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In the latter, one relaxes the requirement of finishing in polynomial time by restricting the combinatorial explosion in the running time to a parameter that for reasonable inputs is much smaller than the input size. New techniques will be developed that will simultaneously utilize the notions of relaxed time complexity and accuracy and thereby make problems for which both these approaches have failed independently, tractable.
It is however conceivable that for some problems even this combined approach may not succeed. But in those situations we will glean valuable insight into the reasons for failure. In parallel to algorithmic studies, an intractability theory will be developed which will provide the theoretical framework to specify the extent to which this approach might work. Thus, on one hand the project will give rise to algorithms that will have impact beyond the boundaries of computer science and on the other hand it will lead to a complexity theory that will go beyond the established notions of intractability.
Both these aspects of my project are groundbreaking -- the new theory will transcend our current ideas of efficient approximation and thereby raise the state of the art to a new level. Project Nutrient sensing by parasites. Summary As any other obligate parasite, Plasmodium depends on its hosts and on the nutrients they provide to survive and complete its life cycle. Our preliminary data provides unequivocal evidence that Plasmodium has the ability to sense the host low-nutrient status and adapt to it by decreasing its multiplication rate.
Thus, the overall goal of the present proposal is to unveil the molecular mechanisms by which parasites are capable to sense and adapt to environmental signals originated from nutrients and to determine its impact on the course and virulence of infection. The present proposal moves towards a change of paradigm on how host-parasite interactions are viewed. By definition, since a parasite requires a host in order to survive, a decrease in the availability of an essential molecule obtained from the host will weaken the parasite and render it incapable of succeeding in its life cycle.
The rationale behind this proposal is that parasites monitor host nutritional environment and, prior to any nutrient s becoming limiting, are able to respond and adapt to the sensed alteration s. Multidisciplinary approaches that combine genetic, genomic, cell biological and physiological methodologies will be used. Results arising from the present proposal will provide novel insights into the cell biology of these parasites and will increase our understanding of the interactions that these parasites maintain with their hosts.
Project New paradigms for correlated quantum matter:Hierarchical topology, Kondo topological metals, and deep learning. Summary Discovering, classifying and understanding phases of quantum matter is a core goal of condensed matter physics. Next to the notion of symmetry breaking phases, the concept of topological phases of matter is a prevailing theme of recent research. Topological phases are envisioned for various applications due to their universal and robust properties, such as protected conducting boundary modes, and provoke fundamental questions about the nature of many-body quantum states by providing the basis for exotic quasiparticles.
In this ERC research project, I propose several new topological phases and novel numerical approaches for studying and classifying the most sought-after topological phases of matter. Concretely, I propose the concept of three-dimensional hierarchical topological insulators, which, in contrast to the known topological phases, do not posses gapless surface, but protected gapless edge modes.
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Moreover, I plan to study topological metals arising in strongly correlated Kondo systems, going beyond the current paradigm of considering topological metals that arise in the absence of electronic correlations. Furthermore, I propose to make the analogous step for topological superconductors, which have been studied as free models to search for Majorana quasiparticles: For the first time, I want to explore strongly interacting systems that realize the more powerful parafermion quasiparticles with numerical techniques.
Finally, in a cross-disciplinary and exploratory sub-project, I will employ methods of deep neural networks to classify strongly correlated quantum phases using supervised learning combined with a technique called deep dreaming. Each of these sub-projects has the potential to make a paradigm-changing contribution to the study of strongly correlated and topological states of quantum matter and the combination of them allows to take advantage of synergy effects and a balance between high-risk and definitely feasible key developments.
Project acronym PariTorMod. Summary The overall theme of the proposal is the interplay between p-adic arithmetic geometry and the Langlands correspondence for number fields. At the heart of the Langlands program lies reciprocity, which connects Galois representations to automorphic forms. Recently, new developments in p-adic arithmetic geometry, such as the theory of perfectoid spaces, have had a transformative effect on the field. This proposal would establish a research group that will develop and exploit novel techniques, that will allow us to move significantly beyond the state of art.
