ERC FUNDED PROJECTS

The scientific goal of the proposal is to answer central questions related to diffeomorphism groups of manifolds of dimension 2 and 3, and to their deformation invariant analogs, the mapping class groups. While the classification of surfaces has been known for more than a century, their automorphism groups have yet to be fully understood. Even less is known about diffeomorphisms of 3-manifolds despite much interest, and the objects here have only been classified recently, by the breakthrough work of Perelman on the Poincar\'e and geometrization conjectures. In dimension 2, I will focus on the relationship between mapping class groups and topological conformal field theories, with applications to Hochschild homology. In dimension 3, I propose to compute the stable homology of classifying spaces of diffeomorphism groups and mapping class groups, as well as study the homotopy type of the space of diffeomorphisms. I propose moreover to establish homological stability theorems in the wider context of automorphism groups and more general families of groups. The project combines breakthrough methods from homotopy theory with methods from differential and geometric topology. The research team will consist of 3 PhD students, and 4 postdocs, which I will lead.

724 992 €

Start date: 2009-11-01, End date: 2014-10-31

Label-free optical nanoscopy, free from photobleaching and photochemical toxicity of fluorescence labels and yielding 3D morphological resolution of <50 nm, is the future of live cell imaging. 3D-nanoMorph breaks the diffraction barrier and shifts the paradigm in label-free nanoscopy, providing isotropic 3D resolution of <50 nm. To achieve this, 3D-nanoMorph performs non-linear inverse scattering for the first time in nanoscopy and decodes scattering between sub-cellular structures (organelles). 3D-nanoMorph innovatively devises complementary roles of light measurement system and computational nanoscopy algorithm. A novel illumination system and a novel light collection system together enable measurement of only the most relevant intensity component and create a fresh perspective about label-free measurements. A new computational nanoscopy approach employs non-linear inverse scattering. Harnessing non-linear inverse scattering for resolution enhancement in nanoscopy opens new possibilities in label-free 3D nanoscopy. I will apply 3D-nanoMorph to study organelle degradation (autophagy) in live cancer cells over extended duration with high spatial and temporal resolution, presently limited by the lack of high-resolution label-free 3D morphological nanoscopy. Successful 3D mapping of nanoscale biological process of autophagy will open new avenues for cancer treatment and showcase 3D-nanoMorph for wider applications. My cross-disciplinary expertise of 14 years spanning inverse problems, electromagnetism, optical microscopy, integrated optics and live cell nanoscopy paves path for successful implementation of 3D-nanoMorph.

1 499 999 €

Start date: 2019-07-01, End date: 2024-06-30

Mucins are a family of high-molecular-weight glycoproteins and a major macromolecular constituent in slimy mucus gels that are covering the surface of internal biological tissues. A primary role of mucus gels in biological systems is known to be the protection and lubrication of underlying epithelial cell surfaces. This is intuitively well appreciated by both science community and the public, and yet detailed lubrication properties of mucins and mucus gels have remained largely unexplored to date. Detailed and systematic understanding of the lubrication mechanism of mucus gels is significant from many angles; firstly, lubricity of mucus gels is closely related with fundamental functions of various human organs, such as eye blinking, mastication in oral cavity, swallowing through esophagus, digestion in stomach, breathing through air way and respiratory organs, and thus often indicates the health state of those organs. Furthermore, for the application of various tissue-contacting devices or personal care products, e.g. catheters, endoscopes, and contact lenses, mucus gel layer is the first counter surface that comes into the mechanical and tribological contacts with them. Finally, remarkable lubricating performance by mucins and mucus gels in biological systems may provide many useful and possibly innovative hints in utilizing water as base lubricant for man-made engineering systems. This project thus proposes to carry out a 5 year research program focusing on exploring the lubricity of mucins and mucus gels by combining a broad range of experimental approaches in biology and tribology.

