can reach levels of 40% 50% compared to the same turbine in a lone-standing case. For large wind farms, the vertical structure and turbulence physics of the flow in the ABL become crucial ingredients in their design and operation. This introduces a new set of scientific challenges related to the design and control of large wind farms. The major ambition of the present research proposal is to employ optimal control techniques to control the interaction between large wind farms and the ABL, and optimize overall farm-power extraction. Individual turbines are used as flow actuators by dynamically pitching their blades using time scales ranging between 10 to 500 seconds. The application of such control efforts on the atmospheric boundary layer has never been attempted before, and introduces flow control on a physical scale which is currently unprecedented. The PI possesses a unique combination of expertise and tools enabling these developments: efficient parallel large-eddy simulations of wind farms, multiscale turbine modeling, and gradient-based optimization in large optimization-parameter spaces using adjoint formulations. To ensure a maximum impact on the wind-engineering field, the project aims at optimal control, experimental wind-tunnel validation, and at including multi-disciplinary aspects, related to structural mechanics, power quality, and controller design.Multi-field and multi-scale Computational Approach to design and durability of PhotoVoltaic ModulesPhotovoltaics (PV) based on Silicon (Si) semiconductors is one the most growing technology in the World for renewable, sustainable, non-polluting, widely available clean energy sources. Theoretical and applied research aims at increasing the conversion efficiency of PV modules and their lifetime. The Si crystalline microstructure has an important role on both issues. Grain boundaries introduce additional resistance and reduce the conversion efficiency. Moreover, they are prone to microcracking, thus influencing the lifetime. At present, the existing standard qualification tests are not sufficient to provide a quantitative definition of lifetime, since all the possible failure mechanisms are not accounted for. In this proposal, an innovative computational approach to design and durability assessment of PV modules is put forward. The aim is to complement real tests by virtual (numerical) simulations. To achieve a predictive stage, a challenging multi-field (multi-physics) computational approach is proposed, coupling the nonlinear elastic field, the thermal field and the electric field. To model real PV modules, an adaptive multi-scale and multi-field strategy will be proposed by introducing error indicators based on the gradients of the involved fields. This numerical approach will be applied to determine the upper bound to the probability of failure of the system. This statistical assessment will involve an optimization analysis that will be efficiently handled by a Mathematicabased hybrid symbolic-numerical framework. Standard and non-standard experimental testing on Si cells and PV modules will also be performed to complement and validate the numerical approach. The new methodology based on the challenging integration of advanced physical and mathematical modelling, innovative computational methods and non-standard experimental techniques is expected to have a significant impact on the design, qualification and lifetime assessment of complex PV systems.RETURN  Rethinking Tunnelling in Urban NeighbourhoodsThis project addresses important challenges at the forefront of geotechnical engineering and building conservation by introducing an entirely new workflow and largely unexploited data source for the predic-tion of building damage < from tunnel-induced subsidence. The project will also make fundamental and ground-breaking advances in the collection and processing of city-scale, aerial laser scanning by avoiding any reliance on existing data for building location identification, respective data affiliation, or building fea-ture recognition. This will create a set of techniques that are robust, scalable, and widely applicable to a broad range of communities with unreinforced masonry buildings. This will also lay the groundwork to rapidly generate and deploy city-scale, computational models for emergency management and disaster re-sponse, as well as for the growing field of environmental modelling.KAdvanced tools for computational design of engineering materialsThe overall goal of the project is to contribute to the consolidation of the nascent and revolutionary philosophy of  Materials by Design by resorting to the enormous power provided by the nowadaysavailable computational techniques. Limitations of current procedures for developing material-based innovative technologies in engineering, are often made manifest; many times only a catalog, or a data basis, of materials is available and these new technologies have to adapt to them, in the same way that the users of ready-to-wear have to take from the shop the costume that fits them better, but not the one that fits them properly. This constitutes an enormous limitation for the intended goals and scope. Certainly, availability of materials specifically designed by goal-oriented methods could eradicate that limitation, but this purpose faces the bounds of experimental procedures of material design, commonly based on trial and error procedures. Computational mechanics, with the emerging Computational Materials Design (CMD) research field, has much to offer in this respect. The increasing power of the new computer processors and, most importantly, development of new methods and strategies of computational simulation, opens new ways to face the problem. The project intends breaking through the barriers that presently hinder the development and application of computational materials design, by means of the synergic exploration and development of three supplementary families of methods: 1) computational multiscale material modeling (CMM) based on the bottom-up, one-way coupled, description of the material structure in different representative scales, 2) development of a new generation of high performance reduced-order-modeling techniques (HP-ROM), in order to bring down the associated computational costs to affordable levels, and 3) new computational strategies and methods for the optimal design of the material meso/micro structure arrangement and topology (MATO) .Novel Energy Materials: Engineering Science and Integrated Systems (NEMESIS)The aim of NEMESIS is to establish a world leading research center in ferroelectric and piezoelectric materials for energy harvesting and energy generation. I will deliver cutting edge multi-disciplinary research encompassing materials, physics, chemistry and electrical engineering and develop ground breaking materials and structures for energy creation. The internationally leading research center will be dedicated to developing new and innovative solutions to generating and harvesting energy using novel materials at the macro- to nano-scale. Key challenges and novel technical approaches are: 1. To create energy harvesting nano-generators to convert vibrations into electrical energy in hostile environments (e.g. wireless sensors in near engine applications). 2. To enable broadband energy harvesting to generate electrical energy from ambient vibrations which generally exhibit multiple timedependent frequencies. 3. To produce Curie-temperature tuned nano-structured pyroelectrics to optimise the electrical energy scavenged from temperature fluctuations. To further enhance the energy generation I aim to couple thermal expansion and pyroelectric effects to produce a new class of thermal energy harvesting materials and systems. 4. To create nano-structured ferroelectric and piezoelectric materials for novel water-splitting applications. Two approaches will be considered, the use of the internal electrical fields present in ferroelectrics to prevent recombination of photo-excited electron-hole pairs and the electric charge generated on mechanically stressed piezoelectric nano-rods which convert water to hydrogen and oxygen.Capillary suspensions: a novel route for versatile, cost efficient and environmentally friendly material designA wide variety of materials including coatings and adhesives, emerging materials for nanotechnology products, as well as everyday food products are processed or delivered as suspensions. The flow properties of such suspensions must be finely adjusted according to the demands of the respective processing techniques, even for the feel of cosmetics and the perception of food products is highly influenced by their rheological properties. The recently developed capillary suspensions concept has the potential to revolutionize product formulations and material design. When a small amount (less than 1%) of a second immiscible liquid is added to the continuous phase of a suspension, the rheological properties of the mixture are dramatically altered from a fluid-like to a gel-like state or from a weak to a strong gel and the strength can be tuned in a wide range covering orders of magnitude. Capillary suspensions can be used to create smart, tunable fluids, stabilize mixtures that would otherwise phase separate, significantly reduce the amount organic or polymeric additives, and the strong particle network can be used as a precursor for the manufacturing of cost-efficient porous ceramics and foams with unpre< cedented properties. This project will investigate the influence of factors determining capillary suspension formation, the strength of these admixtures as a function of these aspects, and how capillary suspensions depend on external forces. Only such a fundamental understanding of the network formation in capillary suspensions on both the micro- and macroscopic scale will allow for the design of sophisticated new materials. The main objectives of this proposal are to quantify and predict the strength of these admixtures and then use this information to design a variety of new materials in very different application areas including, e.g., porous materials, waterbased coatings, ultra low fat foods, and conductive films.OCrystal Engineering of Metal Organic Frameworks for application in Mixed Matrix MembranesWith this proposal, I seek to develop the gas separating membranes of the future. The overall aim is to produce composite membranes comprising engineered Metal Organic Framework (MOF) particles and polymers in the form of Mixed Matrix Membranes (MMMs). By applying these new membranes, energetically more efficient separations will be possible. Despite the superior performance of membranes only based on crystalline materials like zeolites or MOFs, polymeric membranes rule the commercial scene thanks to their easy processing, high reproducibility and mechanical strength. However, the existing polymeric membrane materials are not optimal: improvements in permeability are always at the expense of selectivity and vice versa, while plasticization threatens their application at high pressures. This research aims at utilizing the best of both fields by combining the high selectivity of MOFs with the easy processing of polymers in the form of Mixed Matrix Membranes. The main barrier to achieve this goal is the optimization of the MOF-polymer interaction and mass transport through the composite. This is very challenging because chemical compatibility, particle morphology and filler dispersion play a key role. Innovatively the project will be the first systematic study into this multi-scale phenomenon with investigations at all relevant interactions, including MOF particle tuning targeting the application in MMMs. A thorough study on the synthesis of the selected MOF structures and on the performance of the composites will allow engineering MOFs at the molecular and particle levels, resulting in higher selectivity and faster transport. The use of flexible MOF structures will not only allow a better membrane processing but will also reduce polymer plasticization. This research will deliver a new generation of mixed matrix membranes, outperforming the state of the art polymeric membranes./Durability of geopolymers as 21st century concretesGeopolyConc will provide the necessary scientific basis for the prediction of the long-term durability performance of alkali-activated  geopolymer concretes. These materials can be synthesised from industrial by-products and widely-available natural resources, and provide the opportunity for a highly significant reduction in the environmental footprint of the global construction materials industry, as it expands to meet the infrastructure needs of 21st century society. Experimental and modelling approaches will be coupled to provide major advances in the state of the art in the science and engineering of geopolymer concretes. The key scientific focus areas will be: (a) the development of the first ever rigorous mathematical description of the factors influencing the transport properties of alkaliactivated concretes, and (b) ground-breaking work in understanding and controlling the factors which lead to the onset of corrosion of steel reinforcing embedded in alkali-activated concretes. This project will generate confidence in geopolymer concrete durability, which is essential to the application of these materials in reducing EU and global CO2 emissions. The GeopolyConc project will also be integrated with leading multinational collaborative test programmes coordinated through a RILEM Technical Committee (TC DTA) which is chaired by the PI, providing a route to direct international utilisation of the project outcomes.8Plasma-assisted development and functionalization of electrospun mats for tissue engineering purposesIn this project, I will explore the unique combination of two fascinating research themes: electrospinning and plasma technology. Electrospun nanofibrous matrices (so-called mats) are an exciting class of materials with a wide range of possible applications. Nevertheless, the development and functionalization of these electrospun materials remain very challenging tasks. Atmospheric pressure plasma technology will be utilized by my research group to create advanced biodegradable electrospun mats with unprecedented functionality and performance. To realise such a major breakthrough, plasma technology will be implemented in different steps of the manufacturing process: pre-electrospinning and post-electrospinning. My group will focus on four cornerstone research lines, which have been carefully chosen so that all critical issues one could encounter in creating advanced biodegradable electrospun mats are tackled. Research cornerstone A aims to develop biodegradable electrospun mats with appropriate bulk properties, while in research cornerstone B preelectrospinning polymer solutions will be exposed to non-thermal atmospheric plasmas. This will be realized by probing unexplored concepts such as discharges created inside polymer solutions. In a third cornerstone C, an in-depth study of the interactions between an atmospheric pressure plasma and an electrospun mat will be carried out. Finally, the last cornerstone D will focus on plasma-assisted surface modification of biodegradable electrospun mat      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnoqrstuvwxyz{|}~s for tissue engineering purposes. Realization of these four cornerstones would result in a major breakthrough in their specific field which makes this proposal inherently a relatively high risk/very high gain proposal. I therefore strongly believe that this research program will open a whole new window of opportunities for electrospun materials with a large impact on science and society.DropletMicroarrays: Ultra High-Thr< oughput Screening of Cells in 3D MicroenvironmentsHigh-throughput (HT) screening of live cells is crucial to accelerate both fundamental biological research and discovery of new drugs. Current methods for HT cell screenings, however, either require a large number of microplates, are prone to cross-contaminations and are limited to adherent cells (cell microarrays), or are not compatible with adherent cells as well as with spatial indexing (droplet microfluidics). We recently demonstrated the use of superhydrophobic-superhydrophilic microarrays to create high-density arrays of microdroplets or hydrogel micropads. We propose here to develop a new platform for HT cell screening experiments using the unique properties of the superhydrophilic microarrays separated by superhydrophobic thin barriers. The new technology will allow us to perform up to 300K cell experiments in parallel using a single chip. Individual cell experiments will be performed in thousands of completely isolated microdroplet at defined locations on the chip. This will enable spatial indexing, time-lapse measurements and screening of either adherent or non-adherent cells. Parallel manipulations within individual microreservoirs, such as washing, addition of chemical libraries, or staining will be developed to open new possibilities in the field of live cell studies. Superhydrophobic barriers will allow complete isolation of the microreservoirs, thus preventing crosscontamination and cell migration. We will also develop a technology for the HT screening of cells in 3D hydrogel micropads. We will use these methods to gain better understanding of how different parameters of the 3D cell microenvironment influence various aspects of cell behavior. The project will require the development of new technological tools which can later be applied to a wide range of cell screening experiments and biological problems. Our long term aim is to replace the outdated microplate technology with a more powerful and convenient method for cell screening experiments.EHierarchical Carbon NanomaterialsOver the past years, carbon nanomaterial such as graphene and carbon nanotubes (CNTs) have attracted the interest of scientists, because some of their properties are unlike any other engineering material. Individual graphene sheets and CNTs have shown a Youngs Modulus of 1 TPa and a tensile strength of 100 GPa, hereby exceeding steel at only a fraction of its weight. Further, they offer high currents carrying capacities of 10^9 A/cm2, and thermal conductivities up to 3500 W/mK, exceeding diamond. Importantly, these off-the-chart properties are only valid for high quality individualized nanotubes or sheets. However, most engineering applications require the assembly of tens to millions of these nanoparticles into one device. Unfortunately, the mechanical and electronic figures of merit of such assembled materials typically drop by at least an order of magnitude in comparison to the constituent nanoparticles. In this ERC project, we aim at the development of new techniques to create structured assemblies of carbon nanoparticles. Herein we emphasize the importance of controlling hierarchical arrangement at different length scales in order to engineer the properties of the final device. The project will follow a methodical approach, bringing together different fields of expertise ranging from macro- and microscale manufacturing, to nanoscale material synthesis and mesoscale chemical surface modification. For instance, we will pursue combined top-down microfabrication and bottom-up self-assembly, accompanied with surface modification through hydrothermal processing. This research will impact scientific understanding of how nanotubes and nanosheets interact, and will create new hierarchical assembly techniques for nanomaterials. Further, this ERC project pursues applications with high societal impact, including energy storage and water filtration. Finally, HIENA will tie relations with EU s rich CNT industry to disseminate its technologic achievements.IgY Technology: A Purification Platform using Ionic-Liquid-Based Aqueous Biphasic SystemsWith the emergence of antibiotic-resistant pathogens the development of antigen-specific antibodies for use in passive immunotherapy is, nowadays, a major concern in human society. Despite the most focused mammal antibodies, antibodies obtained from egg yolk of immunized hens, immunoglobulin Y (IgY), are an alternative option that can be obtained in higher titres by non-stressful and non-invasive methods. This large amount of available antibodies opens the door for a new kind of cheaper biopharmaceuticals. However, the production cost of high-quality IgY for large-scale applications remains higher than other drug therapies due to the lack of an efficient purification method. The search of new purification platforms is thus a vital demand to which liquid-liq< uid extraction using aqueous biphasic systems (ABS) could be the answer. Besides the conventional polymer-based systems, highly viscous and with a limited polarity/affinity range, a recent type of ABS composed of ionic liquids (ILs) may be employed. ILs are usually classified as  green solvents due to their negligible vapour pressure. Yet, the major advantage of IL-based ABS relies on the possibility of tailoring their phases polarities aiming at extracting a target biomolecule. A proper manipulation of the system constituents and respective composition allows the pre-concentration, complete extraction, or purification of the most diverse biomolecules. This research project addresses the development of a new technique for the extraction and purification of IgY from egg yolk using IL-based ABS. The proposed plan contemplates the optimization of purification systems at the laboratory scale and their use in countercurrent chromatography to achieve a simple, cost-effective and scalable process. The success of this project and its scalability to an industrial level certainly will allow the production of cheaper antibodies with a long-term impact in human healthcare.ADDITIONAL LOSSES IN ELECTRICAL MACHINESElectrical motors consume about 40 % of the electrical energy produced in the European Union. About 90 % of this energy is converted to mechanical work. However, 0.5-2.5 % of it goes to so called additional load losses whose exact origins are unknown. Our ambitious aim is to reveal the origins of these losses, build up numerical tools for modeling them and optimize electrical motors to minimize the losses. As the hypothesis of the research, we assume that the additional losses mainly result from the deterioration of the core materials during the manufacturing process of the machine. By calorimetric measurements, we have found that the core losses of electrical machines may be twice as large as comprehensive loss models predict. The electrical steel sheets are punched, welded together and shrink fit to the frame. This causes residual strains in the core sheets deteriorating their magnetic characteristics. The cutting burrs make galvanic contacts between the sheets and form paths for interlamination currents. Another potential source of additional losses are the circulating currents between the parallel strands of random-wound armature windings. The stochastic nature of these potential sources of additional losses puts more challenge on the research. We shall develop a physical loss model that couples the mechanical strains and electromagnetic losses in electrical steel sheets and apply the new model for comprehensive loss analysis of electrical machines. The stochastic variables related to the core losses and circulating-current losses will be discretized together with the temporal and spatial discretization of the electromechanical field variables. The numerical stochastic loss model will be used to search for such machine constructions that are insensitive to the manufacturing defects. We shall validate the new numerical loss models by electromechanical and calorimetric measurements.3Next generation of complex metallic materials with intelligent hybrid structuresIn a modern society, metallic materials are crucially important (e.g. energy, safety, infrastructure, transportation, health, medicine, life sciences, IT). Contemporary examples with inherent challenges to be overcome are the design of ultrahigh specific strength materials. There is a critical need for successful developments in this area in particular for reduced energy consumption, reduction of pollutant emissions and passenger safety. Alternative approaches include improved thermal stability and creep resistance of high-temperature alloys for energy conversion, which are generally used in power plants and turbine engines, high temperature process technology, and fossil-fuel driven engines. The ageing European society makes biomedical materials for implant and stent design also crucially important. A drawback of nearly all current high strength metallic materials is that they lack ductility (i.e. are brittle and hard to form)- or on the opposite side, they may be highly ductile but lack strength. The key concept behind INTELHYB is to define new routes for creation of tailored metallic materials based on scale-bridging intelligent hybrid structures enabling property as well as function optimization. The novelty of this proposal as compared to conventional ideas is that they apply to monolithic amorphous materials or bulk microcrystalline. The basis will be founded on innovative strategies for the design, synthesis and characterization of intrinsic length-scale modulation and phase transformation under highly non-equilibrium conditions. This will include the incorporation of dispersed phases which are close to or beyond their thermodynamic and mechanical stability limit thus forming a hierarchically structured hybrid and ductile/tough alloys. Alternatively, the material itself will be designed in a manner such that it is at the verge of its thermodynamic/mechanical stability.Innovative Catalyst Design for Large-Scale, Sustainable ProcessesA systematic and novel, multi-scale model based catalyst design methodology will be developed. The fundamental nature of the models used is unprecedented and will represent a breakthrough compared to the more commonly applied statistical, correlative relationships. The methodology will focus on the intrinsic kinetics of (potentially) large-scale processes for the conversion of renewable feeds into fuels and chemicals. Non-ideal behaviour, caused by mass and heat transfer limitations or particular reactor hydrodynamics, will be explicitly accounted for when simulating or optimizing industrial-scale applications. The selected model reactions are situated in the area of biomass upgrading to fuels and chemicals: fast pyrolysis oil stabilization, glycerol hydrogenolysis and selective oxidation of (bio)ethanol to acetaldehyde. For the first time, a systematic microkinetic modelling methodology will be developed for oxygenates conversion. In particular, stereochemistry in catalysis will be assessed. Two types of descriptors will be quantified: kinetic descriptors that are catalyst independent and catalyst descriptors that specifically account for the effect of the catalyst properties on the reaction kinetics. The latter will be optimized in terms of reactant conversion, product yield or selectivity. Fundamental relationships will be established between the catalyst descriptors as determined by microki< netic modelling and independently measured catalyst properties or synthesis parameters. These innovative relationships allow providing the desired, rational feedback in from optimal descriptor values towards synthesis parameters for a new catalyst generation. Their fundamental character will guarantee adequate extrapolative properties that can be exploited for the identification of a groundbreaking next catalyst generation.?TRansItions and Turbulence Of complex SuspensionsThe aim of this project is to forge a physical understanding of the transitions and of the turbulent flow of semi-dilute/dense non-colloidal suspensions, for different particle features and suspending fluids. It is estimated that 10% of the world energy consumption is due to the transport and handling of granular materials of which particle suspensions are an important part. A deep understanding of the mechanisms underlying the flow of particle suspensions, the transition to turbulence and the turbulence characteristics is crucial for many important practical applications involving engineered complex fluids, such as pastes and paper pulp. A better prediction and control of