ERC FUNDED PROJECTS

For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route. To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation: Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome. Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function. Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach. Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.

1 500 000 €

Start date: 2015-04-01, End date: 2020-03-31

The goal of this project is to develop a mathematical theory for steady three-dimensional water waves with vorticity. The mathematical model consists of the incompressible Euler equations with a free surface, and vorticity is important for modelling the interaction of surface waves with non-uniform currents. In the two-dimensional case, there has been a lot of progress on water waves with vorticity in the last decade. This progress has mainly been based on the stream function formulation, in which the problem is reformulated as a nonlinear elliptic free boundary problem. An analogue of this formulation is not available in three dimensions, and the theory has therefore so far been restricted to irrotational flow. In this project we seek to go beyond this restriction using two different approaches. In the first approach we will adapt methods which have been used to construct three-dimensional ideal flows with vorticity in domains with a fixed boundary to the free boundary context (for example Beltrami flows). In the second approach we will develop methods which are new even in the case of a fixed boundary, by performing a detailed study of the structure of the equations close to a given shear flow using ideas from infinite-dimensional bifurcation theory. This involves handling infinitely many resonances.

1 203 627 €

Start date: 2016-03-01, End date: 2021-02-28

This project studies several mathematical topics with a related theme, all of them part of the relatively new discipline known as additive combinatorics. We look at approximate, or rough, variants of familiar mathematical notions such as group, polynomial or homomorphism. In each case we seek to describe the structure of these approximate objects, and then to give applications of the resulting theorems. This endeavour has already lead to groundbreaking results in the theory of prime numbers, group theory and combinatorial number theory.

1 000 000 €

Start date: 2011-10-01, End date: 2016-09-30

Many Gram-positive (pathogenic) bacteria are dependent on the uptake of vitamins from the environment or from the infected host. We have recently discovered the long-elusive family of membrane protein complexes catalyzing such transport. The vitamin transporters have an unprecedented modular architecture consisting of a single multipurpose energizing module (the Energy Coupling Factor, ECF) and multiple exchangeable membrane proteins responsible for substrate recognition (S-components). The S-components have characteristics of ion-gradient driven transporters (secondary active transporters), whereas the energizing modules are related to ATP-binding cassette (ABC) transporters (primary active transporters). The aim of the proposal is threefold: First, we will address the question how properties of primary and secondary transporters are combined in ECF transporters to obtain a novel transport mechanism. Second, we will study the fundamental and unresolved question how protein-protein recognition takes place in the hydrophobic environment of the lipid bilayer. The modular nature of the ECF proteins offers a natural system to study the driving forces used for membrane protein interaction. Third, we will assess whether the ECF transport systems could become targets for antibacterial drugs. ECF transporters are found exclusively in prokaryotes, and their activity is often essential for viability of Gram-positive pathogens. Thus they could turn out to be an Achilles’ heel for the organisms. Structural and mechanistic studies (X-ray crystallography, microscopy, spectroscopy and biochemistry) will reveal how the different transport modes are combined in a single protein complex, how transport is energized and catalyzed, and how protein-protein recognition takes place. Microbiological screens will be developed to search for compounds that inhibit prokaryote-specific steps of the mechanism of ECF transporters.

1 500 000 €

Start date: 2012-01-01, End date: 2017-12-31

The proposed work concerns the theoretical and numerical development of robust and adaptive methodologies for broadband imaging in clutter. The word clutter expresses our uncertainty on the wave speed of the propagation medium. Our results are expected to have a strong impact in a wide range of applications, including underwater acoustics, exploration geophysics and ultrasound non-destructive testing. Our machinery is coherent interferometry (CINT), a state-of-the-art statistically stable imaging methodology, highly suitable for the development of imaging methods in clutter. We aim to extend CINT along two complementary directions: novel types of applications, and further mathematical and numerical development so as to assess and extend its range of applicability. CINT is designed for imaging with partially coherent array data recorded in richly scattering media. It uses statistical smoothing techniques to obtain results that are independent of the clutter realization. Quantifying the amount of smoothing needed is difficult, especially when there is no a priori knowledge about the propagation medium. We intend to address this question by coupling the imaging process with the estimation of the medium's large scale features. Our algorithms rely on the residual coherence in the data. When the coherent signal is too weak, the CINT results are unsatisfactory. We propose two ways for enhancing the resolution of CINT: filter the data prior to imaging (noise reduction) and waveform design (optimize the source distribution). Finally, we propose to extend the applicability of our imaging-in-clutter methodologies by investigating the possibility of utilizing ambient noise sources to perform passive sensor imaging, as well as by studying the imaging problem in random waveguides.