I intend to make fundamental progress on three major interlinked problems. Torsion in the cohomology of Shimura varieties: in joint work with Scholze, I proved a strong vanishing result for torsion in the cohomology of compact unitary Shimura varieties.
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In work in progress, we have extended this to many non-compact cases. To obtain a complete picture, I propose to develop new techniques using point-counting and the trace formula and combine them with ingredients from arithmetic geometry. Local-global compatibility is essential for establishing new instances of Langlands reciprocity. I will use the results on Shimura varieties described above to prove local-global compatibility for torsion in the cohomology of locally symmetric spaces for general linear groups over CM fields.
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This is one of the fundamental questions in the field. Solving it will require progress on a diverse set of problems in representation theory and integral p-adic Hodge theory. The Fontaine—Mazur conjecture is the most general reciprocity conjecture. Very little is known outside the case of two-dimensional representations of the absolute Galois group of the rational numbers, which relies crucially on a connection to p-adic local Langlands.
I will attack the Fontaine—Mazur conjecture for imaginary quadratic fields. Some crucial inputs will come from the first two projects above. Project Protection against reactive oxygen species in neurodegeneration. Summary Oxidative stress OS is implicated in the pathogenesis of some of the most devastating neurological diseases. Therefore, identification of pathways that counteract oxidative damage may lead to therapeutic strategies applicable to a wide range of disorders. I have recently identified the importance of the mitochondrial oxidation resistance 1 Oxr1 gene for neuronal survival; loss of Oxr1 causes neurodegeneration in mice, whereas over-expression in vitro is able to confer protection against OS.
Deregulation of this protein is also observed in human ALS and additional mouse models of in neurodegeneration. Despite the apparent high level of conservation of Oxr1-related proteins, virtually nothing is known about their function in vivo. This proposal will establish an independent research programme to understand the role of Oxr1 and related proteins as part of novel pathways that provide protection against both OS and neurodegeneration.
Preliminary data I have generated has identified proteins that interact with Oxr1 in neurons; significantly, a number of these binding partners are mutated in neurodegenerative disease. Therefore, using a combination of mutational and biochemical analysis the relationship of these interactions to neuronal cell death will be investigated. Studies will also focus on the role of Oxr1 in mitochondria, examining the significance of this localisation to the control of the OS response.
This will be complemented by in vivo studies in the mouse to to determine whether the loss or disruption of Oxr1-related proteins is critical for CNS function. Using the latest techniques in molecular genetics and in vivo modelling this project has major translational opportunities and will provide an excellent opportunity to answer one of the key questions in neurodegenerative research. Project acronym PartonicNucleus. Summary The representation of the nucleus as an aggregate of protons and neutrons has been quite successful to describe nuclear properties in the past.
However, it is now the time to understand the nuclear structure in terms of quarks and gluons i. With time, most explanations of this phenomenon have come to fail and this major nuclear effect remains today a mystery, but clearly tells us that a description of the nucleus in which protons and neutrons are not affected by their surrounding medium is incomplete. I propose here to use several recent developments in detection technologies and in hadron physics theory to perform new experiments that will unravel the deeper structure of the atomic nucleus. The first measurement will give the 3D tomography of the nucleus in terms of quarks and gluons.
Second, I lay out a strategy to measure transverse momentum dependent parton distribution functions in cold nuclear matter and show how it can help understand the gluon saturation scale, i. Third, I propose to measure reactions, in which we detect nuclear remnants, to link the nucleon and quark dynamics of the nucleus together. This facility offers a unique setup with the most intense multi-GeV electron beam in the world.
Together, these three unique measurements form a comprehensive program to decisively advance our understanding of the nuclear structure in terms of quarks and gluons. Project Re-conceptualizing party democracy. Summary The aim of this project is to provide an empirical and theoretical re-conceptualization of political parties and party democracy. The challenge of democratic legitimacy faced by political parties in modern democracies derives principally from their deteriorating relationship with society, which has been accentuated by a growing disengagement of citizens from conventional party politics.