the flow of suspensions will therefore have a huge impact. Complex fluids are multiscale by nature where the physics at the microscale affects the macroscopic behaviour of the flow and vice versa giving rise to surprising and spectacular phenomena as well as making this one of the most important practical problem still to solve. Investigating the mechanisms by which the system microstructure determines the macroscopic flow properties and vice versa will not only give valuable insights into the nature of flowing suspensions but also will also lead to new ways to model and control it. Future generations of engineering CFD tools will have to contain models for complex suspensions. The fundamental approach proposed here, combined with challenging scientific and engineering examples backed up by experimental evidence, will make this possible and demonstrate it to a wider engineering community. The proposed project is based on highly accurate simulations of multiphase flow systems and state-ofthe-art experiments. Such a holistic approach will enable us to understand the underlying mechanisms of instabilities and suspension turbulence and to develop accurate criteria for their prediction far in advance of what we could achieve with either approach separately.XEngineering Discoidal Polymeric Nanoconstructs for the Multi-Physics Treatment of Brain TumorsDespite significant advances in chemotherapy, the effective treatment of malignant masses via systemically injectable agents are still limited by insufficient accumulation at the biological target (<< 10% injected dose per gram tumor) and non-specific sequestration by the reticulo-endothelial system (tumor/liver < 0.1). The goal of this proposal is to engineer Discoidal Polymeric Nanoconstructs (DPNs) to preferentially target the malignant neovasculature for the delivery of imaging agents, controlled release of therapeutic molecules and thermal energy. The central hypothesis is that the size, shape, surface properties and stiffness (4S parameters) of the DPNs can be controlled during synthesis, and that therapeutic molecules (Temozolomide), Gd(DOTA) complexes and ultra-small Super-Paramagnetic Iron Oxide nanoparticles (USPIOs) can be efficiently incorporated within the DPN polymeric matrix. This will be achieved by pursuing 3 specific aims: i) synthesis and physico-chemical characterization of poly(lactic-co-glycolic acid)/poly(ethylene glycol) DPNs with multiple 4S combinations; ii) in-silico and in vitro rational selection of DPN configurations with preferential tumor deposition, low macrophage uptake and high loading; and iii) in-vivo testing of the DPN imaging and therapeutic performance in mice bearing Glioblastoma Multiforme (GBM). The innovation stays in i) using synergistically three different targeting strategies (rational selection of the 4S parameters; magnetic guidance via external magnets acting on the USPIOs; specific ligand-receptor recognition of the tumor neovasculature); ii) combining therapeutic and imaging molecules within the same nanoconstruct; and iii) employing synergistically different therapeutic approaches (molecular and thermal ablation therapies). This would allow us to support minimally invasive screening via clinical imaging and enhance therapeutic efficacy in GBM patients.]First Biodegradable Biocatalytic VascularTherapeutic ImplantsWe aim to perform academic development of a novel biomedical opportunity: localized synthesis of drugs within biocatalytic therapeutic vascular implants (BVI) for site-specific drug delivery to target organs and tissues. Primary envisioned targets for therapeutic intervention using BVI are atherosclerosis, viral hepatitis, and hepatocellular carcinoma: three of the most prevalent and debilitating conditions which affect hundreds of millions worldwide and which continue to increase in their importance in the era of increasingly aging population. For hepatic applications, we aim to develop drug eluting beads which are equipped with tools of enzyme-prodrug therapy (EPT) and are administered to the liver via trans-arterial catheter embolization. Therein, the beads perform localized synthesis of drugs and imaging reagents for anticancer combination therapy and theranostics, antiviral and anti-inflammatory agents for the treatment of hepatitis. Further, we conceive vascular therapeutic inserts (VTI) as a novel type of implantable biomaterials for treatment of atherosclerosis and reendothelialization of vascular stents and grafts. Using EPT, inserts will tame  the guardian of cardiovascular grafts , nitric oxide, for which localized, site specific synthesis and delivery spell success of therapeutic intervention and/or aided tissue regeneration. This proposal is positioned on the forefront of biomedical engineering and its success requires excellence in polymer chemistry, materials design, medicinal chemistry, and translational medicine. Each part of this proposal - design of novel type< s of vascular implants, engineering novel biomaterials, developing innovative fabrication and characterization techniques  is of high value for fundamental biomedical sciences. The project is target-oriented and once successful, will be of highest practical value and contribute to increased quality of life of millions of people worldwide.GComputational modelling of structural batteriesCompetition in consumer electronics has pushed the boundaries of technological development towards miniaturization, with weight/size limitations and increasing power demands being the two most stringent requirements. Although almost all the components of any portable device become smaller, lighter and more powerful by the months, electrochemical technology is far from presenting us with the ideal battery. From a different perspective, the equation mobile device = casing + electronics + battery could be simplified by merging the structural function of the casing with that of the energy source of the battery into a structural battery. This approach would immediately reduce weight and size of our mobile devices. This project aims at investigating the effect of electrochemicalmechanical interactions on the mechanical performance of structural batteries. Understanding and controlling mechanical degradation in structural batteries is of prime importance given the dual structural-electrical function of these devices. In fact, the main concern when dealing with structural batteries is whether the internal stresses caused by external loads will influence the performance of the battery, and, conversely, whether the functioning of the battery will have a detrimental effect on its mechanical properties. The complexity of these processes can only be addressed with dedicated computational techniques. This project offers a unique opportunity for the design and implementation of the first multiphysics and multiscale computational framework for the analysis of structural batteries. Macroscale processes originating at the level of a basic components will be elucidated through physically-based constitutive laws. The overall impact of this project will be felt across many research communities. Apart from the energy storage community, the developed tools and procedures will influence research and development related to many fibre-reinforced composites..Engineering a scaffold based therapy for corneal regenerationCorneal blindness resulting from disease, physical injury or chemical burns affects millions worldwide and has a considerable economic and social impact on the lives of people across Europe. In many cases corneal transplants can restore vision however the shortage of donor corneas suitable for transplantation has necessitated the development of alternative treatments. The aim of this project is to develop a new approach to corneal tissue regeneration. Previous approaches at engineering corneal tissue have required access to donor cells and lengthy culture periods in an attempt to grow tissue in vitro prior to implantation with only limited success and at great expense. Our approach will differ fundamentally from these in that we will design artificial corneal scaffolds that do not require donated cells or in vitro culture but instead will recruit the patient s own cells to regenerate the cornea postimplantation. These biomaterial scaffolds will incorporate specific chemical and physical cues with the deliberate aim of attracting cells and inducing tissue formation. Studies will be undertaken to examine how different chemical, biochemical, physical and mechanical cues can be used to control the behaviour of corneal epithelial, stromal and endothelial cells. Once the optimal combination of these cues has been determined, this information will be incorporated into the design of the scaffold. Recent advances in manufacturing and material processing technology will enable us to develop scaffolds with organized nanometric architectures and that incorporate controlled growth factor release mechanisms. Techniques such as 3D bio-printing and nanofiber electrospinning will be used to fabricate scaffolds. The ability of the scaffold to attract cells and promote matrix remodelling will be examined by developing an in vitro bioreactor system capable of mimicking the ocular environment and by performing in vivo tests using a live animal model.Insect-inspired capillary nanostampingAim of the proposed project is a) development and establishment of insect-inspired capillary nanostamping (IICN) as next-generation contact nanolithography, b) replacing state-of-the-art lithographic and synthesis protocols requiring use of sacrificial templates or time-consuming selfassembly steps by IICN and c) significant IICN-driven acceleration and upscaling of the production of extended nanostructured systems. To meet these aims, IICN stamp design will be inspired by insect feet depositing small secretion droplets through arrays of hairy contact elements on counterpart surfaces. Monolithic IICN stamps extending cm2 will consist of spongy ink-filled substrates connected to extended arrays of spongy nanoscale dispensing elements with diameters in the 100 nm range (density up to ~130 dispensing elements per square micron). Ink supplied through the spongy pore systems forms capillary bridges between each dispensing element and counterpart surfaces, thus enabling massively parallel capillary bridge-guide< d nanorod synthesis. Capillary bridge rupture during stamp retraction leads to massively parallel lithographic deposition of ink nanodroplet arrays (target nanodroplet volume: a few 10 zeptolitres). IICN model applications include production of a) ultrathin nanoporous membranes for separation; b) ordered silicon nanostructures by IICN-supported metalassisted etching; c) nearly-ergodic arrays of encapsulated liquid nanocontainers for massively parallel ensemble nanochemistry or ensemble tracing of single molecules; d) nearly-ergodic biochips for massively parallel analyte detection with single-molecule resolution. As example for substitution of time-consuming self-assembly in nanomaterial synthesis by IICN, IICN-accelerated production of ordered nanoporous alumina will be studied. To pave the way for upscaling and potential commercialization of IICN, high-throughput IICN devices for automated operation in batch and continuous roller modes will be constructed.TAEROelastic instabilities and control of FLEXible StructuresAeroelastic instabilities are at the origin of large deformations of structures and are limiting the capacities of products in various industrial branches such as aeronautics, marine industry, or wind electricity production. If suppressing aeroelastic instabilities is an ultimate goal, a paradigm shift in the technological development is to take advantage of these instabilities to achieve others objectives, as reducing the drag of these flexible structures. The ground-breaking challenges addressed in this project are to design fundamentally new theoretical methodologies for (i) describing mathematically aeroelastic instabilities, (ii) suppressing them and (iii) using them to reduce mean drag of structures at a low energetic cost. To that aim, two types of aeroelastic phenomena will be specifically studied: the flutter, which arises as a result of an unstable coupling instability between two stable dynamics, that of the structures and that the flow, and vortex-induced vibrations which appear when the fluid dynamics is unstable. An aeroelastic global stability analysis will be first developed and applied to problems of increasing complexity, starting from two-dimensional free-vibrating rigid structures and progressing towards three-dimensional free-deforming elastic structures. The control of these aeroelastic instabilities will be then addressed with two different objectives: their suppression or their use for flow control. A theoretical passive control methodology will be established for suppressing linear aeroelastic instabilities, and extended to high Reynolds number flows and experimental configurations. New perturbation methods for solving strongly nonlinear problems and adjoint-based control algorithm will allow to use these aeroelastic instabilities for drag reduction. This project will allow innovative control solutions to emerge, not only in flutter or vortex-induced vibrations problems, but also in a much broader class of fluid-structure problems.Design, manufacturing and control of INterfaces in THERMally conductive polymer nanocompositesThis proposal addresses the design, manufacturing and control of interfaces in thermally conductive polymer/graphene nanocomposites. In particular, the strong reduction of thermal resistance associated to the contacts between conductive particles in a percolating network throughout the polymer matrix is targeted, to overcome the present bottleneck for heat transfer in nanocomposites. The project includes the investigation of novel chemical modifications of nanoparticles to behave as thermal bridges between adjacent particles, advanced characterization methods for particle/particle interfaces and controlled processing methods for the preparations of nanocomposites with superior thermal conductivity. The results of this project will contribute to the fundamental understanding of heat transfer in complex solids, while success in mastering interfacial properties would open the way to a new generation of advanced materials coupling high thermal conductivity with low density, ease of processing, toughness and corrosion resistance.9Learning From Failing and Passing Executions At the Speed of InternetModern software systems must be extremely flexible and easily adaptable to different user needs and environments. However, this flexibility also introduces relevant quality issues. These problems are so common that is sufficient browsing the Web to find millions of reports about failures observed after updates and incompatibilities caused by the interaction of a newly installed component with the existing components. The impact of problems introduced by end-users can be dramatic because endusers can easily modify applications, like developers do, but end-users have neither the knowledge nor the skill of developers, and they cannot debug and fix the problems that they unintentionally introduce. It is thus necessary to timely develop novel solutions that can increase the reliability of the moderns systems, which can be extended and adapted by end-users, with the capability to automatically address problems that are unknown at development-time. The Learn project aims to produce innovative solutions for the development of systems that can work around the problems introduced by end-users when modifying their applications. The three key elements introduced by Learn to automatically produce a (temporary) fix for the software are: (1) the definition of the InternetLearn infrastructure, which is a network infrastructure that enables communication between every individual instance of a same program running at different end-users sites, thus augmenting each application with the capability to access a huge amount of information collected in-the-field from other sites; (2) the definition of analysis techniques that can learn the characteristics of successful and failed runs by monitoring executions in the field from a number of instance< s running at many end-user sites; and (3) the definition of techniques for the automatic generation and actuation of temporary fixes on an Internet (World) scale.Plasmonic Enhancement and Directionality of Emission for Advanced Luminescent Solar DevicesApplying photovoltaic (PV) panels to buildings is an important application for wider PV deployment and to achieving our 20% Renewable Energy EU targets by 2020. PEDAL will develop a disruptive PV technology where record increases in efficiency are achieved and costs dramatically reduced; (1) Diffuse solar radiation will be captured to produce higher efficiencies with concentration ratios over 3 in plasmonically enhanced luminescent solar concentrators (PLSC). Current LSC efficiency achieved is 7.1%, [1]. This proposal will boost efficiency utilising metal nanoparticles (MNP) tuned to luminescent material type in LSCs, to induce plasmonic enhancement of emission (PI and team have achieved 53% emission enhancement). MNP will be aligned to enable directional emission within the LSC (being patented by PI and team). These are both huge steps in the reduction of loss mechanisms within the device and towards major increases in efficiency.(2) Plasmonically enhanced luminescent downshifting thin-films (PLDS) will be tailored to increase efficiency of solar cells independent of material composition. MNP will be used, where the plasmonic resonance will be tailored to the luminescent species to downshift UV. MNP will be aligned to enable directional emission within the PLDS layer, reducing losses enabling dramatic increases in a layer adaptable to all solar cells.(3) These novel systems will be designed, up-scaled and a building integrated component fabricated, with the ability not only to generate power but with options for demand side management. Previous work has been limited by quantum efficiency of luminescent species, with this breakthrough in both the use of MNP for plasmonic emission enhancement and alignment inducing directionality of emission, will lead to efficiencies of both PLSC and PLDS being radically improved. PEDAL is a project based on new phenomena that will allow far reaching technological impacts in solar energy conversion and lighting.@New era of printed paper electronics based on advanced functional celluloseFully recyclable and low cost electronic goods are still far from reality. My interest is in creating environmental friendly advanced functional materials and processes able to result in new class of paper based electronic products. This represents a reborn of the paper millenary industry for a plethora of low cost, recyclable and disposable electronics, putting Europe in the front line of a new era of consumer electronics. While the vision of the proposal is a very ambitious one, my ground-breaking research work to date related with oxide based transistors on paper (from which I am one of the coinventors) has contributed to the basic technological breakthroughs needed to create the key elements to establish a new era of paper electronics. Field effect transistors (FETs), memory and CMOS devices, with excellent electronic performance and using paper as substrate and dielectric have resulted from my recent work. What I am proposing now is to reinvent the concept of paper electronics. In NEW_FUN I want to develop a completely new and disruptive approach where functionalized cellulose fibers will be used not only as dielectric but also as semiconductor and conductor able to coexist in a multilayer paper structure. That is, assembling paper that can have different functionalities locally, on each face or even along its entire thickness/bulk. This way issues such as failure under bending, mechanical robustness and stability can be minimized. Doing so, electronic and electrochemical devices can be produced not only on paper but also from paper. The outputs of NEW_FUN will open the door to turn paper into a real electronic material making possible disposable/recyclable electronic products, such as smart labels/packages (e.g. food and medicine industry), sensors for air quality control (car, house and industry environments); disposable electronic devices such as bio-detection platforms, labon-paper systems, among others.KLocalization in biomechanics and mechanobiology of aneurysms: Towards personalized medicineRupture of Aortic Aneurysms (AA), which kills more than 30 000 persons every year in Europe and the USA, is a complex phenomenon that occurs when the wall stress exceeds the local strength of the aorta due to degraded properties of the tissue. The state of the art in AA biomechanics and mechanobiology reveals that major scientific challenges still have to be addressed to permit patient-specific computational predictions of AA rupture and enable localized repair of the structure with targeted pharmacologic treatment. A first challenge relates to ensuring an objective prediction of localized mechanisms preceding rupture. A second challenge relates to modelling the patient-specific evolutions of material properties leading to the localized mechanisms preceding rupture. Addressing these challenges is the aim of the BIOLOCHANICS proposal. We will take into account internal length-scales controlling localization mechanisms preceding AA rupture by implementing an enriched, also named nonlocal, continuum damage theory in the computational models of AA biomechanics and mechanobiology. We will also develop very advanced experiments, based on full-field optical measurements, aimed at characterizing localization mechanisms occurring in aortic tissues and at identifying local distributions of material properties at different stages of AA progression. A first in vivo application will be performed on genetic and pharmacological models of mice and rat AA. Eventually, a retrospective clinical study involving more than 100 patients at the Saint-Etienne University hospital will permit calibrating estimations of AA rupture risk thanks to our novel approaches and infuse them into future clinical practice. Through the achievements of BIOLOCHANICS, nonlocal mechanics will be possibly extended to other soft tissues for applications in orthopaedics, oncology, sport biomechanics, interventional surgery, human safety, cell biology, etc.{Engineering Complex Intestinal Epithelial Tissue ModelsEpithelial barriers protect the body against physical, chemical, and microbial insults. Intestinal epithelium is one of the most actively renewing tissues in the body and a major site of carcinogenesis. Functional in vitro models of intestinal epithelium have been pursued for a long time. They are key elements in basic research, disease modelling, drug discovery, and tissue replacing and have become prime models for adult stem cell research. By taking advantage of the self-organizing properties of intestinal stem cells, intestinal organoids have been recently established, showing cell renewal s kinetics resembling to the one found in vivo. However, the development of in vitro 3< D tissue equivalents accounting for the dimensions, architecture and access to the luminal contents of the in vivo human intestinal tissue together with its self-renewal properties and cell complexity, remains a challenge. The goal of this project is to engineer intestinal epithelial tissue models that mimic physiological characteristics found in in vivo human intestinal tissue, to open up new areas of research on human intestinal diseases. The proposed models will address the in vivo intestinal epithelial cell renewal and migration, the multicell-type differentiation and the epithelial cell interactions with the underlying basement membrane while providing access to the luminal content to go beyond the stateof-the-art organoid models. To do this, we propose to develop an experimental setup that combines microfabrication techniques, tissue engineering components and recent advances in intestinal stem cell research, exploiting stem cell self-organizing characteristics. We anticipate this setup to recapitulate the 3D morphology, the spatio-chemical gradients and the dynamic microenvironment of the living tissue. We expect the new device to prove useful in understanding cell physiology, adult stem cell behaviour, and organ development as well as in modelling human intestinal diseases.ZIn-situ produced nanoparticles for enhanced oil recoveryThe era of finding  easy oil is coming to an end, and future supply will become more reliant on fossil fuels produced from enhanced oil recovery (EOR) process. Many EoR methods have been used, including mechanical, chemical, thermal and biological approaches, but there are still 50~70% of the original oil trapped in reservoir rocks after the primary and secondary recovery. NanoEOR, i.e, injecting nanoparticles (NPs) together with flooding fluids, is an emerging field. However all proposed applications are based on pre-fabricated NPs, which encountered enormous problems in NP stabilization and transport under reservoir conditions. This project proposes a revolutionary concept, iNanoEOR: in-situ production of NPs inside the reservoir for enhanced oil recovery. Rather than premanufacturing, dispersing and stabilizing NPs in advance, NPs will be produced in the reservoir by controlled hydrothermal reactions, acting as sensors to improve reservoir characterisation, or as property modifiers to effectively mobilize the trapped oil. This project will validate the innovative iNanoEOR concept by answering three questions: i) how the concept works? ii) what kind of NPs should be produced that can effectively mobilize trapped oil? iii) what are desired NP properties to allow them flow through a reservoir? Three work programs are designed, and a number of breakthroughs beyond state-of-art research are expected, which include i) proof-of-concept of the innovative iNanoEOR, ii) developing a new methodology for temperature measurement inside a reservoir, iii) revelation of the influence of NPs on EOR under reservoir-like conditions, iv) understanding the controlling factors in NP transport at different scales. The project will not only contribute directly to iNanoEOR, but also transfers the PI s expertise in nanomaterials and multiphase flow into oil and gas sector and underpin many NP-related subsurface applications, which currently is non-existing in the Europe. Mixing interfaces as reactive hotspots of porous media flows: theoretical upscaling, experimental imaging and field scale validationIn porous media, mixing interfaces such as contaminant plume fringes or boundaries between water bodies create highly reactive localized hotspots of chemical and microbiological activity, whether in engineered or natural systems. These reactive fronts are characterized by high concentration gradients, complex flow dynamics, variable water saturation, fluctuating redox conditions and multifunctional biological communities. The spatial and temporal variability of velocity gradients is expected to elongate mixing interfaces and steepen concentration gradients, thus strongly affecting biochemical reactivity. However, a major issue with porous media flows is that these essential micro-scale interactions are inaccessible to direct observation. Furthermore, the lack of a validated upscaling framework from fluid- to system-scale represents a major barrier to the application of reactive transport models to natural or industrial problems. The ambition of the ReactiveFronts project is to address this knowledge gap by setting up a high level interdisciplinary team that will provide a new theoretical understanding and novel experimental imaging capacities for micro-scale interactions between flow, mixing and reactions and their impact on reactive front kinetics at the system scale. ReactiveFronts will develop an original approach to this long-standing problem; combining theoretical, laboratory and field experimental methods.The focus on reactive interface dynamics, which represents a paradigm shift for reactive transport modelling in porous media, will require the development of original theoretical approaches (WP1) and novel microfluidic experiments (WP2). This will form a strong basis for the study of complex features at increasing spatial scales, including the coupling between fluid dynamics and biological activity (WP4), the impact of 3D flow topologies and chaotic mixing on effective reaction kinetics (WP3), and the field scale assessment of these interactions (WP5).oTowards a deepened understanding of combustion processes using advanced laser diagnosticsThe field of combustion is of utmost societal/industrial importance while at the same time posing outstanding scientific challenges. In order to handle t< hese, it is extremely important to develop and apply non-intrusive laser-diagnostic techniques with high spatial and temporal resolution for measurements of key parameters such as species concentrations and temperatures. Such techniques have been developed and applied by the PI for more than thirty-five years and the home institute has one of the most advanced instrumentations in academia world-wide. The proposal activities will be divided into two areas including five main Work packages: 1. Development of new diagnostic techniques. We will concentrate on concepts based on structured illumination which will add a new dimension to present diagnostics based on temporal, intensity and spectral properties. It will allow for multiscalar measurements and efficient suppression of background light. Furthermore, we will work with femto/picosecond lasers for investigating the diagnostic applicability of filamentation, new aspects of non-linear techniques, and diagnostic aspects of photodissociation phenomena. 