690 000 €

Start date: 2010-06-01, End date: 2015-11-30

I propose to establish a research group to develop completely new tools in order to solve three important problems on the relationships between automorphic forms and Galois representations, which lie at the heart of the Langlands program. The first is to prove Serre’s conjecture for real quadratic fields. I will use automorphic induction to transfer the problem to U(4) over the rational numbers, where I will use automorphy lifting theorems and results on the weight part of Serre's conjecture that I established in my earlier work to reduce the problem to proving results in small weight and level. I will prove these base cases via integral p-adic Hodge theory and discriminant bounds. The second is to develop a geometric theory of moduli spaces of mod p and p-adic Galois representations, and to use it to establish the Breuil–Mézard conjecture in arbitrary dimension, by reinterpreting the conjecture in geometric terms. This will transform the subject by building the first connections between the p-adic Langlands program and the geometric Langlands program, providing an entirely new world of techniques for number theorists. As a consequence of the Breuil-Mézard conjecture, I will be able to deduce far stronger automorphy lifting theorems (in arbitrary dimension) than those currently available. The third is to completely determine the reduction mod p of certain two-dimensional crystalline representations, and as an application prove a strengthened version of the Gouvêa–Mazur conjecture. I will do this by means of explicit computations with the p-adic local Langlands correspondence for GL_2(Q_p), as well as by improving existing arguments which prove multiplicity one theorems via automorphy lifting theorems. This work will show that the existence of counterexamples to the Gouvêa-Mazur conjecture is due to a purely local phenomenon, and that when this local obstruction vanishes, far stronger conjectures of Buzzard on the slopes of the U_p operator hold.

1 131 339 €

Start date: 2012-10-01, End date: 2017-09-30

In many situations experts act adequately, yet without deliberation. Architects e.g, immediately sense opportunities offered by the site of a new project. One could label these manifestations of expert intuition as ‘higher-level’ cognition, but still these experts act unreflectively. The aim of my project is to develop the Skilled Intentionality Framework (SIF), a new conceptual framework for the field of embodied/enactive cognitive science (Chemero, 2009; Thompson, 2007). I argue that affordances - possibilities for action provided by our surroundings - are highly significant in cases of unreflective and reflective ‘higher’ cognition. Skilled Intentionality is skilled coordination with multiple affordances simultaneously. The two central ideas behind this proposal are (a) that episodes of skilled ‘higher’ cognition can be understood as responsiveness to affordances for ‘higher’ cognition and (b) that our surroundings are highly resourceful and contribute to skillful action and cognition in a far more fundamental way than is generally acknowledged. I use embedded philosophical research in a particular practice of architecture to shed new light on the ways in which affordances for ‘higher’ cognition support creative imagination, anticipation, explicit planning and self-reflection. The Skilled Intentionality Framework is groundbreaking in relating findings established at several complementary levels of analysis: philosophy/phenomenology, ecological psychology, affective science and neurodynamics. Empirical findings thought to be exclusively valid for everyday unreflective action can now be used to explain skilled ‘higher’ cognition as well. Moreover, SIF brings both the context and the social back into cognitive science. I will show SIF’s relevance for Friston’s work on the anticipating brain, and apply it in the domain of architecture and public health. SIF will radically widen the scope of the increasingly influential field of embodied cognitive science.