1 432 920 €

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

The centriole is the largest evolutionary conserved macromolecular structure responsible for building centrosomes and cilia or flagella in many eukaryotes. Centrioles are critical for the proper execution of important biological processes ranging from cell division to cell signaling. Moreover, centriolar defects have been associated to several human pathologies including ciliopathies and cancer. This state of facts emphasizes the importance of understanding centriole biogenesis. The study of centriole formation is a deep-rooted question, however our current knowledge on its molecular organization at high resolution remains fragmented and limited. In particular, exquisite details of the overall molecular architecture of the human centriole and in particular of its central core region are lacking to understand the basis of centriole organization and function. Resolving this important question represents a challenge that needs to be undertaken and will undoubtedly lead to groundbreaking advances. Another important question to tackle next is to develop innovative methods to enable the nanometric molecular mapping of centriolar proteins within distinct architectural elements of the centriole. This missing information will be key to unravel the molecular mechanisms behind centriolar organization. This research proposal aims at building a cartography of the human centriole by elucidating its molecular composition and architecture. To this end, we will combine the use of innovative and multidisciplinary techniques encompassing spatial proteomics, cryo-electron tomography, state-of-the-art microscopy and in vitro assays and to achieve a comprehensive molecular and structural view of the human centriole. All together, we expect that these advances will help understand basic principles underlying centriole and cilia formation as well as might have further relevance for human health.

1 498 965 €

Start date: 2017-01-01, End date: 2021-12-31

"I propose a systematic study of the type of genetic variation enabling adaptation and factors that limit rates of adaptation in natural populations. New methods will be developed for analysing data from experimental evolution and population genomics. The methods will be applied to state of the art data from both fields. Adaptation is generated by natural selection sieving through heritable variation. Examples of adaptation are available from the fossil record and from extant populations. Genomic studies have supplied many instances of genomic regions exhibiting footprint of natural selection favouring new variants. Despite ample proof that adaptation happens, we know little about beneficial mutations– the raw stuff enabling adaptation. Is adaptation mediated by genetic variation pre-existing in the population, or by variation supplied de novo through mutations? We know even less about what factors limit rates of adaptation. Answers to these questions are crucial for Evolutionary Biology, but also for believable quantifications of the evolutionary potential of populations. Population genetic theory makes predictions and allows inference from the patterns of polymorphism within species and divergence between species. Yet models specifying the fitness effects of mutations are often missing. Fitness landscape models will be mobilized to fill this gap and develop methods for inferring the distribution of fitness effects and factors governing rates of adaptation. Insights into the processes underlying adaptation will thus be gained from experimental evolution and population genomics data. The applicability of insights gained from experimental evolution to comprehend adaptation in nature will be scrutinized. We will unite two very different approaches for studying adaptation. The project will boost our understanding of how selection shapes genomes and open the way for further quantitative tests of theories of adaptation."

1 159 857 €

Start date: 2013-04-01, End date: 2018-03-31

"Contemporary database query languages are ultimately founded on logic and feature an additive operation – usually a form of (multi)set union or disjunction – that is asymmetric in that additions or updates do not always have an inverse. This asymmetry puts a greater part of the machinery of abstract algebra for equation solving outside the reach of databases. However, such equation solving would be a key functionality that problems such as query equivalence testing and data integration could be reduced to: In the current scenario of the presence of an asymmetric additive operation they are undecidable. Moreover, query languages with a symmetric additive operation (i.e., which has an inverse and is thus based on ring theory) would open up databases for a large range of new scientific and mathematical applications. The goal of the proposed project is to reinvent database management systems with a foundation in abstract algebra and specifically in ring theory. The presence of an additive inverse allows to cleanly define differences between queries. This gives rise to a database analog of differential calculus that leads to radically new incremental and adaptive query evaluation algorithms that substantially outperform the state of the art techniques. These algorithms enable a new class of systems which I call Dynamic Data Management Systems. Such systems can maintain continuously fresh query views at extremely high update rates and have important applications in interactive Large-scale Data Analysis. There is a natural connection between differences and updates, motivating the group theoretic study of updates that will lead to better ways of creating out-of-core data processing algorithms for new storage devices. Basing queries on ring theory leads to a new class of systems, Algebraic Data Management Systems, which herald a convergence of database systems and computer algebra systems."