However, whereas parties are conventionally being understood in terms of their linkages with society, this project proposes to rethink parties in terms of their linkages with the state and party democracy as based on a conception of parties as public utilities rather than private associations. More specifically, it intends to investigate the contours of such a new conception of political parties and party democracy through a particular focus on the management of parties by the state through public law and regulation.
The project will thereby bridge the existing gap between the empirical study of parties and normative democratic theory and integrate the disciplines of political science and constitutional and public law through a systematic and comprehensive longitudinal and comparative analysis of party regulation in post-war European democracies. In doing so, it will push the boundaries of conventional empirical research on political parties as well as the normative paradigms of modern democracy and will contribute to a better, and more meaningful, understanding of the future of representative democracy and the role of political parties within it.
In doing so, moreover, it will go significantly going beyond conventional — and ultimately unproductive — approaches which, by proposing the revitalization of historically dated organizational linkages between parties and society as the way forward, implausibly suggest that the irreversible process of party transformation can be put to a halt or turned round. Project acronym PAS. Project Persistence of allergic sensitization.
Researcher PI David Voehringer. Summary Allergic disorders are dramatically increasing in the western world over the past several years.
Allergies are inappropriate immune responses directed against harmless environmental antigens. Upon primary allergen encounter B cells are induced to differentiate into IgE producing plasma cells. Mast cells and basophils are then sensitized by binding of allergen-specific IgE molecules to the high-affinity IgE receptor on the cell surface.
A second allergen exposure causes cross-linking of IgE molecules on mast cells and basophils which results in degranulation of pro-inflammatory mediators. Allergen-specific IgE can be detected many months after the sensitization phase despite the fact that IgE has a very short half-life.
This suggests that small amounts of allergen-specific IgE are constantly secreted by long-lived IgE producing plasma cells. The development, turnover and fate of IgE producing cells in vivo are largely unknown. Therefore, we propose to study these important issues by using genetically modified mouse strains and cutting edge technology. The reporter mice will allow us to isolate IgE-producing cells so that we can determine their gene expression profile. Furthermore, we will determine the turnover and lifespan of IgE producing cells in vivo by BrdU incorporation. Finally, we will generate an IgE-Cre knock-in mouse to specifically delete conditional alleles in IgE-producing cells.
Taken together, these important experiments will help us to better understand the biology of IgE-producing cells and may result in development of novel therapeutic strategies. Researcher PI Domenico Marinucci. Summary This is an interdisciplinary project at the interface between Mathematical Statistics, Probability and Cosmological Applications. The principal focus is on the harmonic analysis for isotropic, mean square continuous spherical random fields, with a view to applications to Cosmic Microwave Background radiation data analysis.
Project Patristic sermons in the Middle Ages. The dissemination, manipulation and interpretation of late-antique sermons in the medieval Latin West. The sermons of Augustine, Gregory the Great and other patristic preachers were transmitted throughout medieval Europe in the form of sermon collections, preserved in thousands of manuscripts.
Nearly every manuscript contains a new combination of sermons, attesting to a continuous, widespread engagement with the authorities of the Early Church. The dynamic tradition of reorganising and rewriting the patristic heritage is largely overlooked by scholars of medieval religious practices, who concentrate on medieval preachers, and by scholars of Early Christianity, whose focus is the patristic context.
Medieval collections of patristic sermons were part of the liturgical life of the monastery, but also of an intellectual tradition. They offer unique insights into medieval attitudes toward authority, techniques of appropriation, church organisation, monastic networks and knowledge exchange. PASSIM will execute the first large-scale analysis of the formation and spread of patristic sermon collections in medieval Europe. The project will develop a digital network of manuscripts, using well-tried principles from the field of textual criticism.