1 499 850 €

Start date: 2016-05-01, End date: 2021-04-30

The goal of this project is to investigate two conjectures in arithmetic geometry pertaining to the geometry of projective varieties over finite and number fields. These two conjectures, formulated by Tate and Grothendieck in the 1960s, predict which cohomology classes are chern classes of line bundles. They both form an arithmetic counterpart of a theorem of Lefschetz, proved in the 1940s, which itself is the only known case of the Hodge conjecture. These two long-standing conjectures are one of the aspects of a more general web of questions regarding the topology of algebraic varieties which have been emphasized by Grothendieck and have since had a central role in modern arithmetic geometry. Special cases of these conjectures, appearing for instance in the work of Tate, Deligne, Faltings, Schneider-Lang, Masser-Wüstholz, have all had important consequences. My goal is to investigate different lines of attack towards these conjectures, building on recent work on myself and Jean-Benoît Bost on related problems. The two main directions of the proposal are as follows. Over finite fields, the Tate conjecture is related to finiteness results for certain cohomological objects. I want to understand how to relate these to hidden boundedness properties of algebraic varieties that have appeared in my recent geometric proof of the Tate conjecture for K3 surfaces. The existence and relevance of a theory of Donaldson invariants for moduli spaces of twisted sheaves over finite fields seems to be a promising and novel direction. Over number fields, I want to combine the geometric insight above with algebraization techniques developed by Bost. In a joint project, we want to investigate how these can be used to first understand geometrically major results in transcendence theory and then attack the Grothendieck period conjecture for divisors via a number-theoretic and complex-analytic understanding of universal vector extensions of abelian schemes over curves.

1 222 329 €

Start date: 2016-12-01, End date: 2021-11-30

"When I asked my seven-year-old daughter ""Who is the boy in your class who was also new in school last year, like you?"", she instantly replied ""Daniel"", using the descriptive content in my utterance to identify an entity in the real world and refer to it. The ability to use language to refer to reality is crucial for humans, and yet it is very difficult to model. AMORE breaks new ground in Computational Linguistics, Linguistics, and Artificial Intelligence by developing a model of linguistic reference to entities implemented as a computational system that can learn its own representations from data. This interdisciplinary project builds on two complementary semantic traditions: 1) Formal semantics, a symbolic approach that can delimit and track linguistic referents, but does not adequately match them with the descriptive content of linguistic expressions; 2) Distributional semantics, which can handle descriptive content but does not associate it to individuated referents. AMORE synthesizes the two approaches into a unified, scalable model of reference that operates with individuated referents and links them to referential expressions characterized by rich descriptive content. The model is a distributed (neural network) version of a formal semantic framework that is furthermore able to integrate perceptual (visual) and linguistic information about entities. We test it extensively in referential tasks that require matching noun phrases (“the Medicine student”, “the white cat”) with entity representations extracted from text and images. AMORE advances our scientific understanding of language and its computational modeling, and contributes to the far-reaching debate between symbolic and distributed approaches to cognition with an integrative proposal. I am in a privileged position to carry out this integration, since I have contributed top research in both distributional and formal semantics. "

1 499 805 €

Start date: 2017-02-01, End date: 2022-01-31

The overall goal of this project is to develop new concepts and techniques in geometric and asymptotic group theory for a systematic study of the analytic properties of discrete groups. These are properties depending on the unitary representation theory of the group. The fundamental examples are amenability, discovered by von Neumann in 1929, and property (T), introduced by Kazhdan in 1967. My main objective is to establish the precise relations between groups recently appeared in K-theory and topology such as C*-exact groups and groups coarsely embeddable into a Hilbert space, versus those discovered in ergodic theory and operator algebra, for example, sofic and hyperlinear groups. This is a first ever attempt to confront the analytic behavior of so different nature. I plan to work on crucial open questions: Is every coarsely embeddable group C*-exact? Is every group sofic? Is every hyperlinear group sofic? My motivation is two-fold: - Many outstanding conjectures were recently solved for these groups, e.g. the Novikov conjecture (1965) for coarsely embeddable groups by Yu in 2000 and the Gottschalk surjunctivity conjecture (1973) for sofic groups by Gromov in 1999. However, their group-theoretical structure remains mysterious. - In recent years, geometric group theory has undergone significant changes, mainly due to the growing impact of this theory on other branches of mathematics. However, the interplay between geometric, asymptotic, and analytic group properties has not yet been fully understood. The main innovative contribution of this proposal lies in the interaction between 3 axes: (i) limits of groups, in the space of marked groups or metric ultralimits; (ii) analytic properties of groups with curvature, of lacunary or relatively hyperbolic groups; (iii) random groups, in a topological or statistical meaning. As a result, I will describe the above apparently unrelated classes of groups in a unified way and will detail their algebraic behavior.