2. Phenomenological combustion studies using advanced laser diagnostics. A very important aspect of the project is to use the developed and available diagnostic techniques to assure experimental data in extremely challenging environments and together with modeling experts enhance the understanding of combustion phenomena. Studies will be carried out on three different topics: - Flame structures in laminar flames at high pressure as well as turbulent flames at atmospheric/high pressure. - Biomass gasification, where complex fuels require new techniques to measure nitrogen, alkali, chlorine and sulfur compounds, as well as for measurements inside fuel particles. - Combustion improvement by electric activation which can be introduced to handle flame oscillations and instabilities.Coherent Structures in Wall-bounded TurbulenceTurbulence is a multiscale phenomenon for which control efforts have often failed because the dimension of the attractor is large. However, kinetic energy and drag are controlled by relatively few slowly evolving large structures that sit on top of a multiscale cascade of smaller eddies. They are essentially single-scale phenomena whose evolution can be described using less information than for the full flow. In evolutionary terms they are punctuated  equilibria for which chaotic evolution is only intermittent. The rest of the time they can be considered coherent and predictable for relatively long periods. Coherent structures studied in the 1970s in free-shear flows (e.g. jets) eventually led to increased understanding and to industrial applications. In wall-bounded cases (e.g. boundary layers), proposed structures range from exact permanent waves and orbits to qualitative observations such as hairpins or ejections. Although most of them have been described at low Reynolds numbers, there are reasons to believe that they persist at higher ones in the  LES sense in which small scales are treated statistically. Recent computational and experimental advances provide enough temporally and spatially resolved data to quantify the relevance of such models to fully developed flows. We propose to use mostly existing numerical data bases to test the various models of wall-bounded coherent structures, to quantify how often and how closely the flow approaches them, and to develop moderate-time predictions. Existing solutions will be extended to the LES equations, methods will be sought to identify them in fully turbulent flows, and reduced-order models will be developed and tested. In practical situations, the idea is to be able to detect large eddies and to predict them  most of the time . If simple enough models are found, the process will be implemented in the laboratory and used to suggest control strategies.@MULTI-CONCEPTUAL DESIGN OF FIRE BARRIER: A SYSTEMIC APPROACHThe development of science and technology provides the availability of sophisticated products but concurrently, increases the use of combustible materials, in particular organic materials. Those materials are easily flammable and must be flame retarded to make them safer. In case of fire, people must be protected by materials confining and stopping fire. It is one of the goals of the FireBar-Concept project to design materials and assembly of materials exhibiting low flammability, protecting substrates and limiting fire spread. The objective of FireBar-Concept is to make a fire barrier formed at the right time, at the right location and reacting accordingly against thermal constraint (fire scenario). This fire barrier can be developed in several ways according to the chemical nature of the material and/or of its formulation:- Heat barrier formed by inherently flame retarded materials (e.g. mineral fibers, ceramic & ) and exhibiting low thermal conductiv< ity (note the assembly of those materials can also provide low thermal conductivity controlling porosity and its distribution)- Evolution of reactive radicals poisoning the flame and forming a protective  umbrella avoiding the combustion of the material- Additives promoting charring of the materials and forming an expanding carbonaceous protective coating or barrier (intumescence)- Additives forming a physical barrier limiting mass transfer of the degradation products to the flameThe FireBar-Concept project is multidisciplinary and it requires expertise in material science, chemical engineering, chemistry, thermal science and physics. The approach is to make 5 actions linked together by transverse developments (3) according to this scheme: (i) fundamentals of fire barrier, (ii) multi-material and combination of concepts, (iii) modeling and numerical simulation, (iv) design and development of experimental protocols and (v) optimization of the systems.Characterising the interstellar medium of bright, lensed, star-forming galaxies across cosmic timeThe physical conditions of molecular gas in galaxies, and the impact of star formation and AGN on these conditions and on the emergent stellar IMF, are overarching themes in astrophysics. We are entering an era where numerical simulations of turbulent molecular gas can be informed and constrained by observations of such gas. I propose to investigate, theoretically and observationally, the impact of merger-driven star formation during a vital period in cosmic history, 1 < z < 3, when much of today s stellar mass was formed. It is here that we must study Larson s star-formation laws, and turbulence-regulated aspects of star formation, and look for possibly dramatic differences in the initial conditions of star formation, and the different IMF these may impose. These galaxies were significantly more gas-rich and turbulent than local starbursts, with different fragmentation histories and higher star-formation-rate densities (so more cosmic rays). They should yield cleaner signatures of a topheavy IMF than local starbursts, where periods of ordinary star formation may have diluted such signatures. I will exploit strongly lensed starbursts to study powerful diagnostic rest-frame FIR cooling lines with Herschel's FTS and map velocity fields with JVLA/ALMA, moving beyond studies of integratedgalaxy properties to study the activity within starbursts on sub-kpc scales, distinguishing between fueling mechanisms and testing Larson's relations. At this level of sophistication, the analysis of the ISM at z > 1 begins to be comparable to that possible at z ~ 0. Abundances - probed by multi-species, multi-J isotopologues and molecular diagnostics - will reveal the dominant form of nucleosynthesis enriching their ISM, and gravo-turbulent MHD simulations of gas fragmentation in cosmic-ray-dominated regions will determine how turbulent energy injection affects merger-driven systems, producing IMF libraries as functions of ISM conditions to determine the cosmological consequences.%Accurate ages of starsAge is a fundamental property of stars. It is an essential tool to understand many diverse phenomena in astrophysics, including the evolution of stars, planetary systems, and the Galaxy. However, age is currently the most poorly known property of a star, often to no better than 30-40% accuracy, which is not good enough. The ages of stars cannot be measured directly; they can only be determined by comparing age-sensitive observables with model predictions. Asteroseismology, the study of stellar oscillations, offers the unique opportunity to estimate the ages of stars to within 5-10% of their lifetime. Using state-of-the-art space observations (CoRoT and Kepler) of stellar oscillation frequencies combined with ground-based spectroscopy (e.g. APOGEE), I propose to uniformly determine accurate ages of thousands of stars with unprecedented precision. Building on my extensive experience in this field, I plan to develop and implement new asteroseismic diagnostics for a large number of mainsequence stars, subgiants and red giants. These new age determination methods are expected to be calibrated using stars in binary systems and clusters, and compared with classical methods. Uniform age determinations for a large sample of stars in different directions in the sky will greatly advance the study of stellar populations in the Galaxy. This project is ambitious, and success requires a dedicated approach from a competent team with the right resources and the right leader.[Formation of the First StarsThe appearance of the first stars marked a primary transition in c< osmic history. Their light ended the so-called  dark ages , and they played a key role in the metal enrichment and the reionization of the Universe, thereby shaping the galaxies we see today. Understanding high-redshift star formation is central to many areas of modern astrophysics. However, studying stellar birth in the early Universe is a relatively young field of science, and so still little is known about the origin and observable characteristics of the first stellar populations. Shedding light on the physical processes that govern the formation of stars in the early Universe requires a concerted, multi-facetted approach that combines a range of complementary expertise and innovative techniques. Using novel, high-resolution computer simulations we will (1) identify the physical phenomena that led to the formation of the first and second generations of stars in a systematic and quantitative way, (2) determine their mass distribution, which is the key parameter setting their lifetimes, luminosities, and chemical yields, (3) study the influence of the first stars on their surrounding environment, and (4) by doing so learn more about the subsequent cosmic evolution. We will set up a comprehensive theoretical and computational framework that enables us for the first time to make clear predictions and to compare our results with observational data from the high-redshift Universe as well as from the oldest stellar population in the Milky Way.Habitability of Martian Environments: Exploring the Physiological and Environmental Limits of LifeThe low average temperature and low water activity of the Martian near-surface environment makes it challenging for living organisms to persist and propagate. Nonetheless, recent mission results indicate that environmental conditions exceed locally and temporarily the lower thresholds for life to exist. Furthermore, specific soil minerals, or combinations thereof, appear to provide a suitable habitat for microbial life, especially if associated with low-temperature brines or hygroscopic salts. Thus, a quantitative understanding of the habitability potential of the Martian near-surface environment, past and present, is very much needed and the focus of this proposal. To achieve this objective, we will test different types of soils and some of Earth s hardiest organisms, using them as models ( Marsanalogues ), to see if they can survive and perhaps even grow under the various environmental stresses known to exist on Mars. A major tool of our laboratory investigations will be the experimentally proven state-of-the-art Mars Simulation Chamber at the German AeroSpace Center, to which various soils materials and microorganisms will be exposed. The planned experimental investigations and models will be concurrently updated by analyzed mission data, particularly from landers and rovers (e.g., Curiosity Rover), to adjust our work to the newest Martian geochemical and environmental data available. Results from our proposed work will timely provide critical scientific knowledge to interpret incoming data from ESA s ExoMars mission, which is scheduled for launch in 2016/2018. As one important deliverable of our work we will also construct a Mars Soil Analyzer, an instrument which will be designed for a future mission to Mars with the objective to achieve Technology Readiness Level 6 at the completion of the proposed study.Supernovae: Physics and Cosmology in the Next DecadeExploding stars, or supernovae, impact upon many diverse areas of astrophysics, from galaxy formation, to stellar evolution, to cosmology and studies of dark energy. I am playing a leading role in new, wide-field, high-cadence optical surveys that are revolutionising the study of supernovae, searching vast volumes of space, locating hundreds of events to study their demographics in detail, and uncovering new and bizarre types of explosions. In concert with a major European Southern Observatory public spectroscopic survey, PESSTO, these imaging surveys will provide an extraordinary dataset for understanding all facets of the supernova and explosive transient population. My work will perform several tests of the progenitors and physics of the classical type Ia supernovae in an attempt to understand how these crucial standard candles depend on their progenitor stellar populations. I will use these results to inform a new generation of models of type Ia supernovae. I will t< his distill these results to make a detailed measurement of the dark energy that powers the accelerating universe in which we live, greatly improving upon existing measurements of the variation of dark energy over the last ten billion years. A final aspect of my research is an innovative search for superluminous supernovae: a new class of supernova explosion a hundred times brighter than traditional supernovae, capable of being studied in the very distant universe. These objects may become cosmology's new standard candle, visible far beyond the reach of type Ia supernovae. My new search will significantly increase both the quantity and quality of superluminous supernova observations, allowing us to further our understanding of these enigmatic objects and use them in a cosmological setting for the first time.YDecoding Lights from Exotic WorldsIt is now accepted that exoplanets are ubiquitous. However little is known about those planets we have detected beyond the fact they exist and their location. For a minority, we know their weight, size and orbital parameters. For less than twenty, we have some clues about their atmospheric temperature and composition. How do we progress from here? We are still far from a hypothetical Hertzsprung Russell diagram for planets and we do not even know whether there ever will be such classification for planets. The planetary parameters mass, radius and temperature alone do not explain the diversity revealed by current observations. The chemical composition of these planets is needed to trace back their formation history and evolution, as was the case for the Solar System. Pioneering results were obtained through transit spectroscopy with Hubble, Spitzer and ground-based facilities, enabling the detection of ionic, atomic and molecular species and of the planet s thermal structure. With the arrival of improved or dedicated instruments in the coming decade, planetary science will expand beyond the narrow boundaries of our Solar System to encompass our whole Galaxy. In the next five years, ExoLights will address the following fundamental questions:  Why are exoplanets as they are?  What are the causes for the observed diversity?  Can their formation history be traced back from their current composition and evolution? New spectroscopic observations of a select sample of exoplanets atmospheres (~ 20 out of the 150 observable today) will be analysed with state-of-the art statistical techniques and interpreted through a comprehensive set of spectral retrieval models, developed by the PI and her team. This programme, together with the homogeneous re-analysis of archive observations of a larger sample of exoplanets, will allow us to use the chemical composition as a powerful diagnostic of the history, formation mechanisms and evolution of gaseous and rocky exoplanets.DAn Illumination of the Dark Ages: modeling reionization and interpreting observationsUnderstanding the dawn of the first galaxies and how their light permeated the early Universe is at the very frontier of modern astrophysical cosmology. Generous resources, including ambitions observational programs, are being devoted to studying these epochs of Cosmic Dawn (CD) and Reionization (EoR). In order to interpret these observations, we propose to build on our widely-used, semi-numeric simulation tool, 21cmFAST, and apply it to observations. Using sub-grid, semi-analytic models, we will incorporate additional physical processes governing the evolution of sources and sinks of ionizing photons. The resulting state-of-the-art simulations will be well poised to interpret topical observations of quasar spectra and the cosmic 21cm signal. They would be both physically-motivated and fast, allowing us to rapidly explore astrophysical parameter space. We will statistically quantify the resulting degeneracies and constraints, providing a robust answer to the question, "What can we learn from EoR/CD observations?" As an end goal, these investigations will help us understand when the first generations of galaxies formed, how they drove the EoR, and what are the associated large-scale observational signatures.mSetting the Stage for Solar System FormationLow-mass stars like our Sun are formed in the centers of dark clouds of dust and gas that obscure theirvisible light. Deep observations at infrared and submillimeter wavelengths are uniquely suited to probe the inner regions of these young stellar objects and unravel their structures, as well as the physical and chemical processes involved. These earliest stages are particularly interesting because the properties of the deeply embedded objects reflect the star formation process itself and how it relates to its environment. It is for example during this stage that the final mass of the star and the properties of its disk  and thus ability to form planets  are determined. It is also during these stages that the first seeds for the chemical evolution of the protoplanetary disk<  are planted and where some complex organic, possibly prebiotic, molecules may be formed. I here apply for an ERC Consolidator Grant that will support an ambitious program to map the physics and chemistry of the early Solar System. The proposed research program intends to use new high resolution, high sensitivity observations from the Atacama Large Millimeter Array (ALMA) - including a number of recently approved large programs  coupled to state-of-the-art radiative transfer tools and theoretical simulations to address some of the key questions concerning the physics and chemistry of the earliest stages of the Solar System: How is the chemistry of the earliest protostellar stages related to the physical structure and evolution of the young stellar object and its surrounding environment? Which complex organic molecules are present in the inner regions of low-mass protostars? What are the chances the rich chemistry of the earliest stages is incorporated into planetary systems such as our own?lFulfilling the Potential of Globular Clusters as Tracers of Cosmological Mass AssemblyGlobular clusters (GCs) are among the oldest luminous sources in the universe, bearing witness to theearliest stages of galaxy formation as well as their evolution to the present day. While GCs have played apivotal role in our understanding of the assembly of galaxies, their full potential remains unfulfilled due toour lack of understanding of how they form. One of the largest stumbling blocks has been the anomalouschemistry (both metallicity distributions and abundance patterns) of GCs relative to field stars within galaxy.Here, we will turn the problem around and exploit these differences to understand the co-evolution of GCsand their host galaxies.Our understanding of GCs and their formation has undergone a radical change in the past two decades. First,it is now clear that while traditionally thought of as the quintessential simple stellar populations (i.e., all starswithin a cluster have the same chemical abundances and age), globular clusters host multiple stellarpopulations with spreads in He, many light elements (e.g., Na, O, Al) and even Fe in a few cases. Secondly,GCs, once thought to only be able to form in the special conditions present in the early Universe, are nowknown to be still forming today (known as Young Massive Clusters - YMCS). These two facts have openedup a new window into the interconnectedness of GC and galaxy formation and co-evolution.In this project we will quantitatively test current GC formation models with observations of YMCs, as wellas organise what is known of the stellar populations within GCs (e.g., abundance spreads, CMDmorphologies), providing, for the first time, a global view (i.e., which characteristics are specific toindividual GCs and which are common to all GCs). These results, when combined with what is known aboutmassive cluster formation in the local universe, will provide an unprecedented opportunity to use GCs toconstrain the hierarchical assembly of galaxies.BDo intermediate-mass black holes exist?With this proposed project I will determine whether intermediate-mass black holes (IMBHs) exist. I propose to use ESA's new Gaia mission, the rich Hubble Space Telescope data archive, and state-of-theart techniques to investigate systems predicted to exist but not yet found hitherto, such as recoiled hyper-compact stellar systems, red-supergiant mass donors to ultra-luminous X-ray sources, and white dwarf tidal disruption events. The latter can only be detected if black holes with masses less than 1E5 Msun are involved. Using these systems and events we can probe the sphere of influence of the IMBH and determine the black hole mass dynamically.Currently, there are strong indications for the existence of IMBHs, but dynamical evidence, the irrefutable proof of their existence, is still lacking. Whereas the unequivocal detection of an IMBH will be a breakthrough discovery in itself, it has also important consequences for searches of dark matter annihilation signals, it will provide a baseline for the rate predictions of gravitational wave radiation events involving IMBHs, and the properties of a population of IMBHs provides important constraints on the growth of supermassive black holes and galaxies. Finally, if we discover IMBHs in hyper-compact star clusters it validates numerical relativity simulations that predict that merging black holes receive a recoil kick.My membership of Gaia's Data Processing and Analysis Consortium gives me a distinct advantage in analysing and interpreting Gaia data that, through the superb angular resolution, immediate spectroscopic observations and all-sky coverage, provides unique capabilities ideally suited for answering the question whether IMBHs exist.My proposed project is the first to recognize the potential of Gaia (WP1&2) as well as the implications of having red supergiant mass donors in some ultra-luminous X-ray sources (WP3) for answering the question on the existence of IMBHs.Organizational Industrial OrganizationIndustrial organization has been influential in shaping our understanding of how firms behave in markets, and also Most of the industrial organization literature is based on the premise that firms are represented by a single decision maker, who is driven by a motive of profit maximization and cost minimization. This assumption is nowadays becoming a constraint on IO theory, preventing it from being able to explain certain observed empirical regularities. For instance, it has been well documented that seemingly identical firms often exhibit differing performance or productivity. Under the existing paradigm, this should not occur, since identical firms should choose the same cost-minimizing technology. The goal of this proposal is to develop a new IO theory based on a richer view of the firm, one in which non-trivial conflicts of interest among shareholders, workers, managers and consumers will shape firm boundaries. This "Organizational Industrial Organization'' (OIO) will generate rich new insights for the positive and normative analysis of industries, whether or not firms in these industries have market power. In particular, it will be able to account for heterogeneity in organizations among identical firms, will provide simple explanations for real world examples that would be difficult to understand in the traditional IO setting, but also bring fresh and novel analysis to traditional IO questions like the scale and scope of firms, the dynamics of merger activity, and also to less traditional questions like the roles of the managerial market, finance or corporate governance for industry performance. This proposal details three work packages that the team will develop in priority in this project: - Finance, governanc< e, the managerial market and firm boundaries. - The dynamics of firm boundaries and delegation. - Market power, scale and scopeaInformation Aggregation in ElectionsElections are the foundation for democratic decision making. This research program will examine the effects of biased and privately informed entities election organizers on the ability of elections to aggregate information: Existing theory demonstrates that large electorates can reach correct decisions by aggregating information dispersed among many voters. However, existing theory does not account for the ubiquitous presence of biased organizers who intend to affect the election outcome. Examples of biased organizers may include a CEO holding a shareholder vote, a regional government holding a referendum, and political parties in general elections. This project will develop and analyze new models of voting that account for the effects of biased organizers on information aggregation. One of the examples I consider is an election organizer who can increase voter participation at some cost (e.g., through advertising). Preliminary work suggests that the presence of biased organizers has significant impact. As increasing participation becomes cheap, equilibria exist where the election organizer recruits a large number voters and yet the majority votes almost surely for the organizer s favorite policy. This failure of information aggregation contrasts starkly with existing results for elections in which the number of voters is exogenously large. I will study the effectiveness of institutional safeguards against such manipulation, including supermajority rules, publicity requirements, and the regulation of communication to voters, and I will apply the theory in the context of shareholder voting and corporate control. Thus, this research program has important implications for the design of elections in realistic voting scenarios.GGlobalization, Sports and the Precarity of MasculinityIn the last few decades, the erosion of the social and economic structures that previously provided a straightforward raison d tre to men have transformed, in all societies of the world, masculinity into a problematic category. In the Global South, deepening economic, political and social