Building on this network, PASSIM will pursue three lines of inquiry: the customizing of standard liturgical collections as indicative of individual purposes and contexts, the impact of transmission on the popularity of patristic sermons, and pseudo-epigraphic sermons as revelatory of medieval perceptions of the Church Fathers. PASSIM will bridge two disciplinary divides, between patristic and medieval sermon studies and between textual criticism and reception studies.
Developing an interdisciplinary methodology with a wide applicability in the study of intellectual history, this project will introduce patristic preaching as a vibrant strand in the tapestry of the medieval religious tradition. Researcher PI Oliver Wurl. The oceans are huge reservoirs of CO2, and a better understanding on how the oceans absorb CO2 is critical for predicting climate change. The sea-surface microlayer SML , the aqueous boundary layer between the ocean and atmosphere, plays an important role in the exchange of gases between the ocean and atmosphere.
The effects of the SML on air-sea gas exchange have been widely ignored by past and current research efforts due to uncertainties to what extent the SML covers the oceans. However, we recently reported the ubiquitous coverage of the oceans with SML, which pushes the SML into a new and wider context that is relevant to many ocean and climate sciences. I propose experiments at multiple scales, i. I propose a systematic field study measuring air-sea CO2 fluxes and mapping chemical, biological and physical properties of the SML.
With the experiments on smaller scales, such measurements will allow for the first time i to define new parameters controlling gas fluxes, ii to quantify short-time and seasonal variability, iii to define global proxies for the effects of the SML, and iv to develop and apply a new parameterization for the correction of global CO2 flux data. The results from the proposed studies can form the basis for an improvement of current assessments of CO2 fluxes, and oceanic uptake rates.
A better understanding in the oceanic uptake of atmospheric CO2 is critical in predicting climate trends and establishing policies. Project Passive membrane transport of organic compounds. Summary Passive transport through lipid membranes is ubiquitous and fundamental in living systems. The aim of this proposal is to create novel biotechnological tools to study permeation of organic compounds through lipid membranes and protein pores. In particular, I will focus on strategies employed by living organisms to optimize and regulate permeation directly through their membranes. The fundamental principles are probed by creating macroscopic model systems for biological channels and membranes.
Simultaneously, new microfluidic tools will allow for a screening of biological relevant organic compounds. Biotechnological experiments investigating permeation of organic molecules into single uni-lamellar vesicles will challenge the dogma of protein controlled membranes transport. Indole, an important signaling molecule for E. Microfluidics provide the controlled environment, holographic optical tweezers confine single vesicles in three dimensions to facilitate ionic current detection and simultaneous auto-fluorescence detection.
This unique combination will yield a scalable technology platform to test membrane permeation. However, a deeper understanding of the molecular basis for these passive transport processes is still elusive. Theory predicts that binding potentials for molecules in a protein channel, passive transport can be optimized.
Combining microfluidics with holographic optical tweezers provides the optimal means to test this quantitatively. These model experiments will prove that passive transport can be enhanced and optimized by introducing binding sites in protein channels and membranes. Furthermore, the results will guide future design of e. Researcher PI Philip Schwyzer.
Research will be organized in three strands with staggered start-dates, focusing on three types of locale strongly associated with cultural and individual memory. Strand 1 focuses on the history of death, burial and commemoration at a group of English and Welsh cathedrals. Strand 2 explores the interaction of medieval, early modern and modern people with sites of ancient habitation, including Roman settlements, Iron Age hill forts, and prehistoric tombs. Research in each strand will centre on six case studies drawn from across southern Britain, with clusterings in the southwest and the Welsh borders.
Exemplifying a fresh interdisciplinary approach to the history of memory, the project aims to ignite further research both within Britain and overseas. With its cross-period approach, innovative combination of literary and archaeological perspectives and methodologies, and multicultural focus, this timely project addresses challenges at the frontiers of multiple disciplines. Summary Epigenetic inheritance may not only occur in plants and fungi but also in mammals.