1 065 500 €

Start date: 2011-04-01, End date: 2016-03-31

The proposal consists of an extensive research program to advance the understanding of singular integral operators of Harmonic Analysis in various situations on the borderline of the existing theory. This is to be achieved by a creative combination of techniques from Analysis and Probability. On top of the standard arsenal of modern Harmonic Analysis, the main probabilistic tools are the martingale transform inequalities of Burkholder, and random geometric constructions in the spirit of the random dyadic cubes introduced to Nonhomogeneous Analysis by Nazarov, Treil and Volberg. The problems to be addressed fall under the following subtitles, with many interconnections and overlap: (i) sharp weighted inequalities; (ii) nonhomogeneous singular integrals on metric spaces; (iii) local Tb theorems with borderline assumptions; (iv) functional calculus of rough differential operators; and (v) vector-valued singular integrals. Topic (i) is a part of Classical Analysis, where new methods have led to substantial recent progress, culminating in my solution in July 2010 of a celebrated problem on the linear dependence of the weighted operator norm on the Muckenhoupt norm of the weight. The proof should be extendible to several related questions, and the aim is to also address some outstanding open problems in the area. Topics (ii) and (v) deal with extensions of the theory of singular integrals to functions with more general domain and range spaces, allowing them to be abstract metric and Banach spaces, respectively. In case (ii), I have recently been able to relax the requirements on the space compared to the established theories, opening a new research direction here. Topics (iii) and (iv) are concerned with weakening the assumptions on singular integrals in the usual Euclidean space, to allow certain applications in the theory of Partial Differential Equations. The goal is to maintain a close contact and exchange of ideas between such abstract and concrete questions.

1 100 000 €

Start date: 2011-11-01, End date: 2016-10-31

Social bonding success in life impacts on health, survival and fitness. It is proposed that early and later social experience as well as heritable factors determine social bonding abilities in adulthood, although the relative influence of each is unclear. In humans, the resulting uncertainty likely impedes psychological and psychiatric assessment and therapy. One problem hampering progress for human studies is that social bonding success is hard to objectively quantify, particularly in adults. I propose to directly address this problem by determining the key influences on social bonding abilities in chimpanzees, our closest living relative, where social bonding success can be objectively quantified, and is defined as number of affiliative relationships maintained over time with high rates of affiliation. Objectives. This project will quantify the relative impact of early and later social experience as well as heritable factors on social hormone levels, social cognition and social bonding success in 270 wild and captive chimpanzees, using both cohort and longitudinal data. This will reveal the degree of plasticity in social cognition and bonding behaviour throughout life. Finally, it will evaluate the potential for using endogenous hormone levels as non-invasive biomarkers of social bonding success, as well as identifying social contexts that act as strong natural social hormone releasers. Outcomes. This project will expose what makes some better at social bonding than others. Specifically, it will show the extent to which later social experience can compensate for early social experience or heritable factors in terms of adult social bonding success, the latter being a key factor in determining health and happiness in life. This project also offers the potential for using hormonal biomarkers in clincial settings, as objective assessment of changes in relationships over time, and in therapy by engaging in social behaviours that act as strong social hormone releasers.