insecurities have further compounded the fragility of masculinity. Younger men in particular find it increasingly difficult to secure a productive role in local economies, and many in the world s more destitute countries are investing their hopes in the possibility of becoming a successful professional athlete. But athletic talent can only translate into economic productivity in the industrial North, and athletic migrations have become, for large number of boys, young men, families, villages, nations and states in the Global South, the solution for a masculinity under threat, the way out of economic precarity, and the embodiment of millenarian hope. At the same time, athletic bodies are inherently fragile, the sports industry fickle, and the paths of migrant athletes strewn with obstacles, rendering deeply problematic yet unavoidable the dependence of so many individuals on the success of a few. This multi-sited comparative ethnographic project seeks to investigate the migratory dynamics at play between selected developing countries and selected countries in the industrial world in three different sports, soccer-football, rugby union, and cricket. It explores ways in which these three sports represent for young talented hopeful in the Global South various embodiments of hope for the redemption of masculinity and of its productive potentials. The research will open new theoretical avenues for an understanding of the constitution of masculinity in the context of globalisation, changes in the structure of nation-states and the meaning of citizenship, and the constitution of everyday lives in more destitute regions of the world.zRedefining tie strength  how < social media (can) help us to get non-redundant useful information and emotional supportSocial media offer us effortless ways to stay in touch with large numbers of individuals. These individuals can be friends (strong ties), acquaintances (weak ties), or people we barely know (absent ties). Decades of social capital research have shown that strong ties are useful because they provide us with emotional support and weak ties are useful because they provide us with non-redundant useful information, but absent ties do not provide us with any benefits at all. Now, social media challenge these conclusions. Through social media, people connect to absent ties daily, so apparently there are benefits involved. My central question therefore is: To what extent do social media change how, and from whom, we seek and receive informational and emotional support? Social media technologies have changed the frequency and nature of our social connections. Smart phones allow a constant connection with our social network, sometimes even preventing us from socializing face-to-face. Twitter facilitates asymmetric relationships, such that even marginalized individuals can connect to important information sources. Facebook has set a norm where individuals who in the past we would merely have nodded to, are now embedded in our network of  friends . It seems natural to assume that, if the way we maintain our social network changes, the way we extract social capital from that network also changes. To deepen our understanding of the effects of social media use on receiving informational and emotional support, I will employ several methods. By m eans of a large longitudinal study (subproject 1) in a representative sample, I aim to detect causal relationships between social media use at time t and informational and emotional benefits at time t+x. In addition, two subprojects will study in detail the cognitive and affective processes underlying informational (subproject 2) and emotional (subproject 3) benefits of social media use.fThe Discursive Construction of Academic Excellence.Classifying SSH Researchers Through Text-Processing PracticesDISCONEX investigates two types of text-processing practices by means of which academic researchers are classified in different national and disciplinary fields of the social sciences and humanities (SSH). The research project will produce theoretically informed and empirically grounded insights into the social organization of SSH research. Drawing from constructivist social theory and qualitative methods in discourse analysis and pragmatics, the research team investigates the discursive construction of excellence as a practical accomplishment of readers cooperating with texts. In a first step, we collect CVs from confirmed SSH researchers from France, Germany, the UK and the U.S.. Then we carry out reader interviews to investigate how membership is negotiated in specialized knowledge communities of the SSH. In a second step, we investigate non-academic practices of processing large text collections in order to account for how academic producers are ranked by evaluation professionals and calculative technologies. Finally, by comparing representations of excellence produced by academic and nonacademic actors, DISCONEX will show how knowledge producers and ranking experts account for the representations of other types of readers respectively. In the light of the complex interpretive problems involved in the reading and writing of academic texts, we will produce reflexive knowledge on how SSH researchers are classified in the light of new modes of academic knowledge production. Given the important role that written texts play in SSH discourse, the exchange between the sociology of science and discourse analysis can help establish a new field: the social sciences and humanities studies (SSHS).Authoritarianism in a Global Age: Controlling Information and Communication, Association and People MovementThe overarching research question of this project is: how is authoritarian rule affected by and responding to globalisation of (a) information and communication, (b) association, and (c) people movement? The wholly unpredicted series of revolts that recently spread across the Arab world suggests that the nature and sustainability of contemporary authoritarian rule are not wellunderstood. Openness to global ICT and media, international NGOs, and inflow and outflow of people have thrown up new challenges for authoritarian rulers in terms of how to control citizens. This project investigates changes in both the nature and the sustainability of authoritarian rule in relation to the erosion of decision-making autonomy at the state level posited by globalisation theorists. In four subprojects, this project will investigate: 1. Whether, how and to what exte< nt globalisation of information and communication, association, and people movement affect authoritarian persistence (longitudinal quantitative study, 1970-2011) 2. How, i.e. with what policy mechanisms, authoritarian states respond to globalisation of information and communication, association, and people movement (qualitative multi-sited studies relating to Belarus, China, Iran and Zimbabwe) 3. How to understand the phenomenon of subnational authoritarianism in its engagement with the democratic state and the wider world in relation to information and communication, association, and people movement (mixed method subnational studies of states within India and Mexico) 4. What authoritarianism is in a global age: reconsidering authoritarianism s defining characteristics of low accountability and high coercion, and whether these still relate exclusively to statehood (theory study) The project will transcend the theoretical and empirical separation between globalisation studies (which have neglected authoritarian contexts) and authoritarianism studies(which have taken relatively little notice of effects of globalisation)Unilateralism and the protection of global interests: opportunities and limits of the exercise of state jurisdictionIn the 20th century, states have increasingly sought to apply their laws to situations and persons beyond their borders. They typically did so to protect their own interests from harm spilling over their borders. Recently, however, states appear to be giving their laws  extraterritorial application to protect global interests, not only when prosecuting international criminals, but also by enacting emissions trading schemes to tackle global warming, by taking sanctions against foreign vessels involved in illegal fishing on the high seas docking in their port, and by fighting foreign corrupt practices with a view to furthering good governance in developing countries. Thus, it appears that a novel principle of jurisdiction is crystallizing that protects global interests through unilateral application of domestic (or regional) law. It is the aim of this research to study this development in-depth, and to examine in particular whether, and under what circumstances, international law countenances such an exercise of unilateral jurisdiction that is aimed at the protection of global interests. The project consists of two pillars. Pillar 1 studies three cases of states or regional organizations unilaterally applying their own laws to (partly) foreign situations considered as threatening global interests: (a) the exercise of unilateral jurisdiction aimed at mitigating climate change; (b) the exercise of port state jurisdiction aimed at protecting sustainable fishing and biological diversity on the high seas; (c) the exercise of unilateral jurisdiction to tackle foreign corruption practices. Pillar 2 is synthetic in nature, and assesses whether, and to what extent, general rules of jurisdiction and jurisdictional restraint concerning the protection of global interests are developing across various fields, including but not limited to the fields studied in Pillar 1.Prospects for International Migration GovernanceRisk and uncertainty are inherent in any decision-making procedure, but while a substantial body of work on the governance of international migration focuses on challenges posed to governance systems, we know remarkably little about the impact of risk and uncertainty on: (i) the cognitive biases of actors within migration governance systems; (ii) the susceptibility of these biases to change; (iii) the relationship between cognitive bias and broader questions of systemic resilience, vulnerability and adaptation and (iv) the similarities and differences in migration governance between major world regions. Each of these is a significant gap in our<  knowledge of international migration governance. To address this gap this project will focus on the context of decision to ask: what are the causes and consequences of the cognitive biases concerning risk and uncertainty held by actors in migration governance systems? The project will: (i) test the causes and consequences of the  frames held by actors in migration governance systems, specify the scope for these frames to change and to analyse the likely systemic effects of change on migration governance systems in four major world regions. (ii) develop a comparative regional analysis of the micro-political foundations of migration governance and their implications for system adaptation and change. (iii) significantly advance conceptual and methodological understanding of international migration governance through the use of concepts of systemic adaptation, vulnerability and resilience that bridge behavioural theories of choice with theories of institutional and organisational change. (iv) disseminate the results effectively through a range of appropriate outlets and through engagement with a range of users of the results of this work in academia, policy-making communities, NGOs and the wider public.Understanding contemporary interest group politics: mobilization and strategies in multi-layered systemsThis ERC program addresses an unsettled political science problem, namely how does the shifting of policymaking competencies to higher levels of government affect the opportunities of societal interests to seek representation. On this issue two completely different theoretical expectations exist. One the one hand, the Madisonian view entails that shifting competencies upwards is a healthy antidote to the powers of specific interests that may dominate smaller polities. Multi-levelness may also provide political opportunities as it enables actors to make strategic venue shifts when they are unable to attract the necessary attention at one venue. On the other hand, shifting policymaking upwards may seriously restrict the opportunities for diffuse interests, undermine encompassing forms of interest representation, and increase the barriers for local groups to gain attention. Instead of creating opportunities for all, multi-layered systems may decrease opportunities and reproduce or reinforce representational bias. One of the reasons why the implications of multi-layeredness are so poorly understood is the fact that political science has not developed a proper understanding of what representational bias means; some scholars see bias in terms of mobilization, while others conceive it in terms of the strategic interactions between organized interests and policymakers. This ERC program will integrate theoretically, methodologically and empirically these different aspects of group politics, by taking explicitly into account the nature of multi-layered systems. The innovative character of it lies in the theoretical combination of mapping interest group community dynamics, with a more nuanced characterization of organizational form and an in-depth investigation of bias in terms of strategies.Eradication: the science and politics of a world without AIDSNew biomedical technologies and public health strategies are being tested world-wide with the goal of eradicating the HIV epidemic. Achieving a world without AIDS has become the flagship of the vast global health apparatus, rallying governments, international organisations, philanthropic and pharmaceutical capital, research networks and activists. Mass screening and treatment, preventive drugs and gels, and molecular maps of sexual networks have shifted the biomedical paradigm from one of control to one of eradication. The biopolitical armamentarium of the push to eradicate may inadvertently enable unexpected biological, cultural, social and political transformations. Mass treatment and preventive drugs require very high levels of compliance to achieve the desired public health effects, foreshadowing the coercive potential of eradication efforts. Intensified mapping of  most at-risk populations marks a shift from the existing emphasis on rights and empowerment to one of surveillance and discipline. As these approaches remain unproven, eradication constitutes a global public health experiment of unprecedented proportions, whose outcomes will shape gl      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqstuvwxyz{|}~obal health efforts for decades to come. Eradication efforts to rid the world of HIV are attempts to order nature as revealed through a global epidemic, putting them squarely at the centre of anthropological concern. The two overarching questions are: what will HIV eradication efforts achieve? What are the reasons for the outcome, be it partial success or partial failure? To answer these questions, a multi-sited ethnography will be conducted in Africa, Europe and North America of the science < and politics of HIV eradication. It will focus on the testing, preparation, and implementation of the three key technologies of HIV eradication: universal testing and mass treatment, molecular mapping of sexual and social networks.FThe Vitality of Disease - Quality of Life in the MakingEpidemiological reports from around the world suggest that more people than ever before are living with (especially chronic) diseases. As a consequence, sustained efforts to reduce morbidity and mortality rates have been joined by systematised efforts to improve the lives  the quality of life  of those living with disease in ways that are measurable and auditable.VITAL will focus on the making of  quality of life . While social studies of medicine have of late been marked by a  bio -turn , it is apparent that within contemporary medicine, life is envisaged as much more than cellular and molecular activity; it is also a social activity and a personal experience. Not only is life sustained, it is also lived. In recent decades, morbid living  living with disease  has come to be the object of novel forms of knowledge, expertise, measurement and management while also generating new medical practices and attendant ways of relating to oneself.VITAL suggests a shift in attention from the ways in which the social sciences have previously studied morbid living and related issues of quality of life. Rather than continue longstanding efforts to understand how people cope with disease or to refine definitions and instruments for measuring the quality of life of the sick, in VITAL we will empirically study the co production of  quality of life within healthcare through four ethnographically-grounded studies of how  quality of life is assembled, mobilised, negotiated and practiced in concrete medical settings. The four studies will focus on how knowledge about living with disease is assembled and mobilised, on the one hand, and how morbid living is negotiated and practiced on the other.The key outcomes of VITAL will be theoretical advancement of understandings of vitality in the 21st century beyond molecular biology and methodological innovation to facilitate empirical study of co-production processes that involve social science knowledge and practice.Toxic Expertise: Environmental Justice and the Global Petrochemical IndustryThis research project critically examines  toxic expertise , the contested politics of making scientific claims about the health impacts of toxic pollution. Toxic expertise has a double meaning: scientific expertise about the effects of toxic pollution, and the toxic nature of expertise that is used to justify a lack of corporate social responsibility. The research focuses on the global petrochemical industry as a significant but controversial source of toxic pollution, with unequal regulations and risks across different countries and populations. Debates about the global petrochemical industry reflect conflicting interests between jobs, prosperity, and health. This research contributes to interdisciplinary social scientific research on science and technology, environmental justice movements, and the uneven geography of capitalism. In particular, it develops sociological arguments that scientific  expertise is inherently political and socially constructed. This mixed method comparative research will be conducted in three stages. The first stage will examine toxic expertise in the leading global petrochemical companies and environmental non-governmental organisations in Western Europe, North America, and China. The second stage will focus on in-depth case studies in the United States and China, two of the top petrochemical producers in the world. The third stage will develop an international public resource of toxic expertise to address practical challenges of capacity and scale inherent within both dominant and citizen-led epidemiology, by developing accessible information and tools for understanding, monitoring, and reporting < toxic pollutants and their health impacts. The project offers the first systematic sociological analysis of the global petrochemical industry in relation to environmental justice, responding to calls within critical social science for the democratisation of science which highlight the need for greater accountability and transparency.Becoming Men: Performing responsible masculinities in contemporary urban AfricaThis anthropological study examines the reconfiguration of masculinities in urban Africa over the last 30 years. Focusing on how practices and discourses of empowerment and equality shape male subjectivities, this study builds upon a significant body of nuanced research on masculinities in Africa. Since the mid-1980s academic and public discourses have depicted African masculinity as both precarious and predatory. Economic insecurity, urbanization, shifting gender norms, and growing gender parity have accompanied claims that African masculinity is  in crisis . More recently, new stories of urban men embracing responsible fatherhood, condemning intimate partner violence, and demanding homosexual rights have emerged as exemplars of progressive possibility. To disentangle these seemingly competing claims about African masculinities and shed light on the scientific, political, and economic projects that shape them, this research theorises that the discourses and practices that pathologise and politicise masculinity are simultaneously performing and producing gendered selves on multiple scales in the name of gender equality. Recently,  male involvement has become a rallying cry throughout the vast global development assemblage, around which governments, NGOs, research networks, activists, and local communities fight gender inequality to promote health, economic development, and human rights. In this research, a range of male-involvement initiatives provides a lens through which to study how masculinities are diversely imagined, (re)configured, and performed through men s engagements with this assemblage, in both its local and global manifestations. Multisited ethnographic research will focus on six cities where the PI has active research ties: Nairobi and Kisumu, Kenya; Johannesburg and Durban, South Africa; and Dar es Salaam and Mwanza, Tanzania.No Sword Bites So Fiercly as an Evil Tongue?Gossip Wrecks Reputation, but Enhances CooperationSocial norms in general, and norms of cooperation in particular, are the cement of all human societies. For the difficult problems of the maintenance and enforcement of social norms and of cooperation, humans have developed surprisingly complex solutions. Reputation mechanisms and gossip are certainly among the compound informal solutions. According to common wisdom, gossip channels mainly negative and often fictitious information. If it is so, how can dishonest gossip and the resulting biased reputations legitimize social order and promote cooperation? This is the main puzzle we tackle in the proposed project exploiting a wide scale of instruments. We use analytical modeling and agent based simulation to derive hypotheses. We test simple hypotheses in small group experiments. We develop new methodological tools to appropriately analyze the triadic nature of gossip embedded in network flows of information. We utilize dynamic network datasets from primary and secondary school classes, and we gather qualitative and quantitative information from organizations to test conditional hypotheses about the role that gossip plays in reputation and cooperation in different developmental and social contexts of life. In addition, we apply new communication technologies currently under development to explore the hidden world of gossip and the dynamics of reputations in dormitories and organizations. With the insights gained, we can overcome common stereotypes about gossip and highlight how gossip is related to credible reputational signals, cooperation, and social order. Expected results will help us to outline the conditions that can promote cooperativeness in work groups, and they will help to construct successful prevention strategies of social exclusion and other potentially harmful consequences of the evil tongue.The role of consumer behavior and heterogeneity in the integrated assessment of energy andclimate policiesThe objective of this project is to quantify the role of consumers behaviour on the design and assessment of policies aimed at enhancing energy efficiency and conservation and at promoting climate change mitigation. The project brings together different disciplines  namely energy policy, environmental and ecological economics, behavioral public finance, experimental economics, and technology policy- in an integrated fashion. COBHAM is designed to go beyond the standard analysis of energy and climate policies in the presence of environmental externalities, by accounting for the heterogeneity in consumers preferences, the role of social interactions, and the presence of behavioral tendenc< ies and biases. The project seeks to: i) carry out innovative research in the theoretical understanding of the interplay between behavioral tendencies and environmental externalities; ii) generate new empirical data and research on individual preferences by means of original surveys and controlled experiments; iii) enhance integrated assessment models (IAMs) of economy, energy and climate with an advanced representation of consumers behavior. In doing so, the project will be able to provide a richer characterization of energy demand and of greenhouse gas emission scenarios, to better estimate consumers responsiveness to energy and climate policies, and to provide input to the design of new policy instruments aimed at influencing energy and environmental sustainable behavior. COBHAM is of high public policy relevance given Europe s legislation on energy efficiency and CO2 emissions, and can provide important insights also outside the sphere of energy and climate policymaking.NEXT-GENERATION BUILDING INFORMATION MODELING TO SUPPORT EVALUATION OF HUMAN BEHAVIOR IN BUILT ENVIRONMENTSThis proposal argues that current building modeling tools, including popular BIM (Building Information Modeling) systems, provide a poor, inadequate representation of buildings: they represent only the physical and material characteristics of buildings. Buildings, unlike other products, cannot be understood independently of their context, of their intended use, and of their intended users. This shortcoming hinders the ability of current building models to support evaluations other than those based on physical and material characteristics of the building, such as lighting, energy consumption, and structural stability. In particular, the impact of a building that has not yet been built on the life and activities of its future users a key element in determining whether or not the proposed building will meet the needs of its intended users is not afforded by current building models. To afford comprehensive prediction and evaluation of future buildings, we also need to model the purpose and function of the building, and the social, cultural, and economic profile of the people who will use it. Although predicting users' behavior in a built environment and their interaction with the building and with other people is a highly complex task, vast research exists that is devoted to analyzing and explaining human behavior in built environments. Still, due to the shortcomings of building models, this knowledge rarely make into the practice of architectural design, at the time buildings are being designed. The proposed research aims at remedying that shortcoming by developing a more a comprehensive building modeling method, which will include form, function, and use information. A better model will lead to better designed buildings. In an era when the irrevocable impact of the built environment on the cost, quality, and perhaps even possibility of life on earth has been recognized, the need to make every effort to improve the tools used by building designers is self-evident.Socio-spatial inequality, deprived neighbourhoods, and neighbourhood effectsThe objective of DEPRIVEDHOODS is to come to a better understanding of the relationship between socio-economic inequality, poverty and neighbourhoods. The spatial concentration of poverty within cities is of great concern to national governments, partly based on a belief in neighbourhood effects: the idea that living in deprived neighbourhoods has an additional negative effect on residents life chances over and above the effect of their own characteristics. This belief has contributed to the development of area-based policies designed to introduce a more  favourable socio-economic mix in deprived neighbourhoods. Despite the persistent belief in neighbourhood effects, there is surprisingly little evidence that living < in deprived neighbourhoods really affects individual lives. There is little consensus on the importance of neighbourhood effects, the underlying causal mechanisms, the conditions under which they are important and the most effective policy responses. It is likely that most studies claiming to have found that poor neighbourhoods make people poor(er) only show