While the effect of maternal lifestyle and in utero exposures is well studied, paternal epigenetic inheritance is a novel research field, especially in regard to chemical exposures.
Many environmental pollutants exhibit anti-androgenic function. Despite the vital role of androgens in spermatogenesis, the effects of adult anti-androgen exposure on the sperm epigenome and offspring phenotype have been scarcely studied. The overall aim of this novel project is to increase the understanding of if, and how, male life experiences such as adult exposure to the anti-androgenic model substance and pollutant DBP di-n-butyl phthalate may affect offspring through paternal epigenetic inheritance.
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I accomplish this by integrating animal and human studies, using RNA-sequencing and mass spectrometry-based peptidomics to identify DBP-induced alterations in the sperm transcriptome and peptidome, examine noncoding RNAs and peptides role in embryogenesis, development and long-term health of the offspring in two generations. To validate the mechanistic importance of the sperm molecular alterations microinjections of selected biomolecules into zygotes will be conducted.
This is the first project to investigate multigenerational effects of adult male exposure to anti-androgens in detail, and investigate the role of the sperm peptidome in paternal epigenetic inheritance. Directly linking animal experimental data about paternal transmission to human studies is unique and necessary to determine causal connection between environmentally-induced biomolecular alterations in sperm and offspring phenotype.
The project can contribute to ground-breaking mechanistic understanding of how male life experiences may affect offspring through epigenetic inheritance. The findings may also have important public health implications via new regulations of anti-androgenic chemicals and male preconceptional interventions.
Project Linking Pathogen Evolution and Epidemiology. Summary The goal of the proposed research is a comprehensive understanding of how evolutionary potential of pathogen populations interacts with epidemiological dynamics in natural populations. The empirical work will be conducted on the specialist fungal pathogen Podosphaera plantaginis and its host plant Plantago lanceolata in a large network of host populations. I will address the key theories of pathogen evolution, involving life-history trade-offs, competition for resources under multiple infection, and sexual reproduction.
This project takes advantage of the exceptional research opportunities offered by the focal study species to test models that have not been validated with respect to realized population dynamics and the persistence of pathogen populations. I have studied the coevolutionary dynamics between P. Unique epidemiological data have been collected annually on the occurrence of the pathogen in a network of host populations since Recently, I have generated an EST library for the pathogen that allows and facilitates genetic studies. In the planned research, I will combine laboratory experiments with large-scale population surveys, genetic studies and mathematical modelling to achieve the objectives of this proposal.
The proposed research has potential for groundbreaking results on pathogen evolution and epidemiology through: i Simultaneous study of multiple forces driving pathogen evolution and their importance in natural populations, with direct connections to epidemiology. Project acronym PathoPhageHost. Researcher PI Anat Herskovits. Summary The DNA uptake competence system of the intracellular bacterial pathogen Listeria monocytogenes was considered non-functional. There are no known conditions for DNA transformation and the competence master activator gene, comK, is interrupted by a temperate lysogenic prophage.
We have shown recently that the L. Remarkably, we found that regulation of the competence system relies on the formation of a functional comK gene via a controlled process of prophage excision. Prophage excision was specifically induced during intracellular growth, primarily within phagosomes, yet, unlike classic prophage induction, progeny virions were not produced and bacterial lysis did not occur. This study revealed a unique adaptation of a prophage to the intracellular life style of its host, whereby the prophage serves as a genetic switch to modulate the virulence of its host.
In the proposed project we aim to investigate this phenomenon and study the give-and-take interactions between the L. We will study the prophage determinants and mechanisms that control intracellular excision and maintenance as well as the mechanisms that prevent its virions production and bacterial lysis. Lastly, we will investigate the unexpected function of the competence system in phagosomal escape.
In particular, we will explore the possibility that the competence system serves as an auxiliary secretion system, which secretes proteins that promote phagosomal escape. Project In vivo pathogen proteome profiling using selected reaction monitoring.
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