1 495 000 €

Start date: 2016-04-01, End date: 2021-03-31

The nature of consciousness is one of the great unsolved mysteries of science. Although the global research effort dedicated to explaining how consciousness arises from neural and cognitive activity is now more than two decades old, as yet there is no widely accepted theory of consciousness. One reason for why no adequate theory of consciousness has yet been found is that there is a lack of clarity about what exactly a theory of consciousness needs to explain. What is needed is thus a model of the general features of consciousness — a model of the ‘architecture’ of consciousness — that will systematize the structural differences between conscious states, processes and creatures on the one hand and unconscious states, processes and creatures on the other. The aim of this project is to remove one of the central impediments to the progress of the science of consciousness by constructing such a model. A great many of the data required for this task already exist, but these data concern different aspects of consciousness and are distributed across many disciplines. As a result, there have been few attempts to develop a truly comprehensive model of the architecture of consciousness. This project will overcome the limitations of previous work by drawing on research in philosophy, psychology, psychiatry, and cognitive neuroscience to develop a model of the architecture of consciousness that is structured around five of its core features: its subjectivity, its temporality, its unity, its selectivity, and its dimensionality (that is, the relationship between the levels of consciousness and the contents of consciousness). By providing a comprehensive characterization of what a theory of consciousness needs to explain, this project will provide a crucial piece of the puzzle of consciousness, enabling future generations of researchers to bridge the gap between raw data on the one hand and a full-blown theory of consciousness on the other

1 477 483 €

Start date: 2013-03-01, End date: 2018-02-28

ATM is the protein kinase that is mutated in the hereditary autosomal recessive disease ataxia telangiectasia (A-T). A-T patients display immune deficiencies, cancer predisposition and radiosensitivity. The molecular role of ATM is to respond to DNA damage by phosphorylating its substrates, thereby promoting repair of damage or arresting the cell cycle. Following the induction of double-strand breaks (DSBs), the NBS1 protein is required for activation of ATM. But ATM can also be activated in the absence of DNA damage. Treatment of cultured cells with hypotonic stress leads to the activation of ATM, presumably due to changes in chromatin structure. We have recently described a second ATM cofactor, ATMIN (ATM INteractor). ATMIN is dispensable for DSBs-induced ATM signalling, but ATM activation following hypotonic stress is mediated by ATMIN. While the biological role of ATM activation by DSBs and NBS1 is well established, the significance, if any, of ATM activation by ATMIN and changes in chromatin was up to now completely enigmatic. ATM is required for class switch recombination (CSR) and the suppression of translocations in B cells. In order to determine whether ATMIN is required for any of the physiological functions of ATM, we generated a conditional knock-out mouse model for ATMIN. ATM signaling was dramatically reduced following osmotic stress in ATMIN-mutant B cells. ATMIN deficiency led to impaired CSR, and consequently ATMIN-mutant mice developed B cell lymphomas. Thus ablation of ATMIN resulted in a severe defect in ATM function. Our data strongly argue for the existence of a second NBS1-independent mode of ATM activation that is physiologically relevant. While a large amount of scientific effort has gone into characterising ATM signaling triggered by DSBs, essentially nothing is known about NBS1-independent ATM signaling. The experiments outlined in this proposal have the aim to identify and understand the molecular pathway of ATMIN-dependent ATM signaling.

1 499 881 €

Start date: 2012-02-01, End date: 2018-01-31

Autophagy is a catabolic pathway that delivers cytoplasmic material to lysosomes for degradation. Under vegetative conditions, the pathway serves as quality control system, specifically targeting damaged or superfluous organelles and protein-aggregates. Cytotoxic stresses and starvation, however, induces the formation of larger autophagosomes that capture cargo unselectively. Autophagosomes are being generated from a cup-shaped precursor membrane, the isolation membrane, which expands to engulf cytoplasmic components. Sealing of this structure gives rise to the double-membrane surrounded autophagosomes. Two interconnected ubiquitin (Ub)-like conjugation systems coordinate the expansion of autophagosomes by conjugating the autophagy related (Atg)-protein Atg8 to the isolation membrane. In an effort to unravel the function of Atg8, we reconstituted the system on model membranes in vitro and found that Atg8 forms together with the Atg12–Atg5-Atg16 complex a membrane scaffold which is required for productive autophagy in yeast. Humans possess seven Atg8-homologs and two mutually exclusive Atg16-variants. Here, we propose to investigate the function of the human Ub-like conjugation system using a fully reconstituted in vitro system. The spatiotemporal organization of recombinant fluorescent-labeled proteins with synthetic model membranes will be investigated using confocal and TIRF-microscopy. Structural information will be obtained by atomic force and electron microscopy. Mechanistic insights, obtained from the in vitro work, will be tested in vivo in cultured human cells. We belief that revealing 1) the function of the human Ub-like conjugation system in autophagy, 2) the functional differences of Atg8-homologs and the two Atg16-variants Atg16L1 and TECPR1 and 3) how Atg16L1 coordinates non-canonical autophagy will provide essential insights into the pathophysiology of cancer, neurodegenerative, and autoimmune diseases.