that poor people live in poor neighbourhoods because they cannot afford to live elsewhere. DEPRIVEDHOODS will break new ground by simultaneously studying neighbourhood sorting over the life course, neighbourhood change, and neighbourhood effects, within one theoretical and analytical framework. This project will be methodologically challenging and will be the first integrated, multicountry research project on neighbourhood effects to use unique geo-referenced longitudinal data from Sweden, United Kingdom, Estonia, and The Netherlands. Special attention will be paid to the operationalization of neighbourhoods and how it affects modelling outcomes. Through its integrated and international approach, DEPRIVEDHOODS will fundamentally advance understandings of the ways in which individual outcomes interact with the neighbourhood, which will ultimately lead to more targeted and effective policy measures.WEnergy and emissions thresholds for providing decent living standards to allThere is confusion surrounding how poverty eradication will contribute to climate change. This is due to knowledge gaps related to the material basis of poverty, and the relationship between energy and human development. Addressing this issue rigorously requires bridging gaps between global justice, economics, energy systems analysis, and industrial ecology, and applying this knowledge to projections of anthropogenic greenhouse gases. This project will develop a body of knowledge that quantifies the energy needs and related climate change impacts for providing decent living standards to all. The research will address three questions: which goods and services, and with what characteristics, constitute  decent living standards ? What energy resources are required to provide these goods and services in different countries, and what impact will this energy use have on climate change? How do the constituents of decent living and their energy needs evolve as countries develop? The first task will operationalize basic needs views of human development and advance their empirical validity by discerning characteristics of basic goods in household consumption patterns. The second will quantify the energy needs (and climate-related emissions) for decent living constituents and reveal their dependence on culture, climate, technology, and other contextual conditions in countries. This will be done using lifecycle analysis and input-output analysis, and mapping energy to climate change using state-of-the-art energy-economy integrated assessment modelling tools for 5 emerging economies that face the challenges of eradicating poverty and mitigating climate change. The third task will shed light on path dependencies and trends in the evolution of basic goods and their energy intensity using empirical analysis. This research will identify opportunities to shift developing societies towards lowcarbon pathways, and help quantify burden-sharing arrangements for climate mitigation.BEqualizing or disequalizing? Opposing socio-demographic determinants of the spatial distribution of welfare.This project aims to investigate the extent to which current trends in family formation, living arrangements and gender-specific education levels are related to the spatial distribution of welfare and the emergence of jobless households in contemporary societies. Inter alia, we aim to explore whether the welfare disequalizing, impoverishing and polarizing effects that are currently associated with recent patterns in assortative mating, lone parenthood and household composition are offset by an unprecedented phenomenon that is sweeping the world during the last decades: the rapid process education expansion in tandem with a reversal of the gender gap in education. The extent to which these two opposing forces occur and which of them is more influential in shaping the distribution of welfare between and within countries is among the main goals of this project. To this end, we will draw upon a variety of household surveys and the world largest sources of census microdata: the Integrated Public Use Microdata Series (IPUMS) project and the Latin American and Caribbean Demographic Centre. Because of their unparalleled geographical coverage and detail, these sources of data constitute exceptional instruments to study socio-demographic phenomena that have been vastly underutilized by the international research community. Triangulating our analysis at the micro, meso and macro levels, we will establish formal linkages between welfare distributions and its sociodemographic correlates to unveil insightful relationships that have been unsatisfactorily explored so far because of the lack of appropriately harmonized, sufficiently detailed and georeferenced datasets. We will strongly emphasize the spatial distribution of variables to unravel local patterns that might take place at highly disaggregated levels, therefore not being discernible to traditional (not as finelygrained) approaches.Reshaping society and space: home-based self-employment and businessesThe aim of WORKANDHOME is to develop a new framework for understanding fundamental changes currently taking place to work that situates individuals as economic actors within the context of their wider life domains, household, home and neighbourhood. This will break new ground in how we understand and classify economic activity, the home, the firm, places of econom< ic activity, labour markets and  residential neighbourhoods. Significant and rising numbers of people work from home as a self-employed worker or business owner throughout Europe. This will be the first study that explores social, economic and spatial aspects of homeworking by self-employed workers and business owners including the role of new technologies and social media in dissolving the home -work boundary. This is an important new area for social science research since home-based self-employment and businesses vividly manifest the interconnection of  home and  work and of the  economic and the  social as part of an increasingly complex society. WORKANDHOME will integrate theoretical perspectives from economic geography, entrepreneurship and small business research, sociology, economics, housing and neighbourhood studies. In order to investigate new realities of how people work and live, this study will integrate analytical methods across the social sciences and computer sciences and create a new fusion of primary, secondary and  big social media data from the UK, the Netherlands, Germany, Europe and the world. WORKANDHOME offers a major step forward in understanding how people live, work, do business and shape space. Its integrated and international approach will stimulate considerable interdisciplinary exchange across disciplines in the social sciences for better understanding and tackling contemporary societal and economic changes and challenges.A MULTILEVEL ANALYSIS ON THE EFFECTS OF STRESS ON BIOLOGY, EMOTIONS AND BEHAVIOUR THROUGHOUT CHILDHOODThe overall objective of the proposed research is to improve our understanding of the interplay between biological, environmental, and social factors that influence the development of harmful behaviours in adolescents. We propose to conduct the first multilevel cohort study of its kind that would combine biological, behavioural, and social data from before birth through adolescence for an entire population birth cohort of adolescents. The program is based in Iceland due to a unique infrastructure for the collection of health and social registry data as well as available access to a whole cohort of adolescents. We will extend our previous work using a multilevel developmental framework to identify both individual and collective level variables to study the independent and interactive effects of biological, environmental, and social determinants of adolescent harmful behaviours, with special emphasis on the influence of stress on substance use, self-inflicted harm, suicidal behaviour, and delinquency. Our retrospective longitudinal database will include existing registry information on maternal, child, and environmental determinants of adolescent harmful behaviours, measured prior to birth, at the time of birth, and during the infant, toddler, preschool, middle-childhood and early adolescent years, for the entire 2000 year birth cohort. We will prospectively measure biomarkers in human saliva and use an existing social survey infrastructure to add to the registry database. We have acquired all necessary ethical and organizational permissions and have carried out a preliminary study that shows registry data compliance of over 90% for all variables we intend to combine. This is a fundamental research project, examining unchartered territory. The results of this project will stimulate international research but more importantly, an understanding that will lead to better policies, planning and quality of life for young people in Europe and beyond. The Adaptive Auditory MindListening in realistic situations is an active process that engages perceptual and cognitive faculties, endowing speech with meaning, music with joy, and environmental sounds with emotion. Through hearing, humans and other animals navigate complex acoustic scenes, separate sound mixtures, and assess their behavioral relevance. These remarkable feats are currently beyond our understanding and exceed the capabilities of the most sophisticated audio engineering systems. The goal of the proposed research is to investigate experimentally a novel view of hearing, where active hearing emerges from a deep interplay between adaptive sensory processes and goal-directed cognition. Specifically, we shall explore the postulate that versatile perception is mediated by rapid-plasticity at the neuronal level. At the conjunction of sensory and cognitive processing, rapid-plasticity pervades all levels of auditory system, from the cochlea up to the auditory and prefrontal cortices. Exploiting fundamental statistical regularities of acoustics, it is what allows humans and other animal to deal so successfully with natural acoustic scenes where artificial systems fail. The project builds on the internationally recognized leadership of the PI in the fields of physiology and computational modeling, combined with the expertise of the Co-Investigator in psychophysics. Building on these highly complementary fields and several technical innovations, we hope to promote a novel view of auditory perception and cognition. We aim also to contribute significantly to translational research in the domain of signal processing for clinical hearing aids, given that many current limitations are not technological but rather conceptual. The project will finally result in the creation of laboratory facilities and an intellectual network unique in France and rare in all of Europe, combining cognitive, neural, and computational approaches to auditory neuroscience._Fitting The World to Minds: Brain Basis of Sharing and Transmitting Representations of the Social WorldUnderstanding other peoples minds is one of the most fundamental human skills but also the most demanding challenge our brains pose every day: To understand each other, we need to share neural representations of the external world across brains. Studying how social information is represented similarly across ind< ividual brains and how it flows from brain to brain poses huge conceptual and technical challenges for neuroscientists, who have consequently resorted to experiments using simplistic and impoverished social stimuli. However, recent advances in brain signal analysis enable us to study the brain basis of social interaction under naturalistic settings with unparalleled accuracy. This neuroimaging project aims to bridge the gap between social psychology and cognitive neuroscience by building a comprehensive neurocognitive model of how individuals maintain and communicate shared neural representations of the dynamic social world. The framework relies on testing the assumption that similarities in sensory and higher-order processing across individuals can be quantified by measuring temporal synchronization of their brain activity. We use novel signal analysis methods, experimental techniques and rapid magnetic resonance image acquisition for testing i) whether selective synchronization of brain circuits during social interaction supports interpersonal understanding, ii) whether similarities in cognitive task sets across individuals are associated with increasingly synchronous brain activity, and iii) whether intense emotional experiences enhance synchronization of brain responses and flow of information from brain to brain. The results will significantly improve our understanding of the brain dynamics of social interaction, and the proposed naturalistic neuroscience approach and will potentially contribute to a significant paradigm shift in social and cognitive neuroscience.Understanding Mechanisms of Human Social Interaction using Interactive AvatarsHuman social interaction depends on non-verbal unconscious behaviour as much as on verbal signals. Mimicry (unconscious copying of actions) is a good example of a social behaviour which is caused by and has consequences for our evaluation of others. However, studying mimicry with traditional methods is hard because of the trade-off between good experimental control and realistic social interaction. INTERACT will (1) establish a new approach to the science of mimicry, bringing together methods from social psychology, cognitive neuroscience and computer science, and (2) use this approach to understand the information processing mechanisms underlying mimicry of hand actions. First, we will develop interactive avatars which can mimic a participant s hand actions or be mimicked by the participant in the context of a simple drum rhythm task. Using computer-generated avatars allows us to precisely control and measure movement timing and structure during mimicry, and to record how participants interact with avatars with different socially-relevant features (age / attractiveness or even aliens). Thus, the INTERACT system will enable high-resolution, well-controlled studies of how people detect and control mimicry. Second, we will use the interactive avatars to examine mimicry in unprecedented detail, studying how the timing and structure of an action and form of the avatar impact on the control and detection of mimicry in typical adults. Building on this, we will define the brain mechanisms of mimicry and why mimicry might go wrong in adults with autism spectrum condition. The results will test current hypotheses of mimicry and will reveal the information processing mechanisms underlying human mimicry and its relationship to other social processes. Completion of the project will benefit research and practice in social neuroscience, developmental and educational psychology, computer science and robotics, and all researchers interested in human social behaviour.Restriction and Obviation in Scalar Expressions: the semantics and pragmatics of range markers across and throughout languagesMost languages have a fairly well developed system of words for numbers, called numerals. It is crosslinguistically common, moreover, for languages to have a very rich paradigm of modifiers of such numerals. For instance, English allows the numeral "fifty" to be modified by comparatives ("more than 50"), (adverbial) superlatives ("at least 50"), equatives ("as many as 50"), locative prepositions ("over 50"), directional prepositions ("up to 50"), disjunctions ("50 or more") and adverbs ("exactly 50"). As illustrated by the set of English modifiers, typically, such paradigms do not consist of specialised vocabulary but instead consist of expressions 'borrowed' from other areas of the grammar. This project sets out to use the rich vocabulary of modified numerals to make advances in semantics and pragmatics. In particular, we will look at a subset of modifiers that have restrictions on their use, restrictions that may be obviated in specific contexts. This subset contains e.g. adverbial superlatives and directional prepositions. Accordingly, there is a semantic connection between superlativity and spatial expression that needs to be explored. More importantly, however, the found connections will clarify the nature of numerical, and more generally scalar, quantification. This is very welcome, since there is a surprising lack of insight in how we use numerical expressions to communicate quantitative information. In particular, there is no consensus as to what semantic and pragmatic processes govern the relatively simple meanings conveyed by sentences containing numerals and similarly scalar expressions. What is needed right now to break through this standstill are projects that aim at uncovering hitherto unexplored connections within language. Significant theoretical progress moreover relies on access to large bodies of new and reliable data. To this end, the project includes i< ndepth cross-linguistic and experimental studies.}In control of exciton and charge dynamics in molecular crystalsThe aim of the work proposed here is to achieve control over charge and excited state dynamics in organic crystalline materials and in this way to come to solid state materials with explicit built-in functionality. The charge and excited state dynamics do not only depend on the properties of individual molecules but are to a large extent determined by the interactions between multiple molecules. By careful engineering of the properties of individual molecules and of the way they aggregate in the solid crystalline state it is in principle possible to design materials that exhibit a specific functionality. Examples of this are materials that are optimized to give high charge carrier mobilities and high exciton diffusion coefficients. It is also possible to design more complex functionality. An example of this is singlet exciton fission, a process by which one singlet excited state transforms into a combination of two triplet states. This spin-allowed process can in principle increase the efficiency of organic solar cells by a factor 1.5. A second example is upconversion of low energy photons into higher energy photons. This is possible by combining two low-energy triplet excited states into a single singlet excited state by triplet-triplet annihilation. Finally, it is possible gain control over charge separation on the interface of two different materials to increase the charge separation efficiency in photovoltaic cells. In this work, we will explore ways to achieve control of charge and exciton dynamics in a combined effort including organic synthesis, computational chemistry and time-resolved spectroscopy and conductivity experiments. This research represents a major step forward in the understanding of the relation between molecular and solid state structure and the electronic properties of organic crystalline materials. This is of considerable fundamental interest but also has direct implications for the utilization of these materials in electronic devices.7Parsing low-resource languages and domainsThere are noticeable asymmetries in availability of high-quality natural language processing (NLP). We can adequately summarize English newspapers and translate them into Korean, but we cannot translate Korean newspaper articles into English, and summarizing micro-blogs is much more difficult than summarizing newspaper articles. This is a fundamental problem for modern societies, their development and democracy, as well as perhaps the most important research problem in NLP right now. Most NLP technologies rely on highly accurate syntactic parsing. Reliable parsing models can be induced from large collections of manually annotated data, but such collections are typically limited to sampled newswire in major languages. Highly accurate parsing is therefore not available for other languages and other domains. The NLP community is well aware of this problem, but unsupervised techniques that do not rely on manually annotated data cannot be used for real-world applications, where highly accurate parsing is needed, and sample bias correction methods that automatically correct the bias in newswire when parsing, say, micro-blogs, do not yet lead to robust improvements across the board. The objective of this project is to develop new learning methods for parsing natural language for which no unbiased labeled data exists. In order to do so, we need to fundamentally rethink the unsupervised parsing problem, including how we evaluate unsupervised parsers, but we also need to supplement unsupervised learning techniques with robust methods for automatically correcting sample selection biases in related data. Such methods will be applicable to both crossdomain and cross-language syntactic parsing and will pave the way toward robust and scalable NLP. The societal impact of robust and scalable NLP is unforeseeable and comparable to how efficient information retrieval techniques have revolutionized modern societies.>What you get is what you see: How Reward Determines PerceptionThe expectation of a reward is known to be the driving force behind adaptive behaviour and learning. The effects of reward arise in dopaminergic reward circuitry at the centre of our primitive brain, which guides our goal-directed behaviour and fosters motivational control. A lot is known about the motivational effect of reward, but its effect on attention and perception has only marginally been explored. Recent studies from my lab suggest that such an effect of reward on perception is substantial and, crucially, arises instantly and is not related to a person s motivation or strategy. Rewarding experiences change our brain: objects associated with reward appear to be more strongly represented in the visual cortex. This makes these objects to stand out from the environment. It makes that we perceive them, and focus on them, even when we try to ignore these objects. The research plan presented here will examine the neural response in early visual brain areas to objects associated with high versus low reward. We will measure the response of the brain, specifically the dopaminergic reward circuitry, when a reward is delivered. To investigate how these effects depend on dopamine, we plan to conduct studies involving Parkinson s patients which allow us to directly manipulate the amount of dopamine in the brain. By means of deep brain stimulation, we link the effect even more tightly to the reward circuitry, by replacing reward by stimulation of this circuitry. As a final frontier we will relate individual reward sensitivity (a personality trait related to the mesolimbic dopamine system) to the development of addiction and risk seeking behaviour. The proposed research will have tremendous impact on the study of cognition, education, and (risky) dec< ision making, as well as on a variety of clinical syndromes in which both attention and reward have been critically implicated, such as (drug) addiction and obesity.BHuman Volition, Agency and ResponsibilityAt the heart of human nature lies the idea of a free agent, whose conscious thoughts and decisions motivate their voluntary actions, and who is therefore responsible for what they do. Voluntary actions can be defined as actions that an individual agent generates internally, rather than in response to any environmental event. However, the concept of voluntary action remains controversial, and lacks a scientific evidence base. Neuroscience rejects dualistic notions of  conscious free will , and instead views actions as products of mechanistic brain processes, which are often unconscious. Thus, volition is often eliminated from psychology, or replaced with alternative, more behaviourist formulations such as  executive function , or  reward-directed action . However, the generative quality of human action, and the strong subjective experience of agency and responsibility for one s own actions, still require scientific investigation. Even if we may not have conscious free will as envisaged, cognitive neuroscience has acquired appropriate methods to investigate and measure what we do have, and to explore implications for society. HUMVOL therefore aims to investigate scientifically the neural bases of human volition (Work Package WP1), agency (WP2) and responsibility (WP3). Subjective aspects are not neglected, because they may offer powerful cues to the mechanisms and functions of voluntary action. The core methods are behavioural, psychophysical and neural experiments with healthy volunteers. EEG and fMRI will allow direct measures of brain processes associated with volition, while subliminal priming and non-invasive brain stimulation will allow their direct manipulation. Mental chronometry and explicit agency judgements allow the impact of these processes on subjective experience to be assessed. Finally, interdisciplinary engagements will focus on how neuroscientific evidence could influence societal concepts of voluntary action, particularly in the Law.A Process Ontology for Contemporary BiologyThis project aims, first, to rethink central issues in the philosophy of biology by elaborating an ontology for biology that takes full account of the processual nature of living systems as an interacting hierarchy of processes at diverse spatial and temporal scales. The concept of a stable biological thing will be analysed as a stabilised process relative to an appropriate time scale, and this conception should make possible a better understanding of familiar biological pluralisms (about genes, organisms, species, etc& ) in terms of different ways in which distinct scientific practices intersect with biological processes. Second, the concept of process developed will be used to rethink some further highly topical philosophical issues in contemporary philosophy of science. The processual perspective will be deployed to provide a critique of the widely discussed recent versions of mechanism. The project will explore generally the relevance of this perspective to influential contemporary accounts of causation and explanation, especially those that have been derived from mechanism. Finally the project will apply the preceding ideas  to some important areas of contemporary biology: systems biology, synthetic biology, and microbiology. These investigations will be carried on in parallel with the more general philosophical enquiries, with the idea that the two will be mutually informative: the philosophical analyses will not only be applied to scientific concepts, but will also themselves be evaluated for their relevance to real cutting edge biology. This evaluation will be guided by interaction with scientific practitioners and an expert Advisory Board, as well as text-based study. The project aims to be of direct relevance t< o both philosophy and science.The plasticity of parental caregiving: characterizing the brain mechanisms underlying normal and disrupted development of parentingThe survival of species depends critically on infant survival and development. Human infants are, however, vulnerable and completely dependent on caregiving parents, not just for survival but also for their development. Darwin and Lorenz have long argued that there are specific infant facial features that elicit attention and responsiveness in adults. Until recently this has not been possible to study but neuroimaging has started to reveal some of the brain circuitry. However, it is not known how the brain changes over time in new parents as they gain experience with caregiving. Equally, little is known about the underlying brain mechanisms associated with disruption to normal parental caregiving. I propose to study the brain changes associated with normal and disrupted development of parental caregiving in new parents who will undergo neuroimaging and psychological testing using standardised databases and test batteries of caregiving tasks. Subproject 1 will investigate the normal development of parental caregiving, beginning before pregnancy, using a longitudinal study of structural and functional brain changes in both women and men combined with their behavioural measures on caregiving tasks. Subproject 2 will investigate the disrupted development of parental caregiving using a cross-sectional design to study the brain and behavioural effects on caregiving during potential disruptive