1 480 548 €

Start date: 2012-01-01, End date: 2016-12-31

I propose a program of research that may forever change the way that we understand and use quantum field theory to make predictions for experiment. This will be achieved through the advancement of new, constructive frameworks to determine and represent scattering amplitudes in perturbation theory in terms that depend only on observable quantities, make manifest (all) the symmetries of the theory, and which can be efficiently evaluated while minimally spoiling the underlying simplicity of predictions. My research has already led to the discovery and development of several approaches of this kind. This proposal describes the specific steps required to extend these ideas to more general theories and to higher orders of perturbation theory. Specifically, the plan of research I propose consists of three concrete goals: to fully characterize the discontinuities of loop amplitudes (`on-shell functions') for a broad class of theories; to develop powerful new representations of loop amplitude {\it integrands}, making manifest as much simplicity as possible; and to develop new techniques for loop amplitude {integration} that are compatible with and preserve the symmetries of observable quantities. Progress toward any one of these objectives would have important theoretical implications and valuable practical applications. In combination, this proposal has the potential to significantly advance the state of the art for both our theoretical understanding and our computational reach for making predictions for experiment. To achieve these goals, I will pursue a data-driven, `phenomenological' approach—involving the construction of new computational tools, developed in pursuit of concrete computational targets. For this work, my suitability and expertise is amply demonstrated by my research. I have not only played a key role in many of the most important theoretical developments in the past decade, but I have personally built the most powerful computational tools for their

1 499 695 €

Start date: 2018-02-01, End date: 2023-01-31

"During the last decade, a strikingly successful cosmological concordance model has been established. With only six free parameters, nearly all observables, comprising millions of data points, may be fitted with outstanding precision. However, in this beautiful picture a few ""blemishes"" have turned up, apparently not consistent with the standard model: While the model predicts that the universe is isotropic (i.e., looks the same in all directions) and homogeneous (i.e., the statistical properties are the same everywhere), subtle hints of the contrary are now seen. For instance, peculiar preferred directions and correlations are observed in the cosmic microwave background; some studies considering nearby galaxies suggest the existence of anomalous large-scale cosmic flows; a study of distant quasars hints towards unexpected large-scale correlations. All of these reports are individually highly intriguing, and together they hint toward a more complicated and interesting universe than previously imagined -- but none of the reports can be considered decisive. One major obstacle in many cases has been the relatively poor data quality. This is currently about to change, as the next generation of new and far more powerful experiments are coming online. Of special interest to me are Planck, an ESA-funded CMB satellite currently taking data; QUIET, a ground-based CMB polarization experiment located in Chile; and various large-scale structure (LSS) data sets, such as the SDSS and 2dF surveys, and in the future Euclid, a proposed galaxy survey satellite also funded by ESA. By combining the world s best data from both CMB and LSS measurements, I will in the proposed project attempt to settle this question: Is our universe really anisotropic? Or are these recent claims only the results of systematic errors or statistical flukes? If the claims turn out to hold against this tide of new and high-quality data, then cosmology as a whole may need to be re-written."

1 500 000 €

Start date: 2011-01-01, End date: 2015-12-31

Vaccines and immunodiagnostics have been vital for public health and medicine, however a quantitative molecular understanding of vaccine-induced antibody responses is lacking. Antibody research is currently going through a big-data driven revolution, largely due to progress in next-generation sequencing (NGS) and bioinformatic analysis of antibody repertoires. A main advantage of high-throughput antibody repertoire analysis is that it provides a wealth of quantitative information not possible with other classical methods of antibody analysis (i.e., serum titers); this information includes: clonal distribution and diversity, somatic hypermutation patterns, and lineage tracing. In preliminary work my group has established standardized methods for antibody repertoire NGS, including an experimental-bioinformatic pipeline for error and bias correction that enables highly accurate repertoire sequencing and analysis. The overall goal of this proposal will be to apply high-throughput antibody repertoire analysis for quantitative vaccine profiling and discovery of next-generation immunodiagnostics. Using mouse subunit vaccination as our model system, we will answer for the first time, a fundamental biological question within the context of antibody responses - what is the link between genotype (antibody repertoire) and phenotype (serum antibodies)? We will expand upon this approach for improved rational vaccine design by quantitatively determining the impact of a comprehensive set of subunit vaccination parameters on complete antibody landscapes. Finally, we will develop advanced bioinformatic methods to discover immunodiagnostics based on antibody repertoire sequences. In summary, this proposal lays the foundation for fundamentally new approaches in the quantitative analysis of antibody responses, which long-term will promote the development of next-generation vaccines and immunodiagnostics.

1 492 586 €

Start date: 2016-06-01, End date: 2021-05-31