1 499 726 €

Start date: 2015-04-01, End date: 2020-03-31

Exciting findings from animal electrophysiological research in the last years suggest that an increased rate of body movements results in an enhanced response of neurons within the visual system despite the absence of visual changes. It is unclear why such modulation occurs in areas which process visual input. In humans, little is known about the influence of body movements on sensory brain areas mainly due to the technical challenges of measuring brain responses during pronounced muscle activity. However, psychophysical studies in humans show that also percept and perceptual demands are connected to the rate of movements. These two lines of evidence suggest a general link between rhythmic body movements and perceptual processes. The main aim of the proposed research is to decode the relationship between body movements and percept and to identify the underlying mechanism. To this end human non-invasive recordings from electro- and magnetoencephalography (EEG, MEG) as well as invasive human and animal multi-electrode recordings collected during movement execution will be analyzed. Directly relating perceptual processes and their underlying neuronal oscillations to rhythmic body movements offers an approach circumventing some of the methodological problems. This research could uncover a new mechanism of how our system modulates perceptual processes through body movements. The proof of such a mechanism would constitute a ground-breaking step in understanding perception during natural behavior. We need to keep in mind that in the awake state our body is constantly in motion. However, up to now, the vast majority of studies which investigate sensory brain responses are conducted under strict movement suppression. Besides facilitating exciting new insights, this research can strengthen the assumption that the knowledge we have gathered about artificial situations generalizes to our natural behavior.

1 422 907 €

Start date: 2016-07-01, End date: 2021-06-30

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

1 602 600 €

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

Bacterial biofilm formation is a paramount developmental process in both Gram-positive and Gram-negative species and in many pathogens has been associated with processes of horizontal gene transfer, antibiotic resistance development and pathogen persistence. Bacterial biofilms are collaborative sessile macrocolonies embedded in complex extracellular matrix that secures both mechanical resistance and a medium for intercellular exchange. Biogenesis platforms for the secretion of biofilm matrix components - many of which controlled directly or indirectly by the intracellular second messenger c-di-GMP - are important determinants for biofilm formation and bacterial disease, and therefore present compelling targets for the development of novel therapeutics. During my Ph.D. and post-doctoral work I studied the structure and function of c-di-GMP-sensing protein factors controling extracellular matrix production by DNA-binding at the transcription initiation level or by inside-out signalling mechanisms at the cell envelope, as well as membrane exporters involved directly in downstream matrix component secretion. Here, I propose to apply my expertise in microbiology, protein science and structural biology to study the structure and function of exopolysaccharide secretion systems in Gram-negative species. Using Pseudomonas aeruginosa, Vibrio spp. and Escherichia coli as model organisms, my team will aim to reveal the global architecture and individual building components of several expolysaccharide-producing protein megacomplexes. We will combine X-ray crystallography, biophysical and biochemical assays, electron microscopy and in cellulo functional studies to provide a comprehensive view of extracellular matrix production that spans the different resolution levels and presents molecular blueprints for the development of novel anti-infectives. Over the last year I have laid the foundation of these studies and have demonstrated the overall feasibility of the project.