changes to the parent or child. Specifically, my focus will be on A) parental sleep disruption and B) infant craniofacial abnormality of cleft lip and palate. Finally, understanding the full brain mechanisms and architecture underlying parental caregiving requires a mechanistic synthesis of the findings of normal and disrupted development. Subproject 3 will use our existing advanced computational models to combine the findings from normal and disrupted development in order to identify the fundamental brain mechanisms and networks underlying the development of parenting.Empowering expectations for health and disease: training the immune and endocrine systemExpectations about health and disease induce immune and endocrine responses and directly affect health and treatment outcomes. However, there is an urge to understand the mechanical underpinnings how expectations affect immune and endocrine responses and how this knowledge can be used for therapeutic interventions. My research group studies the main expectancy learning mechanisms for itch and pain as a generic expectancy model across symptoms and conditions. We recently showed that dual expectancy learning processes (i.e. conditioning and suggestions) are most powerful for itch symptoms, corresponding with findings for other symptoms and conditions. Based on these studies, I propose a groundbreaking dual expectancy learning approach, testing whether combined expectancy learning processes (i.e. both conditioning and suggestions, offered with personalized cues and exposure to relevant stressors) affect most profoundly the immune and endocrine system, in turn affecting health and disease outcomes. The major aim is to unravel the central mechanisms of how peoples expectations affect immune and endocrine responses and related health outcomes, through the use of pioneering multidisciplinary methods in healthy and clinical populations. First, we systematically train immune and endocrine responses and relate them to psychological, neurobiological and genetic mechanisms. Second, we test these manipulations for physical health challenges (e.g. inflammatory or allergic histamine reactions) in healthy subjects and patients. Third, we study the long-term effects in chronic inflammatory itch and pain conditions (e.g. replacing anti-inflammatory pharmacotherapies, reducing side effects). This interdisciplinary, crossboundary project progresses key theoretical knowledge of the central expectation mechanisms for immune and endocrine responses. Findings open new horizons for health prevention and therapeutic interventions for various inflammatory conditions and physical symptoms.Motivating Motor Learning: The Role of Reward, Punishment and DopamineMotor learning (the ability of the brain to learn and update how an action is executed) is a fundamental process which influences many aspects of our lives such as learning to walk during childhood; the dayto-day behavioural adjustments required as an adult or in healthy ageing; and the rehabilitation process following an illness or injury. Despite the impact to society, it has proved extremely difficult to develop interventions that significantly enhance human motor learning. Therefore, devising protocols which optimise motor learning is a state-of-the-art research question that promises to deliver scientific, clinical and societal impact.Seeking reward and avoiding punishment are powerful factors in motivating humans to alter behaviour during cognition-based learning (selecting which action to perform), with sensitivity to reward and punishment being biased by the availability of dopamine in the brain. Intriguingly, reward and punishment are also known to affect generic motor learning (deciding how an action is executed) tasks which involve multiple underlying mechanisms. However to establish their potential for optimizing motor learning, we must understand how explicit reward- and punishment-based motivational feedback impact motor learning systems with unique computational and anato< mical features (use-dependent/model-free/model-based). Using an unprecedented combination of behavioural analysis, computational modelling, genetics and pharmacology, MotMotLearn will provide the first systems-based account of how reward, punishment and dopamine influence motor learning. This novel approach will enable MotMotLearn to develop theoretically grounded protocols that utilise reward/punishment in conjunction with dopaminergic medication to optimise motor learning in healthy individuals and stroke patients suffering motor impairments. MotMotLearn will have a profound scientific impact in motor learning with applications to development, ageing, rehabilitation and sports.At the roots of corruption: a behavioral ethics approachFor many years, human cooperation has been praised as beneficial in organizational and personal settings. Indeed, cooperation allows people to develop trust, build meaningful relationships, achieve mutually beneficial outcomes, and strengthen bonding with one's group members. However, while the benefits of cooperation are clear, very little is known about its possible negative aspects. Such negative aspects include the potential emergence of unethical conduct among cooperating partners, or as termed here  corrupt collaboration. Such joint unethical efforts, benefiting (directly or indirectly) one or more of the involved parties, occur in business, sports, and even academia. Corrupt collaboration emerges when one party bends ethical rules (here: lie) to set the stage for another party to further bend ethical rules and get the job done, that is, secure personal profit based on joint unethical acts. We propose that corrupt collaborations most commonly occur when all involved parties gain from the corrupt behavior. The current proposal is aimed at unfolding the roots and nature of corrupt collaborations; their existence, the psychological and biological processes underlying them, and the settings most likely to make corrupt collaboration emerge and spread. Accordingly, the information gathered in the current proposal has the potential to change the commonly held conceptions regarding the unidimensional  positive  nature of cooperation. It will help create a comprehensive understanding of cooperation and, specifically, when it should be encouraged or, alternatively, monitored.Cultural Evolution of Kinship Diversity: Variation in Language, Cognition, and Social Norms Regarding FamilyWhy do human societies differ in whom they class as family? Why are cousins classed with siblings in some societies but not others? Accounting for the variable ways that cultures classify kin is an enduring puzzle. The VARIKIN project takes a cultural evolutionary approach to variety and unity and engages different fields cultural phylogenetics, corpus linguistics, and cross-cultural child development. VARIKIN-Evolution asks how and why does kinship diversity evolve across cultures and over time? Using comparative phylogenetic modeling of cultural evolution we investigate the dynamics of how kinship terminologies and family norms change in eight language families. Are there  universal patterns of change, or does local cultural history and context determine changes in family organisation? How do social norms drive change in kinship terminology? VARIKIN-Usage investigates how people use kinship language by using corpus linguistics, surveys, and interviews to quantify patterns of usage in spoken and written language. How frequently are kinship terms used in different contexts and what meanings are more prevalent? Do patterns vary between languages, and can the patterns of usage at the individual level be linked to historical processes of change? VARIKINDevelopment investigates how children acquire and understand kinship across cultures. Using participant observation and elicitation tasks, we characterise children s social learning of kinship in a small-scale, non-Western community. Are there cross-cultural patterns of acquisition? Can socialisation produce constraints on the kinds of kinship children can learn? These three research directions are united by a coherent framework for the integration of macro- and micro-evolutionary processes. Wit< h a highly multidisciplinary background, the Applicant is uniquely positioned to direct this vanguard project towards a comprehensive understanding of diversity in how we classify our social worlds.OTransdiagnostic views on eating disorders and obesity and new approaches for treatmentEating disorders such as Anorexia Nervosa (AN), Bulimia Nervosa (BN), Binge Eating Disorder (BED) and overweight/obesity are highly prevalent in the EU and worldwide. They cause tremendous suffering, elevate suicide rates, and account for multiple organic effects that increase all-cause mortality. Etiological and maintenance factors are not well understood and transdiagnostic theoretical models across eating and weight disorders are largely missing. The present project aims to develop an integrated theoretical framework by studying psychological factors that contribute to non-homeostatic eating across the full spectrum of eating-related disorders. It is proposed that high levels on psychological traits such as restraint eating (i.e., chronic dieting behaviour), emotional eating (i.e., eating in response to negative emotional events rather than hunger), craving/food addiction (i.e., intense and chronic urge to consume palatable foods), impulsivity (i.e., inadequate food consumption planning and low self-control), and low self-esteem influence neural systems that balance appetitive (mostly bottom-up) with regulatory (mostly top-down) processes. This model is tested in the four patient groups and healthy controls utilizing an integrated set of assessment methods, involving psychometric testing, smartphone based ambulatory assessment, and neurocognitive laboratory measurement. Derived from this model, novel behavioural interventions such as smartphone based stimulus control and cognitive inhibition training will be developed. Results will have implications for theoretical models of eating and weight disorders as well as for neuroaffective models of appetite regulation. Smartphone technology might usefully complement current interventions in supporting an effective transfer to daily life and help alleviate the burden for patients with eating-related mental and physical diseases.Millet and beans, language and genes. The origin and dispersal of the Transeurasian family.The question about the origin and dispersal of the Transeurasian languages (i.e. Japonic, Koreanic, Tungusic, Mongolic and Turkic) is one of the most disputed issues in linguistic history. Eurasia3angle will address this question from an interdisciplinary perspective. My key objective is to effectively synthesize linguistic, archaeological and genetic evidence in a single approach, for which I use the term triangulation. To this end, my project will bring together a highly qualified interdisciplinary team of doctoral and postdoctoral researchers along with world-eminent experts, who will focus on testing the Farming/Language Dispersal Hypothesis for the Transeurasian languages. The FLDH attributes the dispersal of some of the world's major language families to the adoption of agriculture and subsequent population expansion, whereby the language of new farmers displaced that of preexisting hunter gatherers. In contrast to its application to the major language families in East Asia, the FLDH has not been tested yet for the Transeurasian languages. My research team will specifically investigate the hypothesis that the Transeurasian languages derive from a homeland in South Manchuria and that their early dispersal should be associated with the spread of cultivation of millet and beans. For this purpose, we will use advanced techniques recently introduced to the individual disciplines, such as the application of phylogenetic methods to linguistic classification, a focus on derivational morphology in the reconstruction of subsistence-related language, a matrix-based comparison of archaeological cultures and a model-based approach applied to genome-wide autosomal data. Converging these partial perspectives into a more holistic understanding of what really happened in the past is quite a challenge. However, if successful, this research will be a break-through in the investigation of human prehistory in general and in the long-standing Transeurasian debate in particular.dResource Bounded Graph Query AnsweringWhen we search for a product, can we find, using a single query, top choices ranked by Google and at the same time, recommended by our friends connected on Facebook? Is such a query tractable on the social graph of Facebook, which has over 1.31 billion nodes and 170 billion links? Is it feasible to evaluate such a query if we have bounded resources such as time and computing facilities? These questions are challenging: they demand a departure from the traditional query evaluation paradigm and from the classical computational complexity theory, and call for new resource-constrained methodologies to query big graphs.This project aims to tackle precisely these challenges, from fundamental problems to practical techniques, using radically new approaches. We will develop a graph pattern query language that allows us to, e.g., unify Web search (via keywords) and social search (via graph patterns), and express graph pattern association rules for social media marketing. We will revise the conventional complexity theory to characterize the tractability of queries on big data, and formalize parallel scalability with the increase of processors. We will also develop algorithmic foundations and resource-constrained techniques for querying big graphs, by ``making big data small''. When exact answers are beyond reach in big graphs, we will develop data-driven and query-driven approximation schemes to strike a balance between the accuracy and cost. As a proof of the theory, we will develop GRACE, a system to answer graph pattern queries on big GRAphs within bounded resourCEs, based on the techniques developed. We envisage that the project will deliver methodological foundations and practical techniques for querying big graphs in general, and for improving search engines and social media marketing in particular. A breakthrough in this subject will advance several fields, including databases, theory of computation, parallel computation and social data analysis. From Open to Closed Loop Optimal Control of PDEsThe proposal addresses some of the most pressing topics in optimal control of partial differential equations (PDEs): Non-smooth, non-convex optimal control and computational techniques for feedback control. These two topics will be applied to the large scale optimal control problems for the bidomain equations, which are the established model to describe the electrical activity of the heart. Due to their rich dynamical systems behavior these systems are particularly challenging.The use of nonsmooth functionals is of great practical relevance in many diverse situations. They promote sparsity, and provide a perfect formulation for switching and multi-bang controls, and for the optimal actuator location problem. For inverse problems the case $L^{p}$ with $p\in (0,1)$ is of special statistical importance, and $L^0$ can be the basis of a new formulation for topology optimization problems. But lack of Lipschitz continuity and of convexity are significant obstacles which can only be overcome by the development of new analytical and numerical concepts. The new algorithmic concepts will also be applicable to important non-smooth problems in continuum mechanics, as for instance the quasi-static evolution of fractures.Closed loop control is of paramount importance due to its {\bf robustness} against system perturbations. Nevertheless, numerical realization of optimal feedback strategies for nonlinear PDEs has barely be< en touched since the curse of dimensionality makes direct numerical treatment of the Hamilton-Jacobi-Bellman equation unfeasible. We shall therefore develop and analyze suboptimal strategies based on model reduction and interpolation techniques, and on model predictive control. The availability of boundary and near-to-the boundary measurements together with dynamic observer techniques will allow to test the proposed methods to obtain suboptimal feedback controls for the bidomain equations.qAristotle in the Italian Vernacular: Rethinking Renaissance and Early-Modern Intellectual History (c. 1400 c. 1650)From the twelfth to the seventeenth century, Aristotle s writings lay at the foundation of Western culture, providing a body of knowledge and a set of analytical tools applicable to all areas of human investigation. Scholars of the Renaissance have emphasized the remarkable longevity and versatility of Aristotelianism, but their attention has remained firmly, and almost exclusively, fixed on the transmission of Aristotle s works in Latin. Scarce attention has gone to works in the vernacular. Nonetheless, several important Renaissance figures wished to make Aristotle s works accessible and available outside the narrow circle of professional philosophers and university professors. They believed that his works could provide essential knowledge to a broad set of readers, and embarked on an intense programme of translation and commentary to see this happen. It is the argument of this project that vernacular Aristotelianism made fundamental contributions to the thought of the period, anticipating many of the features of early modern philosophy and contributing to a new encyclopaedia of knowledge. Our project aims to offer the first detailed and comprehensive study of the vernacular diffusion of Aristotle through a series of analyses of its main texts. We will thus study works that fall within the two main Renaissance divisions of speculative philosophy (metaphysics, natural philosophy, mathematics, and logic) and civil philosophy (ethics, politics, rhetoric, and poetics). We will give strong attention to the contextualization of the texts they examine, as is standard practice in the best kind of intellectual history, focusing on institutional contexts, reading publics, the value of the vernacular, new visions of knowledge and eclecticism. With the work of the PI, two professors, 5 post-docs and two PhD students we aim to make considerable advances in the understanding of both speculative and civil philosophy within vernacular Aristotelianism.iVisual Representations of the Third Plague PandemicThe project will investigate how the emergence of photography as a new technology played a pivotal role in the wider acceptance of bacteriological explanations of pestilence in the course of the third plague pandemic (1855-1959) and how it transformed public consciousness of infectious disease, hygiene, and the role of international cooperation in the protection of public health, by establishing plague as a paradigmatic agent of death and disorder in the modern age, whilst, at the same time, opening up an era where the meaning of health emergencies is actively and publically negotiated on a cross-cultural global basis. The project will collect and analyse for the first time all visual documents of the third plague pandemic, which broke out in 1855 in Southwest China and raged across the globe until 1959, causing the death of approximately 12 million people. The project s aim is to engage in a historical and anthropological analysis of this global network of visual representations, underlining how it played a crucial role in the negotiation of geopolitical, colonial and biopolitical relations at the turn of the 20th century, with great bearing on public health consciousness and the social imagination of a new era of globalised hygienic modernity. Research will focus on four regions: China and Japan; India; Africa; South and North America, the first investigated by the Principal Investigator, while the rest being allocated to 3 postdoctoral researchers, all employed full-time in the project. While investigating the visual record of plague in< their respective regions, researchers will engage in a collaborative and interdisciplinary analysis of the entangled history of the visual representation of the third pandemic, taking as a common analytical ground 4 different but vitally interlinked aspects of the visual representation of the pandemic: a) the built environment; b) civil disturbance and public order; c) death, corpses and burial; d) race, class and discrimination.BNarrative Modes of Historical Discourse in AsiaModern historiography produced in Asia belongs to the history-paradigm of the European humanities and it is from within these epistemological confines that Western as well as Eastern scholars of Asian studies view the Asian writing of the past. While source criticism and historicism have today become key parts of historical consciousness in Asia, Asian historical representations are nonetheless firmly embedded in pre-modern Asian literary traditions via specific uses in historical writing of traditional rhetorical structures of narrative, emplotment, tropes, and literary imagery. Taking such linkage between present and past Asian traditions of historiography as its premise, project NAMO  with four team members consisting of the PI and three Postdocs  will examine the literary features of Asian historiography in India, China, and Tibet across the longue dure of the classical, medieval, and modern periods. First, a new method for the study of the literary forms that characterize historiography in Asia will be established by adapting basic analytical principles from Asian literary theories drawn from twelve classical Indian and Chinese works on poetics. Next, the team will determine the specific literary characteristics of narrative, plot, tropes, and historical explanation found in seventeen classical and medieval histories composed in China, India, and Tibet. Finally, it will be examined to which extent those traditional literary features still function as constitutive rhetorical elements in modern Asian history writing. This will be done by analyzing the literary forms used in a selection of twenty representative histories written in the People's Republic of China and the Republic of India during the period 1980-2010. The outcome will be a novel approach for the empirical study of Asian history that will open up a new level of comparative work in the theory of history across non-Western and Western traditions.North Atlantic Fisheries: An Environmental History, 1400-1700NorFish aims to understand the restructuring of the North Atlantic fisheries, fish markets and fisherydependent communities in the late medieval and early modern world. The project exploits a multidisciplinary, humanities-led approach to marine environmental history, assessing and synthesizing the dynamics and significance of the North Atlantic fish revolution, equipped by methodological advances in which the PI has been to the fore in delivering. It establishes a robust quantitative framework of extractions, supplies and prices, while also charting the qualitative preferences and politics that motivated actors of the fish revolution across the North Atlantic. Fish contributed to environmental and societal change in the North Atlantic for over 300 years, shifting from being a high-priced, limited resource in the late Middle Ages to a low-priced, abundant one by early modern times. Conditioned by market forces, the  fish revolution of the 1500s and 1600s reshaped alignments in economic power, demography, and politics. With acute consequences in peripheral Atlantic settlements from Newfoundland to Scandinavia, it held strategic importance to all the major western European powers. While the fish revolution catalysed the globalization of the Atlantic world, we lack adequate baselines and trajectories for key questions of natural abundance, supply and demand, cultural preferences, marketing technologies, plus national and regional strategies. In short, the core questions are what were the natural and economic causes of the fish revolution, how did marginal societies adapt to< changing international trade and consumption patterns around the North Atlantic, and how did economic and political actors respond? The answers will help explain the historic role of environment and climate change, how markets impacted marginal communities, and how humans perceived longterm change.QPhilosophy of Pharmacology: Safety, Statistical standards and Evidence AmalgamationThe project intends addresses safety assessment in pharmacology with a view on philosophical work on causality and causal inference from statistical data ((Pearl 2000; Spirtes, Glymour, Scheines 2000, Woodward 2003, Cartwright, 2007b). This interest is motivated by the fact that current evidence standards emphasize internal validity of studies and hence randomization, disregarding alternative routes to causal assessment, such as the joint support of different sorts of evidence to a given hypothesis. This may be particularly detrimental in that, much of the evidence for harms comes from anecdotal reports, case series, or survey data, which standard guidelines of evidence evaluation regard as being of poorer quality with respect to controlled (randomized) experiments. Although the role of this "lower level" evidence is increasingly acknowledged to be a valid source of information for the risk profile of medications (Howick et al. 2009, Hauben and Aronson, 2007), current practices have difficulty in assigning it a precise epistemic status and integrating it with more standard methods of hypothesis testing. The philosophical debate has already addressed similar questions in relation to the assessment of treatment efficacy (Worral 2010, Papineau, 1993; Cartwright, 2007). However, none of these contributions expressly addresses the specific issues arising in causal assessment for harms. The project intends to change the evidence standards for safety assessment by providing a unified framework for the amalgamation of diverse evidence in safety assessment. In particular, the project intends to: 1) present a foundational analysis on statistical/causal inference with a focus on safety assessment; 2) Build a unified epistemic framework within which different kinds of evidence can be combined and used for decision; 3) Provide the theoretical framework for the development of new standards of drug evaluation.Film Colors. An Interdisciplinary Approach.Film is in essence colored light projected onto a screen. Its aesthetics are thus highly determined by the material properties of film and the optical configuration of the cinematic apparatus. To this day, however, there is no systematic study of the relationship between the technology and aesthetics of film colors, despite the fact that, following the digital turn in film production and distribution, the understanding of this relationship is more essential than ever before.Over 200 film color processes were developed since the invention of film. They are presented on the Timeline of Historical Film Colors, which will be an integral part of the project.The groundbreaking nature of this project lies in a truly interdisciplinary research design with a novel methodology to explore the interaction of technological advances and limitations with film color aesthetics, identifying diachronic patterns of stylistic means. To this end it develops a tool through recent advancements in digital humanities for crowd-sourcing of color analyses of large groups of films. In-depth studies of technical papers and scientific measurements of film colors will investigate the technical basis of films aesthetic appearance. These insights will be applied to the digitization and restoration of historical films to explore and disseminate the results. While every serious art restoration connects scientific analyses with art-historical and aesthetic investigations, a similar approach is rarely applied to film. In summary, the present research proposal capitalizes on the principal investigator s preceding studies to bridge the gap between technology and aesthetics. With the methods described here, the results will trace previously hidden roots of aesthetic developments of film colors. While the project is ambitious, it builds on a sizable methodological foundation to optimize risk management and guarantee significant advances in the understanding of film colors.Lived Ancient Religion: Questioning "cults" and "polis religion"This project takes a completely new perspective on the religious history of Mediterranean antiquity, starting from the individual and  lived religion instead of cities or peoples.  