1 499 901 €

Start date: 2018-08-01, End date: 2023-07-31

The aim of this transdisciplinary project is to develop and analyse multiscale mathematical models of pattern formation in multicellular systems controlled by the dynamics of intracellular signalling pathways and cell-to-cell communication and to develop new mathematical methods for the modelling of such complex processes. This aim will be achieved through a close collaboration with experimental groups and comprehensive analytical investigations of the mathematical problems arising in the modelling of these biological processes. The mathematical methods and techniques to be employed will be the analysis of systems of partial differential equations, asymptotic analysis, as well as methods of dynamical systems. These techniques will be used to formulate the models and to study the spatio-temporal behaviour of solutions, especially stability and dependence on characteristic scales, geometry, initial data and key parameters. Advanced numerical methods will be applied to simulate the models. This comprehensive methodology goes beyond the state-of-the-art, since usually the analyses are limited to a single aspect of model behaviour. Groundbreaking impacts envisioned are threefold: (i) The project will contribute to the understanding of mechanisms of structure formation in the developmental process, in the context of recently discovered signalling pathways. In addition, some of the factors and mechanisms playing a role in developmental processes, such as Wnt signalling, are implicated in carcinogenesis, for instance colon and lung cancer. (ii) Accurate quantitative and predictive mathematical models of cell proliferation and differentiation are important for the control of tumour growth and tissue egeneration; (iii) Qualitative analysis of multiscale mathematical models of biological phenomena generates challenging mathematical problems and, therefore, the project will lead to the development of new mathematical theories and tools.

750 000 €

Start date: 2008-09-01, End date: 2013-08-31

Boundary layer theory is a large component of fluid dynamics. It is ubiquitous in Oceanography, where boundary layer currents, such as the Gulf Stream, play an important role in the global circulation. Comprehending the underlying mechanisms in the formation of boundary layers is therefore crucial for applications. However, the treatment of boundary layers in ocean dynamics remains poorly understood at a theoretical level, due to the variety and complexity of the forces at stake. The goal of this project is to develop several tools to bridge the gap between the mathematical state of the art and the physical reality of oceanic motion. There are four points on which we will mainly focus: degeneracy issues, including the treatment Stewartson boundary layers near the equator; rough boundaries (meaning boundaries with small amplitude and high frequency variations); the inclusion of the advection term in the construction of stationary boundary layers; and the linear and nonlinear stability of the boundary layers. We will address separately Ekman layers and western boundary layers, since they are ruled by equations whose mathematical behaviour is very different. This project will allow us to have a better understanding of small scale phenomena in fluid mechanics, and in particular of the inviscid limit of incompressible fluids. The team will be composed of the PI, two PhD students and three two-year postdocs over the whole period. We will also rely on the historical expertise of the host institution on fluid mechanics and asymptotic methods.

1 267 500 €

Start date: 2015-09-01, End date: 2020-08-31

The aim of the proposed project is to shed light on early childhood gender-differentiated socialization and gender-specific susceptibility to parenting within families in relation to disruptive behaviour in boys and girls in the first four years of life. The popular saying boys will be boys refers to the observation that boys show more disruptive behaviours (e.g., noncompliance or aggression) than girls, a pattern that has been confirmed frequently in scientific research. There is also evidence that parents treat boys differently from girls in ways that are likely to foster boys disruptive behaviour, and that boys are more susceptible to problematic family functioning than girls. The crucial question is whether gender differences in socialization, susceptibility to socialization, and children s behavioural outcomes are also salient when the same parents are doing the parenting of both a boy and a girl. Within-family comparisons are necessary to account for structural differences between families. To this end, families with two children born 22-26 months apart will be recruited from the general population. To account for birth order and gender-combination effects, the sample includes four groups of 150 families each, with the following sibling combinations: girl-boy, boy-girl, girl-girl, and boy-boy. The study has a four-wave longitudinal design, based on the youngest sibling with assessments at ages 12, 24, 36, and 48 months, because gender differences in disruptive behaviour develop during the toddler years. Each assessment consists of two home visits: one with mother and one with father, including observations of both children and of the children separately. Parenting behaviours will be studied in reaction to specific child behaviours, including aggression, noncompliance, and prosocial behaviours.

1 611 970 €

Start date: 2010-02-01, End date: 2015-03-31

Damage to parietal cortex after stroke causes patients to become unaware of large parts of their surroundings and body parts. This so-called spatial neglect is hypothesised to be brought about by a stroke-induced imbalance between the left and right hemisphere. Some patients experience a partial recovery of lost abilities, but the factors that drive this rebalancing are unknown. The research proposed here will overcome this bottleneck in our understanding of the brain recovery phenomenon, and develop therapeutic approaches that for the first time will control, steer and speed up brain rebalancing after stroke. To that goal, we introduce a revolutionary approach in which TMS, fMRI, and EEG are applied simultaneously in healthy human volunteers to artificially unbalance the brain, and then study and control processes of rebalancing. Because we are one of the few groups worldwide that has accomplished this methodology, and that has the expertise to fully analyse the data it will yield, we are in a unique position to deliver both fundamental insights into brain plasticity, and derived new therapies. In brief, we will use TMS to (i) mimic spatial neglect in healthy volunteers while simultaneously monitoring the underlying neural network effects using fMRI/EEG, and to (ii) determine which exact brain reorganisation leads to an optimal behavioral recovery after injury. Importantly, we will use cutting-edge fMRI pattern recognition and machine learning algorithms to predict which concrete TMS treatment will specifically support this optimal functional reorganisation in the unbalanced brain. Finally, we will directly translate these fundamental findings into clinical practise and apply novel TMS protocols to rebalance the brain in patients suffering from parietal stroke.

1 344 853 €

Start date: 2011-04-01, End date: 2016-03-31

Thanks to the recent advances in mapping brain activation during task performance using functional Magnetic Resonance Imaging (i.e., studying the brain in action), it is now possible to study one of the oldest questions in psychology: how the development of neural circuitry underlies the development of cognition and emotion. The ‘Storm and Stress’ of adolescence, a period during which adolescents develop cognitively with great speed but are also risk-takers and sensitive to opinions of their peer group, has puzzled scientists for centuries. New technologies of brain mapping have the potential to shed new light on the mystery of adolescence. The approach proposed here concerns the investigation of brain regions which underlie developmental changes in cognitive, emotional and social-emotional functions over the course of child and adolescent development. For this purpose I will measure functional brain development longitudinally across the age range 8-20 years by using a combined cross-sectional longitudinal design including 240 participants. Participants will take part in two testing sessions over a four-year-period in order to track the within-subject time courses of functional brain development for cognitive, emotional and social-emotional functions and to understand how these functions develop relative to each other in the same individuals, using multilevel models for change. The cross-sectional longitudinal assessment of cognitive, emotional and social-emotional functional brain development in relation to brain structure and hormone levels is unique in the international field and has the potential to provide new explanations for old questions. The application of brain mapping combined with multilevel models for change is original, and allows for the examination of developmental trajectories rather than age comparisons. An integrative mapping (i.e., combined with task performance and with biological markers) of functional brain development is important not only for theory development, but also for understanding how children learn new tasks and participate in a complex social world, and eventually to tailor educational programs to the needs of children.

1 500 000 €

Start date: 2011-02-01, End date: 2016-01-31

Eukaryotic cells constantly convert signals between biochemical energy and mechanical work to timely accomplish many key functions such as migration, division or development. Filopodia are essential finger-like structures that emerge at the cell front to orient the cell in response to its chemical and mechanical environment. Yet, the molecular interactions that make the filopodia mechanosensitive are not known. To tackle this challenge we propose unique biophysical in vitro and in vivo experiments of increasing complexity. Here we will focus on how the underlying actin filament bundle regulates filopodium growth and retraction cycles at the micrometer and seconds scales. These parallel actin filaments are mainly elongated at their barbed-end by formins and cross-linked by bundling proteins such as fascins. We aim to: 1) Elucidate how formin and fascin functions are regulated by mechanics at the single filament level. We will investigate how formin partners and competitors present in filopodia affect formin processivity; how fascin affinity for the side of filaments is modified by filament tension and formin presence at the barbed-end. 2) Reconstitute filopodium-like actin bundles in vitro to understand how actin bundle size and fate are regulated down to the molecular scale. Using a unique experimental setup that combines microfluidics and optical tweezers, we will uncover for the first time actin bundles mechanosensitive capabilities, both in tension and compression. 3) Decipher in vivo the mechanics of actin bundles in filopodia, using fascins and formins with integrated fluorescent tension sensors. This framework spanning from in vitro single filament to in vivo meso-scale actin networks will bring unprecedented insights into the role of actin bundles in filopodia mechanosensitivity.

1 499 190 €

Start date: 2016-03-01, End date: 2021-02-28