Lived ancient religion suggests a set of experiences, of practices addressed to, and conceptions of the divine, which are appropriated, expressed, and shared by individuals in diverse social spaces. Within this spatial continuum from the primary space of a) the family, b) the secondary space of associations, c) to the shared space of public institutions and d) trans-local literary communication four re< search fields are defined. In each of them a sub-project addresses representative complexes of evidence in different parts of the Mediterranean in the Imperial period. They are bound together by the transversal analysis of the interaction of individuals with the agents of traditions and providers of religious services in the various fields. The methodological innova?tion of the  lived ancient religion approach is defined through the notions of religious experience, embodiment, and  culture formed in interaction", which are intended to replace the present foci of symbols, rituals, and  culture as text . In order to transgress the usual research boundaries of  cults and  religions the bodies of evidence brought together within the sub-projects cover ancient Mediterranean religion geographically in an extended manner, focusing on Egypt and Italy, Syria and Greece, but also including evidence from the Western and Danubian provinces as well as from North Africa. The project of  Lived Ancient Religion is pioneering inasmuch as it develops and tests a far-reaching alternative model to  cults and  polis religion in order to analyse and describe ancient Mediterranean religion. Its risk lies in modifying the methodology implied in the  lived religion approach to contemporary religion for the necessities of a body of evidence that is characteristic of a  dead religion .The Carceral Archipelago: transnational circulations in global perspective, 1415-1960This project centres  the carceral archipelago in the history of the making of the modern world. It analyses the relationships and circulations between and across convict transportation, penal colonies and labour, migration, coercion and confinement. It incorporates all the global powers engaged in transportation for the purpose of expansion and colonization - Europe, Russia, Latin America, China, Japan  over the period from Portugal s first use of convicts in North Africa in 1415 to the dissolution of Stalin s gulags in 1960. It uses an innovative theoretical base to shift convict transportation out of the history of crime and punishment into the new questions being raised by global and postcolonial history. The project maps for the first time global networks of transportation and penal colonies. It undertakes case study archival research on relatively unexplored convict flows, and on the mobility of ideas and practices around transportation and other modes of confinement. It analyses its findings within the broader literature, including on transportation but also debates around the definition of freedom/ unfreedom, the importance of circulating labour, and global divergence and convergence. It redefines what we mean by  transportation, explores penal transportation as an engine of global change, de-centres Europe in historical analysis, and defines long-term impacts on economy, society and identity. It places special stress on investigating whether a transnational approach to the topic gives us a fresh theoretical starting point for studying global history that moves beyond  nation or  empire. The project lies at the intersections of national, colonial and global history, and economic, social and cultural history. It will be of wide interest to scholars of labour, migration, punishment and confinement; comparative and global history; diaspora, creolization and cultural translation; and museum and heritage studies.7The Dissolution of the Japanese Empire and the Struggle for Legitimacy in Postwar East Asia, 1945-1965This five-year project aims to understand how political rule and legal authority were redrafted in postwar East Asia after the Japanese surrender in 1945. The research will shed light on the social and political transformations that continue to have deep resonance in our world in the form of East Asia s regional alliances and < Japan s relations with its closest neighbors  China, North and South Korea, and Taiwan. The renovation of East Asia after the fall of the Japanese empire has mainly been written from a western perspective, owing to the preponderance of postwar American scholarship and its political dominance, but also the systematic declassification and easy access to government and private archival papers. Even with the economic rise and growing importance of contemporary China, the region s understanding of its own past and its internal dynamics remain deeply rooted to the contours of the manner in which World War II ended. This narrative is linked to the process of how Japanese imperial rule was judged at the local level through war crimes trials and the pursuit of justice against imperial supporters. The search for war criminals, collaborators or suspected traitors offered a means to resolve the upturned former imperial hierarchies, dealing with grudges and finding justice for committed atrocities. Such moves demonstrated that the new authorities were  just, a crucial element to bolster domestic and international mobilization campaigns for support. This new research makes clear that Japan s sudden surrender in no way signified that the country would immediately disavow its extensive imperial ideology; such a move would require a long time to inculcate.Neither visitors, nor colonial victims: Muslims in Interwar Europe and European Trans-cultural HistoryNo comprehensive attempt has yet been made to cover the history of Muslims in interwar Europe. Historians of the modern Middle East underestimate the role of interwar Muslim actors in writing a history of Islam, whereas historians of Europe underestimate their role in intra-European developments. Existing works focus either on the nineteenth-century Muslim travelers, diplomats, students and residents or on the later post-World War II influx of Muslim immigrant workers. Based on personal and official archives, memoirs, press writings and correspondences, this project analyses the multiple aspects of the global Muslim religious, political and intellectual affiliations in interwar Europe, broadly defined. How did Muslims in interwar Europe act and interact among each other; and within the European socio-political and cultural context? The project answers this question by studying the intellectual and religio-political roles played by Muslim  intellectual agents during the interwar years and up until the rest of World War II (1918-1946). We hypothesize that histoire croise (entangled history) is the most appropriate approach to study the encounters and experiences of Muslim actors in interwar Europe from within. By exploring the complex relationship between the historical data and the social, political, theological and cultural patterns of Muslims as a new social structure in interwar Europe, the study represents a step towards a systematic global approach of Muslim connections in interwar Europe. The project contributes to our historical conceptualization of Europe itself as much as to our understanding of the contemporary scene of Islam in Europe and the world today, without resorting to a neatly tailored hypo                          ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s u v w x y z { | } ~  thesis. Many Muslim groups in the West nowadays still trace their heritage to the ideas of the great reformers of the early 20th century. More historical reflection on Islam in Europe can put the present  fear" for Islamization of the West into perspective.FCOLONISATION AND CULTURAL DIVERSIFICATION IN UNFAMILIAR LANDSCAPESThis project explores the relationship between climate change and human behaviour. During the harshest conditions of the last ice age European human populations abandoned northern latitudes, with their range contracting to southern regions. By the time ice sheets retreated and large areas of land became available for resettlement there had been a hiatus of at least 7000 years. This projectexamines the recolonisation of these Northern regions which took place during a period of rapid climate change, the last major global warming event on earth. As people move eastwards and northwards increasing diversification is seen in their stone and bone tool industries which indicate human development. This project examines whether climate a) drove the human dispersal and development, b) played a more indirect role, or c) was of little significance to humans at this time. State-of-the-art < scientific techniques (radiocarbon dating, DNA, stable isotope, clumped isotope and charcoal ring width analyses) will be used to create integrated chronological, palaeoclimatic and palaeoecological frameworks that are directly linked to the Late and Final Palaeolithic archaeological record. Temporal and spatial trends in climate change, prey abundance and behaviour, and technological development will be compared and considered in light of regional and global climate trends and archaeological evidence for hunting strategies, human mobility and landscape use. Such data will provide an insight into the conditions Palaeolithic people experienced and how this influenced their perceptions of the landscape they inhabited and the decisions they made.Jews and Christians in the East: Strategies of Interaction between the Mediterranean and the Indian OceanThis project analyzes Jews in Eastern Christian communities and Eastern Christian sources, beyond the Byzantine context, namely, relations between Jews and Christian communities in the Middle East Central Asia, the Caucasus, Ethiopia, and South India. In order to obtain a truly accurate understanding of the dynamics of Jewish-Christian relations in the non-Latin world during the Middle Ages, these various regions and traditions must be studied together because they were all profoundly interconnected through the exchange and translation of texts, artistic motifs and techniques, and other goods, via long-distance trade along the  silk road , the Mediterranean, and the Indian Ocean, which, of course, also entailed the movement and encounter of peoples, Jews and Christians among them. The research team endeavors to answer four intertwined questions: 1) what we can know about actual  real-life interactions between Jews and a variety of Eastern Christian communities; 2) what were the meanings and functions of invented or rhetorical Jewish identities; 3) what is the significance of JewishChristian polemics, both written and visual, in lands or among communities where: a) there were supposedly few to no Jews, or Jewish identity was  invented ; b) there were Jewish and Christian communities who had the opportunity to be in regular contact with one another; 4) how were Christian stories, laws, biblical interpretations, or motifs in which Jews featured prominently, or Jewish tales and motifs about Christians transformed as they were transported from one cultural milieu to another? Because scholars have examined Jewish relations with Christians, and even Muslims primarily in the context of uneven power relationships; namely Jewish-Christian relations in Western Europe or Byzantium, or Jewish-Muslim relations in the Islamic one leaving Jewish-Christian relations untouched apart from shared communal structures, this project opens a new field.Crisis on the margins of the Byzantine Empire: A bio-archaeological project on resilience and collapse in early Christian development of the Negev DesertThis project proposes an innovative, integrative and data-intensive approach to understand the parameters for long-term sustainable functioning of complex societies under vulnerable conditions. The broad aim of the research is to explore contexts of collapse and resilience in an ancient society with high levels of socio-political complexity and technological ingenuity within a resource-limited environment. It focuses on the Byzantine early Christian urban centres of the Negev Desert (4th-7th cent. AD) disclosing both the triumph of human ingenuity in conquering the desert through large-scale human settlement and agricultural development as well as a striking and as yet ambiguous case of wholesale systemic collapse. To test hypotheses regarding social disintegration, economic stress, environmental degradation due to climatic or anthropogenic causes, and the question of plague the project integrates approaches in the archaeology of households, landscapes and garbage through use of biomolecular, botanical, zoological, geological, chronometric, artifactual and contextual sources of data. Dealing with societal vulnerability in marginal regions is timely and relevant in a world where accelerating development rapidly expands such problems, previously localized, to global levels. Although it is a risky endeavour to engage the record of past societies to inform the present and forecast the future due to the typically underdetermined nature of historical and proxy data, this project offers substantial gain to theoretical and empirical research on societal vulnerability in two main avenues: (1) providing an opportunity to critically re-evaluate the current state of knowledge in the field based on an extensive corpus of new, high-quality data and (2) drawing more nuanced and informed broad generalizations regarding limiting states for human ingenuity in reconciling social and economic development with sustainable management of the environment and its resources.Novel materials architecture based on atomically thin crystalsWe propose a new paradigm in materials science  heterostructures based on two-dimensional atomic crystals (and their hybrids with metallic and semiconducting quantum dots and nanostructures), and develop several devices which are based on such concept. Two-dimensional (2D) atomic crystals (such as graphene, monolayers of bo< ron nitride, molybdenum disulphide, etc) possess a number of exciting properties, which are often unique and very different from those of their tree-dimensional counterparts. However, it is the combinations of such 2D crystals in 3D stacks that offer truly unlimited opportunities in designing the functionalities of such heterostructures. One can combine conductive, insulating, probably superconducting and magnetic 2D materials in one stack with atomic precision, fine-tuning the performance of the resulting material. Furthermore, the functionality of such stacks is  embedded in the design of such heterostructure. We will create several types of devices based on such heterostructures, including tunnelling transistors, charge and spin drag, photodetectors, solarcells, lasers and other optical and electronic components. As the range of available 2D materials broadens, so the possible functionality of the 2D-based heterostructures will cover larger and larger area. We will concentrate on creating and understanding of the prototypes of such hetersotructures and apply efforts in developing methods for their mass-production suitable for various applications. The development of such novel paradigm in material science will only by possible by bringing together a Synergy group of researchers with complementary skills, knowledge and resources.[Effects of phosphorus limitations on Life, Earth system and SocietyP is an earthbound and finite element and the prospect of constrained access to mineable P resources has already triggered geopolitical disputes. In contrast to P, availabilities of carbon (C) and nitrogen (N)to ecosystems are rapidly increasing in most areas of the globe. The resulting imminent change in the stoichiometry of available elements will have no equivalent in the Earth s history and will bear profound, yet, unknown consequences for life, the Earth System and human society. The ongoing shifts in C:N:P balances in ecosystems will necessarily affect the structure, function and diversity of the Earth system. P-market crises might put pressure on the global food system and create environmental ripple effects ranging from expansion of agricultural land to P-price-induced changes in land management exacerbating the stoichiometric resource imbalance. Yet, the impacts of this unprecedented human disturbance of elemental stoichiometry remain a research enigma. The IMBALANCE-P-team, that gathers four leading researchers in the fields of ecosystem diversity and ecology, biogeochemistry, Earth System modelling, and global agricultural and resource economics, is formidably positioned to address this Earth System management challenge by providing improved understanding and quantitative foresight needed to formulate a range of policy options that will contain the risks and mitigate the consequences of stoichiometric imbalances. IMBALANCE-P will integrate some of Europe's leading integrated assessment and Earth system models, calibrated using ecosystem nutrient limitation data obtained from field experiments. The project will establish an international process of sciencebased P-diplomacy.zArctic Sea Ice and Greenland Ice Sheet SensitivityThe cryosphere is in fast transition. The possibility that the ongoing rapid demise of Arctic sea ice may instigate abrupt changes on the Greenland Ice Sheet (GIS) is not tackled by current research. Ice cores from the GIS show clear evidence of past abrupt warm events,up to 15 degrees warming in less than a decade, possibly caused by disappearing se ice in the Nordic Seas..Arctic sea ice extent was in 2012 half of the 1979-2000 average. Satellite data document an increasing loss of GIS ice mass since 1990 and temperatures have risen markedly at the GIS summit. Strong transient changes in both Arctic cryospheric entities prompts the question: Is the dramatic decline in Arctic Sea Ice heralding a new phase of abrupt change, similar to those recorded in ocean sediments and ice cores? Such changes would have major consequences for the GIS mass balance and global climate and sea level. Ice2Ice will approach this complex problem by integrating 4 PI teams from three Nordic world class research centres comprising empiricists and dynamicists specialized in Arctic and Greenland atmospheric, oceanic and cryospheric sciences. With an innovative combination of synchronized records of GIS parameters, records of sea ice change and models ranging from global climate models to regional and process models, Ice2Ice will be the first concerted effort to tackle the question of the cause and future implications of past abrupt climate change in Greenland, the main hypothesis being that Arctic and sub-Arctic sea ice < cover is key to understand past and future Greenland temperature and ice sheet variations. In Ice2Ice this will be done by:a)describing the nature, timing and extent of abrupt events across climate archives,b)resolving mechanisms behind the sudden demise of sea ice cover,c)identifying the risk that the ongoing rapid diminution of Arctic sea ice cover could give abrupt GIS changes in the future, d)determining the impacts of such changes for the GIS, Arctic and global climate.CSpin-charge conversion and spin caloritronics at hybrid organic-inorganic interfacesOrganic semiconductors are enabling flexible, large-area optoelectronic devices, such as organic lightemitting diodes, transistors, and solar cells. Due to their exceptionally long spin lifetimes, these carbonbased materials could also have an important impact on spintronics, where carrier spins, rather than charges, play a key role in transmitting, processing and storing information. However, to exploit this potential, a method for direct conversion of spin information into an electric signal is indispensable. Spin-charge conversion in inorganic semiconductors and metals has mainly relied on the spin-orbit interaction, a fundamental relativistic effect which couples the motion of electrons to their spins. The spin-orbit interaction causes a flow of spins, a spin current, to induce an electric field perpendicular to both the spin polarization and the flow direction of the spin current. This is called the inverse spin Hall effect (ISHE). We have very recently been able to observe for the first time the inverse spin-Hall effect in an organic conductor. This breakthrough raises important questions for our understanding of spin charge conversion in materials with intrinsically weak spin-orbit coupling. It also expands dramatically the range of materials and structures available to address some currently not well understood scientific questions in spintronics and opens opportunities for realising novel spintronic devices for spin-based information processing and spin caloritronic energy harvesting that make use of unique properties of hybrid, organic-inorganic structures. The main objective of the proposed research is to take spintronics to a level that inorganic spintronics cannot reach on its own. The project is based on new theoretical and experimental methodologies arising at the interface between two currently disjoint scientific communities, organic semiconductors and inorganic spintronics, and aims to exploit synergies between chemistry, physics and theory.5European Molecular Biology Laboratory, Heidelberg, De(Technische Universiteit Delft, Delft, Nl,Helsingin Yliopisto, Helsingin Yliopisto, FiKCommissariat A L Energie Atomique Et Aux Energies Alternatives,Grenoble, Fr*Weizmann Institute Of Science, Rehovot, Il=Erasmus Universitair Medisch Centrum Rotterdam, Rotterdam, NlCThe University Court Of The University Of St Andrews, St Andrews,Uk%University College London, London, Uk:Centre National De La Recherche Scientifique, Grenoble, FrKThe Chancellor, Masters And Scholars Of The University Of Oxford,Oxford, Uk)Forschungsverbund Berlin E.V., Berlin, DeLunds Universitet, Lund, SeRThe Chancellor, Masters And Scholars Of The University Of Cambridge, Cambridge, Uk4Fundacio Centre De Regulacio Genomica, Barcelona, Es.Academisch Ziekenhuis Groningen, Groningen, NlLUniversity College Dublin, National University Of Ireland, Dublin,Dublin, Ie8Stichting Het Nederlands Kanker Instituut, Amsterdam, Nl%Freie Universitaet Berlin, Berlin, De0Deutsches Krebsforschungszentrum, Heidelberg, De&Kobenhavns Universitet, Copenhagen, DkOMedical Research Council/The Francis Crick Institute Limited,Swindon/London, Uk University Of Dundee, Dundee, UkLMax Planck Gesellschaft Zur Foerderung Der Wissenschaften E.V.,G?Ttingen, DeInstitut Curie, Paris, FrTMax-Delbruck-Centrum Fur Molekulare Medizin In Der Helmholtzgemeinschaft, Berlin, DeVib, Ghent, BeJMax Planck Gesellschaft Zur Foerderung Der Wissenschaften E.V.,Dresden, De'The University Of Warwick, Coventry, UkLDeutsches Institut Fuer Ernaehrungsforschung Potsdam Rehbrucke, Nuthetal, De'Universiteit Maastricht, Maastricht, Nl,Universita Degli Studi Di Milano, Milano, It!Tel Aviv University, Tel Aviv, Il Bilkent 躰iversitesi, Ankara, Tr Universite De Geneve, Geneve, ChLInstitut National De La Sante Et De La Recherche Medicale (Inserm),Paris, Fr+Instituto De Medicina Molecular, Lisboa, Pt!Helsingin Yliopisto, Helsinki, FiTFundacion Centro Nacional De Investigaciones Cardiovasculares Carlos Iii, Madrid, EsJAcademisch Medisch Centrum Bij De Universiteit Van Amsterdam,Amsterdam, Nl(Kobenhavns Universitet, Copenhagen N, Dk Uppsala Universitet, Uppsala, SeLFundaci Institut De Recerca Contra La Leucemia Josep Carreras, Barcelona,Es$Karolinska Institutet, Stockholm, Se7Centre National De La Recherche Scientifique, Dijon, Fr7Institut Du Cerveau Et De La Moelle Epiniere, Paris, Fr*Universita Degli Studi Di Parma, Parma, ItANorges Teknisk-Naturvitenskapelige Universitet Ntnu, Trondheim,No!Ospedale San Raffaele, Milano, ItUniversitaet Wien, Wien, At*Katholieke Universiteit Leuven, Leuven, Be$Universite De Lausanne, Lausanne, Ch+Kungliga Tekniska Hoegskolan, Stockholm, SeUniversitetet I Oslo, Oslo, NoQFundacao D. Anna Sommer Champalimaud E Dr. Carlos Montez Champalimaud, Lisboa, Pt1The Hebrew University Of Jerusalem, Jerusalem, Il6Centre National De La Recherche Scientifique, Lyon, FrUniversitaet Ulm, Ulm, De Universitaet Zu Koeln, Koeln, De Universitaet Zuerich, Zurich, Ch*Rijksuniversiteit Groningen, Groningen, Nl?Biomedical Sciences Research Center Alexander Fleming, Vari, ElYFundacion Para La Formacion E Investigacion Sanitarias De La Region De Murcia, Murcia, Es1Universitair Medisch Centrum Utrecht, Utrecht, Nl#Humanitas Mirasole Spa, Rozzano, ItJAgencia Estatal Consejo Superior De Investigaciones Cientificas,Madrid, EsACentro De Neurociencias E Biologiacelular Associacao, Coimbra, PtOUniversiteit Maastricht/Katholieke Universiteit Leuven,Maastricht/Leuven, Nl/Be%Linkopings Universitet, Linkoping, Se Stichting Vu-Vumc, Amsterdam, Nl'Universitat De Barcelona, Barcelona, Es"University Of Bristol, Bristol, UkOulun Yliopisto, Oulu, FiUCommissariat A L Energie Atomique Et Aux Energies Alternatives,Fontenay-Aux-Roses, Fr/Stichting Katholieke Universiteit, Nijmegen, Nl,Hadassah Medical Organization, Jerusalem, Il*The University Of Edinburgh, Edinburgh, Uk!Universidad De Murcia, Murcia, Es4Universitaetsklinikum Hamburg-Eppendorf, Hamburg, De,The University Of Birmingham, Birmingham, Uk.Universita Degli Studi Di Perugia, Perugia, It.Ludwig Boltzmann Gesellschaft Gmbh, Vienna, At2National University Of Ireland, Galway, Galway, Ie>Fundacio Institut De Bioenginyeria De Catalunya, Barcelona, Es$Universite De Bordeaux, Bordeaux, FrUniversiteit Gent, Gent, Be Ita-Suomen Yliopisto, Kuopio, Fi4Veterinaermedizinische Universitaet Wien, Vienna, At7Centre National De La Recherche Scientifique, Orsay, Fr It?-Suomen Yliopisto, Kuopio, Fi@The University Court Of The University Of Aberdeen, Aberdeen, Uk$The University Of Exeter, Exeter, UkAarhus Universitet, Aarhus, Dk%Goeteborgs Universitet, Goeteborg, Se@Imperial College Of Science, Technology And Medicine, London, UkGMax Planck Gesellschaft Zur Foerderung Der Wissenschaften E.V.,Pl?N, DeEesti Maaulikool, Tartu, Ee2The Hebrew University Of Jerusalem., Jerusalem, Il@Queen Mary And Westfield College University Of London, London,Uk6Ludwig-Maximilians-Universitaet Muenchen, Muenchen, De6Universite Catholique De Louvain, Louvain-La-Neuve, BeKMax Planck Gesellschaft Zur Foerderung Der Wissenschaften E.V.,T黚ingen, De(Universidad De Vigo, Vigo Pontevedra, Es9Centre National De La Recherche Scientifique, Roscoff, Fr*The University Of Sheffield, Sheffield, Uk1Royal Holloway And Bedford New College, Egham, Uk*Universita Degli Studi Di Udine, Udine, It,Universita Degli Studi Di Padova, < Padova, It-Universidad Politecnica De Madrid, Madrid, EsUniversitaet Basel, Basel, Ch Vib, Gent, BeKAgencia Estatal Consejo Superior De Investigaciones Cientificas,Paterna, Es&The James Hutton Institute, Dundee, Uk1Danmarks Tekniske Universitet, Kongens Lyngby, Dk#Jyvaskylan Yliopisto, Jyvaskyla, Fi#Universitaet Bayreuth, Bayreuth, De:Westfaelische Wilhelms-Universitaet Muenster, Muenster, De;Centre National De La Recherche Scientifique, Marseille, FrDUniversidad Del Pais Vasco/ Euskal Herriko Unibertsitatea, Bilbao,Es!Universitaet Leipzig, Leipzig, DeUniversite De Liege, Liege, Be!Universiteit Utrecht, Utrecht, Nl5Universite Pierre Et Marie Curie - Paris 6, Paris, Fr"University Of Glasgow, Glasgow, Uk*University Of Southampton, Southampton, Uk"Universitetet I Bergen, Bergen, No.Norsk Institutt For Luftforskning, Kjeller, No&K?Benhavns Universitet, Copenhagen, Dk5Universita' Degli Studi Di Milano-Bicocca, Milano, It4Universita Degli Studi Di Roma La Sapienza, Roma, It0Technische Universitaet Darmstadt, Darmstadt, De,Universite Libre De Bruxelles, Bruxelles, Be3Istituto Nazionale Di Fisica Nucleare, Frascati, It!Universitaet Hamburg, Hamburg, De"Uniwersytet Warszawski, Warsaw, Pl-Chalmers Tekniska Hoegskola Ab, Goeteborg, Se)Universiteit Van Amsterdam, Amsterdam, Nl8Rheinische Friedrich-Wilhelms-Universitat Bonn, Bonn, De,The University Of Nottingham, Nottingham, Uk+Queen Mary University Of London, London, Uk@Universidad De Santiago De Compostela, Santiago De Compostela,EsQCommissariat A L Energie Atomique Et Aux Energies Alternatives,Gif-Sur-Yvette, Fr<Budapesti Muszaki Es Gazdasagtudomanyi Egyetem, Budapest, HuAInstituto Superior Tecnico, Lisboa, Pthttps://Tecnico.Ulisboa.Pt/The Provost, Fellows, Foundation Scholars & The Other Members Of Board Of The College Of The Holy & Undivided Trinity Of Queen 6Ludwig-Maximilians-Universitaet Muenchen, Garching, De!Politecnico Di Milano, Milano, It2Universite Joseph Fourier Grenoble 1, Grenoble, Fr&Technische Universitaet Wien, Wien, At=Centre National De La Recherche Scientifique, Montpellier, Fr*Ecole Normale Superieure De Lyon, Lyon, Fr,Consiglio Nazionale Delle Ricerche, Roma, ItHMax Planck Gesellschaft Zur Foerderung Der Wissenschaften E.V.,Mainz, De"Syddansk Universitet, Odense M, DkCollege De France, Paris, FrCardiff University, Cardiff, Uk3Karlsruher Institut Fuer Technologie, Karlsruhe, De"Aalto-Korkeakoulusaatio, Aalto, Fi6Ecole Polytechnique Federale De Lausanne, Lausanne, ChQAsociacion Centro De Investigacion Cooperativa En Biomateriales,San Sebastian, Es*Scuola Normale Superiore Di Pisa, Pisa, ItUniversiteit Leiden, Leiden, Nl@Friedrich-Alexander-Universitaet Erlangen Nuernberg, Erlangen,De>Centre National De La Recherche Scientifique, Villeurbanne, Fr,The University Of Manchester, Manchester, Uk-Universidad Del Pais Vasco Ehu Upv, Leioa, EsRGeorg-August-Universitaet Goettingen Stiftung Oeffentlichen Rechts, Goettingen, De'Fundacion Imdea Nanociencia, Madrid, Es!Universiteit Twente, Enschede, Nl@Rheinisch-Westfaelische Technische Hochschule Aachen, Aachen, De6Fondazione Istituto Italiano Di Tecnologia, Genova, It0Technische Universiteit Eindhoven, Eindhoven, Nl"University Of Kent, Canterbury, Uk*Universidad Autonoma De Madrid, Madrid, EsThe Provost, Fellows, Foundation Scholars & The Other Members Of Board Of The College Of The Holy & Undivided Trinity Of Queen Elizabeth Near Dublin, Dublin, Ie*The University Of Liverpool, Liverpool, UkUniversity Of Bath, Bath, Uk8Julius-Maximilians Universitaet Wuerzburg, Wuerzburg, De0University Of Newcastle Upon Tyne, Newcastle, Uk>Universite D'Auvergne Clermont-Ferrand 1, Clermont-Ferrand, Fr?Institute Of Science And Technology Austria, Klosterneuburg, At.Technische Universitaet Muenchen, Muenchen, De=Gottfried Wilhelm Leibniz Universitaet Hannover, Hannover, DePInstitut National De Recherche En Informatique Et En Automatique, Le Chesnay, Fr+It University Of Copenhagen, Copenhagen, Dk$Ruhr-Universitaet Bochum, Bochum, De7Panepistimio Kritis (University Of Crete), Rethymno, El.Technische Universitaet Muenchen, Garching, DeWInstitut National De Recherche En Informatique Et En Automatique, Villers-L鑣-Nancy, FrTBarcelona Supercomputing Center - Centro Nacional De Supercomputacion, Barcelona, Es:Centre National De La Recherche Scientifique, Toulouse, Fr*Zentrum Fuer Telematik E.V., Wuerzburg, De Aalborg Universitet, Aalborg, Dk$Universitetet I Tromsoe, Tromsoe, No<Foundation For Research And Technology Hellas, Heraklion, ElKoc University, Istanbul, Tr%Fundacion Imdea Networks, Leganes, Es5Fondazione Istituto Italiano Di Tecnologia, Milan, It!Universita Del Salento, Lecce, ItBCentre National De La Recherche Scientifique, Sophia-Antipolis, Fr7Centre National De La Recherche Scientifique, Paris, FrKScuola Imt (Istituzioni, Mercati, Tecnologie) Alti Studi Di Lucca,Lucca, ItDCentre Internacional De Metodes Numerics En Enginyeria,Barcelona, Es"Universidade De Aveiro, Aveiro, PtSLeibniz-Institut Fuer Festkoerper- Und Werkstoffforschung Dresden E.V., Dresden, De&Universitaet Osnabrueck, Osnabr點k, DeBOffice National D'Etudes Et De Recherches Aerospatiales, Meudon,Fr&Politecnico Di Torino, Alessandria, It4Universita' Degli Studi Di Milano-Bicocca, Milan, ItONova Id Fct - Associacao Para A Inovacao E Desenvolvimento Da Fct, Caparica, PtjAssociation Pour La Recherche Et Le Developpement Des Methodes Et Processus Industriels, Saint-Etienne, FrUniversity Of Leeds, Leeds, Uk"Universite De Rennes I, Rennes, FrQUniversite Des Sciences Et Technologies De Lille - Lille I, Villeneuve D Ascq, Fr6Ruprecht-Karls-Universitaet Heidelberg, Heidelberg, De*Technische Universitaet Berlin, Berlin, De/Liverpool John Moores University, Liverpool, UkCStichting Sron Netherlands Institute For Space Research, Utrecht,Nl-Medien In Der Bildung Stiftung, Tuebingen, De%Universiteit Antwerpen, Antwerpen, BeJMagyar Tudomanyos Akademia Tarsadalomtudomanyi Kutatokozpont, Budapest, Hu4Technion - Israel Institute Of Technology, Haifa, IlDInternationales Institut Fuer Angewandte Systemanalyse,Laxenburg, At+Centre D Estudis Demografics, Barcelona, Es(Haskolinn I Reykjavik Ehf, Reykjavik, Is#Ecole Normale Superieure, Paris, Fr/Paris-Lodron-Universitat Salzburg, Salzburg, AtGMax Planck Gesellschaft Zur Foerderung Der Wissenschaften E.V.,Jena, DeUniversitaet Graz, Graz, At+Universita Ca' Foscari Venezia, Venezia, ItUniversitat Erfurt, Erfurt, De&University Of Leicester, Leicester, UksThe Chancellor, Masters And Scholars Of The University Of Cambridge/University College London, Cambridge/London, Uk#Ruhr-Universitat Bochum, Bochum, DeUniversity Of Haifa, Haifa, IlICentro De Investigacion Ecologica Yaplicaciones Forestales,Bellaterra, Esy橆v{薔 7m Functional protein dynamics studied by solution- and solid-state NMR spectroscopyProteins are highly flexible objects that perform their functions by sampling a wide range of conformations. The characterization of such motions is, therefore, crucial to establish the link between protein structure and function. In this project we will use advanced nuclear magnetic resonance in solution state and solid state to characterize functionally important motions in two challenging classes of proteins. The first target of these studies will be a < large molecular chaperone of close to 1MDa in size. Conformational changes and dynamics are a prerequisite for the function of this assembly, as it binds, encloses and folds unfolded substrate proteins. Atomic-resolution structures of such large objects frozen in their crystal lattice do not provide access to dynamic information nor insight into the folding process itself. Here, we will exploit the complementary advantages of solid- and solution-state NMR spectroscopy to probe the dynamics, allostery and binding in a H"1MDa object. Furthermore, we will study how the chaperone cage influences folding, by observing in real time and at atomic resolution how substrate proteins achieve their native fold inside and outside this large molecular edifice. We will furthermore study the mechanism of substrate translocation across membranes by characterizing structure, interactions and dynamics in a solute carrier protein. The dynamics of integral membrane proteins is currently poorly understood. This relates to the need to address membrane protein dynamics in an environment that closely resembles the native membrane. NMR techniques on proteoliposomes as well as nanodiscs are uniquely suited to get insight into native dynamics. We will use such techniques to relate the process of substrate translocation to inherent protein dynamics over a wide range of time scales. The development of novel NMR methods will be an integral part of these studies, and will allow us to probe protein motion at unprecedented detail.RS Individualized early risk assessment for heart diseasesHeart failure (HF) is the common end-stage of different medical conditions. It is the only growing cardiovascular disease and its prognosis remains worse than that of many malignancies. The lack of evidence-based treatment for patients with diastolic HF (HFpEF) exemplifies that the current  one for all therapy has to be advanced by an individualized approach. Inherited cardiomyopathies can serve as paradigmatic examples of different HF pathogenesis. Both gain- and loss-of-function mutations of the same gene cause disease, calling for disease-specific agonism or antagonism of this gene2 s function. However, mutations alone do not predict the severity of cardiomyopathies nor therapy, because their impact on cardiac myocyte function is modified by numerous factors, including the genetic context. Today, patient-specific cardiac myocytes can be evaluated by the induced pluripotent stem cell (hiPSC) technology. Yet, unfolding the true potential of this technology requires robust, quantitative, high content assays. Our recently developed method to generate 3D-engineered heart tissue (EHT) from hiPSC provide an automated, high content analysis of heart muscle function and the response to stressors in the dish. The aim of this project is to make the technology a clinically applicable test. Major steps are (i) in depths clinical phenotyping and genotyping of patients with cardiomyopathies or HFpEF, (ii) follow-up of the clinical course, (iii) generation of hiPSC lines (40 patients, 40 healthy controls), and (iv) quantitative assessment of hiPSC-EHT function under basal conditions and in response to pro-arrhythmic or cardio-active drugs and chronic afterload enhancement. The product of this study is an SOP-based assay with standard values for hiPSC-EHT function/stress responses from healthy volunteers and patients with different heart diseases. The project could change clinical practice and be a step towards individualized risk prediction and therapy of HF.L Prosaposin and GPR37 in synucleinopathiesThe next breakthrough in the treatment of synucleinopathies, incl Parkinson2 s disease (PD), will be aimed at interference of disease progression based on insights into the underlying pathogenic process. The pathological hallmark of PD are<  Lewy bodies (LBs), in which -synuclein is the major constituent together with other PD-linked gene products (DJ-1, LRRK2, parkin, and GBA) and aggregated GPR37. GPR37 is exceptional among GPCRs having a high propensity for intracellular receptor accumulation and aggregation leading to neurotoxicity. However, unexpectedly, our results suggest that GPR37 is neuroprotective in dopaminergic when located at the plasma membrane. Consistently, prosaposin (PSAP), and its neurotrophic fragment prosaptide, were recently identified as agonists at GPR37. PSAP is a neuroprotective protein that regulates intracellular lysosomal enzyme function, with saposin C being a co-factor of GBA. In addition, we hypothesize that PSAP is secreted following cellular stress and, via membraneous GPR37, cue dopamine neurons to initiate survival pathways. Pivotal to this programme is modeling and analysis of the atomic structures of GPR37 in complex with prosaptide, which will grossly facilitate mechanistic understanding and drug development with potential use in diagnosis and treatment. Novel applications and technological advancements of fluorescence correlation spectroscopy will be implemented for single molecule trafficking of GPR37 and its ligands and will examine whether GPCR multimerization beyond dimer formation may be neurotoxic. Normal and cGPR37KO mice will be virally transduced by -synuclein to delineate in the relative contributions of improved lysosomal function versus GPR37 agonism for neuroprotection by prosaptides. Evolving from the autopsy studies that anti GPR37 label LBs and that prosaposin is released upon cellular injury, we will develop GPR37 ligands as PET tracers for LBs in synucleinopathies.}~a Determination of top couplings in associated top pair events using ATLAS dataThe discovery of a new particle, compatible with the Higgs boson, at the Large Hadron Collider, marked a major triumph of the Standard Model of particle physics. However, many fundamental questions remain and direct or indirect evidence of new physics can be probed with the large number of protonproton collision data, collected in 2011 and 2012 at 7 and 8 TeV centre-of-mass energy. With this proposal we plan to exploit the large sample of top-quark pair events that is already recorded, and the sample that will be collected from 2015 onwards, at the ultimate energy of 14 TeV. In particular we plan to study the coupling of top quarks to neutral bosons, by measuring the production of associated tt ? , tt ? Z and tt ? H. Anomalous electromagnetic or weak couplings could be uncovered by studyingkinematic properties of the resulting photon or Z-boson, once the signal is established. By studying the tt ? H production in detail the mechanism of Yukawa coupling of the Higgs boson to fermions will be tested, possibly providing important confidence in the characterisation of the new boson. In all measurements we plan to include the tt ? dilepton channel, that, despite the smaller branching fraction has typically superior signal-to-noise ratios. An essential part of the programme will be the calibration of the b-tagging algorithms, where we plan to use tt ? events. For associated Higgs production we willexplore the decays H! bb? and H! .PQ\]r Development of a Bio-Inspired Blood Factory for Personalised HealthcarePersonalized medicine is a medical model that proposes the customization of healthcare, with decisions and practices being tailored to the individual patient by use of patient-specific information and/or application of patient-specific cell-based therapies. BioBlood aims to deliver personalised healthcare through a  step change in the clinical field of haemato-oncology. BioBlood represents an engineered bio-inspired integrated experimental/modelling platform for normal and abnormal haematopoiesis that receives disease & p<atient input (patient primary cells & patient/disease-specific data) and will produce cellular (red blood cell product) and drug (optimal drug treatment) therapies as its output. Blood supply to meet demand is the primary challenge for Blo od Banks and requires significant resources to avoid shortages and ensure safety. An alternative, practical and cost-effective solution to conventional donated blood is essential to reduce patient morbidity and mortality, stabilise and guarantee the donor supply, limit multiple donor exposures, reduce risk of infection of known or as yet unidentified pathogens, and ensure a robust and safe turn-around for blood supply management. BioBlood aims to meet this challenge by developing a novel in vitro platform for the mass production of RBCs for clinical use. More than 32b/year is spent to develop and bring new drugs to market, which takes 14 years. Most patients diagnosed with leukaemias are unable to tolerate treatment and would benefit from novel agents. There is a need to optimise current treatment schedules for cancers such as AML to limit toxicities and improve clinical trial pathways for new drugs to enable personalised healthcare. BioBlood s in vitro & in silico platform would be a powerful tool to tailor treatments in a patient- and leukaemia-specific chemotherapy schedule by considering the level of toxicity to the specific individual and treatment efficiency for the specific leukaemia a priori.2 Molecular and Structural Biology and Biochemistry7 Genetics, Genomics, Bioinformatics and Systems Biology# Cellular and Developmental Biology. Physiology, Pathophysiology and Endocrinology# Neurosciences and Neural Disorders Immunity and Infection. Diagnostic Tools, Therapies and Public Health Earth System Science3 Evolutionary, Population and Environmental Biology Mathematics# Fundamental Constituents of Matter! Computer Science and Informatics# Products and Processes Engineering Condensed Matter Physics" Synthetic Chemistry and Materials* Physical and Analytical Chemical Sciences" The Human Mind and Its Complexity& Systems and Communication Engineering Universe Sciences& Markets, Individuals and Institutions, Institutions, Values, Beliefs and Behaviour- The Social World,Diversity and Common Ground. The Social World, Diversity and Common Ground" Environment, Space and Population! Cultures and Cultural Production The Study of the Human Past Synergy4 Applied life Sciences and Non-Medical Biotechnology 7鱏 7 Project ID 7啒遅 7 y橆v#嵑N 7 #嵑NEmail 7漁XbUSMO 7 Q@W 7觺槝鰁魰 7 : 31/10/2020 7 : 31/7/2020 72 4U65sY6785':dp;< =( g? 蹳BUyC鳧5/Fl僄螲 +JhnK疞鯩3DOqP闝'8SU漈V-zW靀 /ZL][z痋 腯 \_y 檂 赼!c>bd宔襢h2Oil杍阫Xmu絥9pV瀜.s/穞\v]豾UyV箊*|+ 杴 魚 [\ 蟻CD鯀BC茍覌RS蕩 !陹艣斻/uV洷^ CN[;馄c癆 fr?E坠絆pTV鑙[撫x癣,;"j @ 臞 ! ib +< o鶝 ys-A 迨Ttz:_~ 0 O6&!< "Q%5I(*< .z0 3 7s:j=+睝 K< [L}nccB  De揪毿vR)r;DM _鑠簜趯  d褚MbP?_*+%,A&C&"褳SO,燫梶"&16 gaT6e-N齎xvz篘XT剉'k遶褃x釼&j礪?'j礪?(~窟镧?)~窟镧?M   4dXA4PRIV 4  x6userUntitled ddX2222222222user   " U 匓(? 匓(?&\(U} D}  D} `D} `H} D} `#D}  H} 'D} " D} # D R C  ,A , , , , , , , , , , , , , , ,,,,,,,,,,,,,,,,, @ @ @ I @ @ I @ @B?B瘕A B C B B C > BB@B淬A B C B B C > B B@B衯A B C B B C > BB@B紛A B C B B C > BB@B4A B C B B C5 > BB@B郧A B C B B C > BB@B迒% B C B B C > B+B @B&% B C B B C > Bu B"@B魜#A B C B B C > B B$@B茒' B C B B C > B B&@B禊A B Ct B) B C* > B B(@B璞A B Cu B+ B C, > B B*@B,A B Cv B- B C. > BB,@B胺A B Cw B/ B C > BB.@BA B Cx B0 B C1 > BB0@B磘#A B Cy B2 B C3 > BB1@B#A B Cz B4 B C5 > BB2@B$#A B C{ B6 B C > BB3@B#A B C| B7 B C. > BB4@B( B C} B8 B C9 > BB5@B犈A B C B* B2 C+ > BB6@BA B C[ B B Cj > BB7@B燃A B C\ B B] C > BB8@BlA B C] B B^ C > BB9@BA B C^ B B_ C > BB:@B(A B C_ B B C > B)B;@B校A B C` B B` C > B)B<@B劥A B Ca B Ba C > BB=@BDA B Cb B Bb C >  BEB>@B額% B Cc B Bc C >! BuB?@BD"A B Cd B Bd C >" BDl~xxxxxxxxxxxxxxxxxxxxxxxxxxxxx ,!,",#,$,%,&,',(,),*,+,, ,-,.,/,0,1,2,3,4,5,6,7,8,9,:,;,<,=,>,?, B@@Bv% B Ce B B C ># Bu!B@@B飘% !B !Cf !B !Be !C !>$ !BB"BA@B琾#A "B "Cg "B "Bf "C ">% "B5#BA@Bv& #B #Ch #B #BF #C[ #>& #B5$BB@B(x#A $B $Ci $B $Bg $C $>' $B5%BB@B嗰& %B %Cj %B %B %CB %>( %B&BC@B ' &B &Ck &B &Bh &C &>) &B5'BC@B軋#A 'B 'Cl 'B 'Bd 'C '>* 'B(BD@BL#A (B (Cm (B (B (C (>+ (B{)BD@B鹇#A )B )Cn )B )B )C )>, )B*BE@B' *B *Co *B *B *C9 *>- *B5*F+BE@B柕( +B +Cp +B +Bi +C +>. +BT,BF@B( ,B ,Cq ,B ,B ,C ,>/ ,B-BF@B剟#A -B -C -B -Bs -C ->H -B.BG@BN{' .B .C .B .B{ .C .>` .B/BG@B`#A /B /C /BD /B /C /> /B0BH@BA 0B 0C 0BB 0B> 0CC 0> 0B1BH@B<A 1B 1C  1BD 1B? 1CE 1> 1B2BI@BtA 2B 2C! 2BF 2B@ 2C 2> 2B 3BI@B炻A 3B 3C" 3BG 3BA 3CH 3> 3B 4BJ@B犖A 4B 4C# 4BI 4BB 4CJ 4> 4B5BJ@BDA 5B 5C$ 5BK 5B 5C 5> 5B6BK@B4A 6B 6C& 6BM 6B 6C 6> 6B'7BK@BxA 7B 7C' 7BN 7B 7C 7> 7B8BL@B让A 8B 8C( 8BO 8B 8C 8> 8B'9BL@BㄎA 9B 9C) 9BP 9BC 9C. 9> 9B:BM@BA :B :C* :BQ :BD :CR :> :B:E;BM@B^% ;B ;C+ ;BS ;B8 ;C ;> ;B<BN@B% <B <C, <BT <B <C <> <B=BN@B恘#A =B =C- =BU =BE =CV => =B>BO@BP~#A >B >C. >BW >B >C >> >B?BO@B ' ?B ?C/ ?BX ?B ?C# ?> ?BDlxxxxxxxxxxxxxxxxxxxxxxxxxxxxx@,A,B,C,D,E,F,G,H,I,J,K,L,M,N,O,P,Q,R,S,T,U,V,W,X,Y,Z,[,\,],^,_,@BP@B #A @B @C0 @BY @B @C @> @BAB@P@B緞' AB AC1 ABZ ABF AC[ A> AB1BBP@B.' BB BC2 BB\ BBG BC] B> BBCB繮@B6' CB CC3 CB^ CB CCv C> CBDBQ@B DB1EB@Q@B^( EB EC5 EB` EBH ECa E> EBFBQ@B寉$A FB FC6 FBb FBI FCc F> FBGB繯@B4A GB GC GBG GB GCH G> GBuHBR@B袏A HB HC HBI HB HC H> HB'IB@R@B,"A IB IC IBJ IB IC' I> IBsJBR@BX#A JB JC JBL JB JC J> JBKB繰@B躸$A KB KC KBM KB KCx K> KBKFLBS@BLA LB LC LB LB LC L>Y LBZMB@S@BlA MB MC MB MB MC> M>[ MB\NBS@B嗦A NB NC NB NB NC N>] NBOB繱@BA OB OC OB OB OCf O>^ OBPBT@BA PB PC PB PB PC P>_ PBQB@T@BPA QB QC QB QB QC Q>` QBRBT@B慁A RB RC RB RB RC R>a RB)SB繲@B谤A SB SC SB SB SC S>b SBTBU@BA TB TC TB TB TC T>c TBdUB@U@B牟A UB UC UB UB UC U>e UBVBU@B牬A VB VC VB VB VCH V>f VBWB繳@B魟A WB WC WB WB WC, W>h WB'XBV@B,A XB XC XB XB XC X>i XBYB@V@B,A YB YC YB YB YC Y>j YBkZBV@BA ZB ZC ZB ZB ZC Z>l ZB[B繴@B剴A [B [C [B [B [C [>m [B)\BW@B詵A \B \C \B \B \C \>n \Bk\E]B@W@B唷A ]B ]C ]B ]B ]C ]>o ]BQ^BW@B及A ^B ^C ^B ^B ^C ^>p ^B/_B繵@BpA _B _C _B _B _C _>q _BDlxxxxxxxxxxxxxxxxxxxxxxxxxxxxx`,a,b,c,d,e,f,g,h,i,j,k,l,m,n,o,p,q,r,s,t,u,v,w,x,y,z,{,|,},~,,`BX@B`A `B `C `B `B `C `> `B+aB@X@B% aB aC aB aB aC a>r aBsbBX@B仍"A bB bC bB bB bC> b>t bBucB繶@B% cB cC cB cB cC c>v cB cEdBY@B揶& dB dC dB dB dC d>w dBeB@Y@B╲#A eB eC eB eB eC e>x eBfBY@B6' fB fC fB fB fC f>y fBgB繷@B' gB gC gB gB gC g>z gB{hBZ@B溂#A hB hC hB hB hC h>| hB{iB@Z@B~' iB iC iB iB iCf i>} iBjBZ@B枌' jB jC jB jB jC1 j>~ jBkB繸@Bx#A kB kC kB kB kC k> kBlB[@B8#A lB lC lB lB lCV l> lBmB@[@B烍( mB mC mB mB mC m> mBnB[@BV' nB nC nB nB nC' n>= nB5oB繹@B錃A oB oC oB oB oC o>g oBdpB\@B貀A pB pC pB pB pC p> pBqB@\@B氨A qB qC qB qB" qC q> qB rB\@BA rB rC rB rB rC r> rBsB繺@BㄍA sB sC sB sB# sC s> sBtB]@B瑎A tB tC tB tB$ tC  t> tBuB@]@BA uB uC uB  uB uC u> uBvB]@B煳A vB vC vB  vB vC v> vB)wB繻@Bn% wB wC wB  wB wC' w> wBxB^@B& xB xC xB  xB xC x> xB1yB@^@B攙#A yB yC yB yB% yC y> yB5zB^@B爒#A zB zC zB zB& zC z> zBzF{B繼@B&& {B {C {B {B' {C {> {B|B_@B,#A |B |C |B |B( |C |> |B}B@_@B黸$A }B }C }B }B) }C }> }B~B_@BlA ~B ~C ~B' ~B= ~C@ ~> ~BB繽@BDA B C B( B C) > BkDlxxxxxxxxxxxxxxxxxxxxxxxxxxxxx , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,B`@B迡% B C B* B C > BB `@B,t#A B C B+ B C, > BB@`@B恦#A B C B- B C. > B5B``@B' B C B/ B C > BB`@Bh#A B C B0 B C1 > B1B燻@B爄A B C B B C > BB繾@BTA B C B B C > BB郹@BlA B C B B C > B!Ba@B4A B C B B C > BB a@B慀A B C B B C > B$B@a@B橓A B C B B C > BB`a@B利A B C B B C > BBa@B悬A B C B B  C > BB燼@BA B C B B  C. > B$B繿@BA B C B B  C > BB郺@B貁A B C B B C > BBb@B鼞A B C B B  Cp > BB b@BLA B C B B  C > B B@b@B犖A B C B B C > B)B`b@B% B C B B C > BuBb@B4"A B C B B C > BB燽@B4"A B C B B C > BB纀@B% B C B B C. > BB郻@B漂% B C B B C > BBc@B.& B C B B C > BB c@B@z#A B C B B C > BB@c@B鲺& B C B B C > BB`c@Bf& B C B B C > BKBc@B饊#A B C B B C. > BB燾@BxA B C B B* C' > BB纁@B蠢A B C B B& C > BB郼@BXA B C B B+ C > BDlxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,Bd@BA B C  B B, C > B\B d@BHA B C  B B- C > BB@d@BhA B C  B  B C > BB`d@B╰A B C  B! B. C" > BBd@BpvA B C  B# B C > B/B燿@B黽A B C B$ B/ C% > B!B纃@ByA B C B& B0 C' > B'B郿@B靰A B C B( B1 C) > BkBe@B源A B C B, B C > BB e@B6% B C B- B3 C. > B B@e@B啱% B C B/ B4 C0 > B)B`e@BPs#A B C B1 B5 C2 > B5Be@B\#A B C B3 B6 C4 > BB爀@B竴#A B C B5 B7 C6 > BB纄@B ' B C B7 B8 C > BB鄀@Bw' B C B: B: C; > B{Bf@Bx#A B C B< B; C= > BB f@Bn' B C B> B< C > BB@f@B灃' B C B? B= C@ > BB`f@B|p$A B C BA B C' > B{Bf@BA B Ci B B C > BB爁@BA B Cj B B C > BB纅@B责A B Ck B B C > BB鄁@B戴A B Cl B B C > BBg@B`A B Cm B B C > BB g@B4A B Cn B B C >  B B@g@B尨A B Co B! B C >  BB`g@B啋% B Cp B" B C# >  B Bg@B>~' B Cq B$ B C% > BB爂@B瀺' B Cr B& B C' > BB纆@B( B Cs B( B C > BB鄃@B A B C Br B C >L BDlxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,Bh@BlA B C Bs B Ct >M BB h@BA B C Bu B Cv >N BB@h@BA B C Bw B Cx >O BB`h@B軛A B C By B Cz >P BQBh@B涿A B C B{ B C| >R B/B爃@Bd"A B C B} B C~ >S BTB纇@B涮"A B C B B CH >U BTB鄅@B' B C B B C >V BBi@B' B C B B C >W BB i@B炢( B C B B C >X BB@i@Bd A B C B B3 C. >v BB`i@BA B C B B C >w BBi@BPA B C B B C9 >x B!B爄@B炷A B C B B3 C. >y B'B纈@B槄A B C B B$ C  >z BQB鄆@B8A B C B B C >{ B Bj@B"A B C B B C  >| BTB j@B斲"A B C B! B3 C. >} BB@j@B缚A B C B B. C" >t BBB`j@B庲& B C B B4 C0 >u B1Bj@B4A B C B B C > B\B爅@BdA B C B B C > BB纉@B<A B C B B C > BB鄇@B<A B C B B C > BkBk@B埬A B C B B C > B B k@B信A B C B B CF > B)B@k@B`"A B C B B C > BB`k@Bv% B C B B C9 > B/Bk@Bv' B C B B  C > BB爇@B孢( B C B B! C > B{B纊@B宩$A B C BE B CF > BB鄈@BA B C_ B B C > BDlxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,Bl@BHA B C` B B C > BB l@BXA B Ca B B C > BB@l@B BB`l@BpA B Cc B B C > BBl@B湺A B Cd B B C > BB爈@B兜% B Ce B B C > BB纋@B栰& B Cf B B C > BB鄉@B芾#A B Cg B B C > BBm@Bd#A B Ch B B C > BB m@BhA B C BU B CV >9 B$B@m@B待A B C BW B CH >: BB`m@BA B C BX B C >; BBm@B疮A B C BY B CF >< B!B爉@B劜A B C BZ B C[ >= B'B續@BじA B C B\ B C >> BB鄊@BXA B C B] B C^ >? BBn@B${A B C B_ B C` >@ B B n@B榹A B C Ba B Cb >A BBB@n@B虘A B C Bc B Cd >C BB`n@BxA B C Be B Cf >D BBn@Bl"A B C Bg B Ch >E B+B爊@B詚#A B C Bi B Cj >F BB纍@BP#A B C Bk B Cl >G BB鄋@Bv' B C Bm B Cn >H B5Bo@B澜#A B C Bo B Cp >I B5B o@B謱' B C Bq B Cp >J BKB@o@BA B C B B C > BkB`o@B A B C7 Bd BJ Ce > BBo@BxA B C8 Bf B' C > B B爋@B A B C9 Bg B Cf > B B纎@B創A B C: Bh B C > BB鄌@B軚A B C; Bi BK Cj > B$Dlxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx , , , , , , , , ,  ,  ,  ,  ,  , , , , , , , , , , , , , , , , , , ,Bp@BA B C< Bk BL Cl > BuBp@B4"A B C= Bm B C9 > B B p@Bdz#A B C> Bn B' C > BB0p@B寊#A B C? Bo BM Cp > BB@p@B#A B C@ Bq BN C > BBPp@B~' B CA Br B$ C  > BB`p@Bn( B CB Bs B Cz > BGBpp@B茡' B C B7 B C > BBp@B(A B C~ B: B C >  B! B恜@BA B C B; B C< >" B! B爌@BA B C B= B C> ># B$ B皃@B劧A B C B? B C@ >% B B纏@B0A B C BA B CB >& B' B衟@B A B C BC B CD >( B)B鄍@B% B C BE B CF >* B+B餻@BV% B C BG B CH >, B-Bq@B樫"A B C BI B CJ >. B/Bq@B$t#A B C BK B C >0 B1B q@B榵#A B C BL B CM >2 BB0q@B企& B C BN B CO >3 BB@q@B,#A B C BP B C' >4 B5BPq@B{' B C BQ B CR >6 B5B`q@B辿' B C BS B CT >7 B8Bpq@BdA B C B8 B9 C9 > BBq@BA B C B B C >G BB恞@B湸A B C B B Cf >I B B爍@BA B C B Bt C >J BB皅@B鹕A B C B B C >K BB纐@B紨A B C B Bu C >L B$B衠@B A B C B B[ C >M B$B鄎@BPxA B C B BG C] >N BB餼@B~A B C B B C >O BDlxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx  ,! ," ,# ,$ ,% ,& ,' ,( ,) ,* ,+ ,, ,- ,. ,/ ,0 ,1 ,2 ,3 ,4 ,5 ,6 ,7 ,8 ,9 ,: ,; ,< ,= ,> ,? , Br@B鄝A B C B B C >P B!Br@B鋩A !B !C !B !B !C !>Q !B"B r@B話A "B "C "B "BG "C] ">R "B#B0r@B,A #B #C #B #B #C #>S #B)$B@r@BdA $B $C $B $Bv $C $>T $B%BPr@B卸A %B %C %B %BH %Ca %>U %B&B`r@B淅A &B &C &B &Bw &C &>V &B'Bpr@B妓A 'B 'C 'B 'B  'C '> 'B)(Br@B@"A (B (C (B (B (C (>W (B+)B恟@B敉"A )B )C )B )B )Cj )>X )B *B爎@B蓿% *B *C *B *BU *C *>Y *B/+B皉@B鹬"A +B +C +B +B +C +>Z +B ,B纑@B枸"A ,B ,C ,B ,B ,C ,>[ ,B+-B衦@B(t#A -B -C -B -BY -C= ->\ -B1.B鄏@B庻& .B .C .B .By .C .>^ .B1/B餽@B' /B /C /B /Bz /C />_ /B0Bs@B #A 0B 0C 0B 0BY 0C= 0>a 0B1Bs@B瑢#A 1B 1C 1B 1B| 1C 1>b 1B2B s@Bn~' 2B 2C 2B 2B} 2C 2>c 2B53B0s@B迠' 3B 3C 3B 3B 3C 3>d 3B{4B@s@B迴' 4B 4C 4B 4B~ 4C 4>e 4B5BPs@B鎾' 5B 5C 5B 5B 5C 5>f 5B6B`s@B4n$A 6B 6C 6B 6B 6C 6>g 6B7Bps@B( 7B 7C 7B 7B 7C 7>h 7BK8Bs@Bn( 8B 8C 8B 8B 8C 8>i 8B9B恠@B磡A 9B 9C 9BZ 9BO 9Cu 9> 9B:B爏@B貪"A :B :C :B[ :B :C\ :> :B;B皊@B<% ;B ;C ;B] ;B( ;C ;> ;B<B纒@B=% <B <C <B^ <B <C <> <B=B衧@B膛"A =B =C% =BL =B =C9 => =B->B鄐@B0A >B >CC >Bt >BO >Cu >> >B ?B餾@B(A ?B ?CD ?Bv ?BP ?C ?> ?BDlxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx@ ,A ,B ,C ,D ,E ,F ,G ,H ,I ,J ,K ,L ,M ,N ,O ,P ,Q ,R ,S ,T ,U ,V ,W ,X ,Y ,Z ,[ ,\ ,] ,^ ,_ ,@Bt@B<A @B @CE @Bw @BQ @Cx @> @B ABt@BdA AB ACF ABy ABR ACz A> AB BB t@B A BB BCG BB{ BBS BC| B> BBCB0t@B\xA CB CCH CB} CB CC C> CB'DB@t@B赖A DB DCI DB~ DB DC D? DBEBPt@B惻A EB ECJ EB EB ECf E> EBQFB`t@BhA FB FCK FB FBT FC F> FBGBpt@B茋% GB GCL GB GBU GC G>  GBHBt@B0h#A HB HCM HB HBV HC H>  HB5IB恡@Bv' IB ICN IB IBL ICl I>  IB5I EJB爐@B' JB JCO JB JBT JC J>  JBKB皌@B#A KB KCP KB KBO KCu K>  KBLB纓@Bny' LB LCQ LB LBQ LCx L> LBMB衪@B効#A MB MCS MB MB MC9 M> MB1NB鄑@B苼' NB NCT NB NBM NCp N> NBOB餿@B#A OB OCU OB OBX OC O> OBPBu@B瀳' PB PCV PB PBY PC= P> PBQBu@B唽' QB QCW QB QBZ QC Q> QBRB u@Bn' RB RCX RB RB[ RC R> RBSB0u@B黬$A SB SCY SB SB\ SC S> SBTB@u@B( TB TCZ TB TB& TC T> TBUBPu@B#A UB UC UB UBx UC U>] UBVB`u@BA VB VCr VB VBI VCc V>0 VB$WBpu@BPA WB WCt WB WB WC W>2 WB$XBu@B鋶A XB XCu XB XBj XC X>3 XBYB恥@B$A YB YCv YB YB' YC Y>4 YB!ZB爑@B魴A ZB ZCw ZB ZBk ZC Z>5 ZB![B皍@B0A [B [Cx [B [Bl [C [>6 [B\B纔@BTA \B \Cy \B \B \C \>7 \B]B衭@B悪A ]B ]Cz ]B ]B ]C ]>8 ]Bk] F^B鄒@B埀A ^B ^C{ ^B ^Bm ^C ^>9 ^B)_B饀@BHA _B _C| _B _Bi _C _>: _B)Dlxxxxxxxxxxxxxxxxxxxxxxxxxxxxx`,a,b,c,d,e,f,g,h,i,j,k,l,m,n,o,p ,q ,r ,s ,t ,u ,v ,w ,x ,y ,z ,{ ,| ,} ,~ , ,`Bv@B犆A `B `C} `B `Bn `C `>; `B)aBv@B"A aB aC~ aB aB aC a>< aB+bB v@B娉% bB bC bB bBo bC b>> bB cB0v@B撅& cB cC cB cB cC. c>? cBdB@v@B& dB dC dB dBp dC d>@ dBeBPv@B #A eB eC eB eBq eC e>A eBfB`v@B' fB fC fB fBr fC f>B fBgBpv@B>' gB gC gB gB gC g>C gB5hBv@B.|' hB hC hB hB hC h>D hBhGiB恦@B#A iB iC iB iB iC i>E iBjB爒@B顤' jB jC jB jB= jC@ j>F jBkB皏@BTl#A kB kCR kB kBW kC k> kBlB纕@B A lB lC lB2 lB lC3 l> lB mB衯@BA mB mC mB4 mBH mCa m> mBnB鄓@B A nB nC nB5 nB nC n> nBoB饁@Bx"A oB oC oB6 oB$ oC  o> oB!pBw@B|%A pB pC pB8 pB pC' p> pBqBw@BTA qB qC qB9 qB qC q> qBrB w@B溑A rB rC rB: rB rC r> rBsB0w@BhA sB sC sB; sB sC s> sBtB@w@B螒% tB tC tB< tB tC t> tBuuBPw@B荣"A uB uC uB= uBL uCl u> uBTvB`w@B`t#A vB vC vB> vB vC v> vBwBpw@Bn& wB wC wB? wB3 wC. w> wBxBw@B' xB xC xB@ xB xC x> xB1yB恮@BV' yB yC yBA yB yCB y> yB1zB爓@Bɑ#A zB zC zBC zB zC. z> zB{B皐@B~ ' {B {C {B# {B {C9 {> {B|B纖@B$#A |B |C |B$ |B3 |C. |> |B}B衱@B謼' }B }C }B% }B }C& }> }B{~B鄔@B' ~B ~C ~B" ~B ~C' ~>~ ~BB饂@BV( B C BK BY C= > BDlxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx , , , , , , , , , , , , , , , , , ,Bx@B A B C BN B CO > BBx@BxA B C BP B CQ > B!B x@B A B C BR B C > B!B0x@BA B C BS B$ C  > B+B@x@B拼% B C BT B CU > BBPx@B畡' B C BV B CW > BB`x@B畵' B C BX B CY > BBpx@B嘻& B Cs B B C >1 BBx@BXA B C B B C >j BB恱@B,A B C B  B C. >k B'B爔@BこA B C B  B C  >l BB皒@B|A B C B  B C  >m BB纗@B鏃% B C B B' C >n B+B衳@B~% B C B B C >o BuB鄕@Bf& B C B BK Cj >p B5B饃@B#A B C B B C' >q BBy@B #A B C B B C >r BBy@BP#A B C B B C >s B( Txxxxxxxxxxxxxxxxx>@BB   Sheet1ggD  鄥燆鵒h珣+'迟0@HT` x Microsoft Excel@&灼@_r黒H胀諟.摋+,0 PXd lt|  Sheet1Sheet1!Print_AreaSheet1!Print_Titles 工作表 命名范围 F#Microsoft Office Excel 2003 工作表Biff8Excel.Sheet.89瞦CompObj o