ERC FUNDED PROJECTS

"Ageing 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-of-living’ 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."

1 499 768 €

Start date: 2013-01-01, End date: 2017-12-31

We have recently discovered a series of carbene iridium complexes that are highly active in water oxidation catalysis (Angew. Chem. Int. Ed. 2010, 49, 9765, see also picture). As the water oxidation half-cycle is the demanding (and thus far prohibitive) step when splitting water to oxygen and hydrogen, these iridium complexes hold great potential for the generation of hydrogen as fuel from renewable, non-fossil sources. A key component for the efficient water oxidation appears to be the mesoionic carbene ligand, which is non-innocent and capable of assisting in proton-coupled electron transfer processes. Within this proof-of-concept project we now aim at evaluating a range of factors that will be pivotal to move this fundamentally interesting reactivity pattern into a prototypical device for energy generation. The principal goal thus consists of establishing the viability and to address technical issues and overall directions for using carbene iridium complexes in energy conversion processes. Clarification of intellectual property rights and deciding on an appropriate patent/licensing strategy constitutes a primary subaim. A specific and critical point to be addressed pertains to the robustness and activity of the catalyst in order to warrant the costs for using a precious metal in energy conversion and storage processes. Optimized catalysts will thus be essential, and will be combined with a photo-absorbing semiconductor as water reduction catalyst to accomplish full water splitting in a single, eventually light-driven device. In parallel, industrial contacts will be sought to identify domains for application of the catalytic device, in which longevity will be among the key criteria.

136 076 €

Start date: 2012-10-01, End date: 2013-09-30

New developments on tissue engineering strategies should realize the complexity of tissue remodelling and the inter-dependency of many variables associated to stem cells and biomaterials interactions. ComplexiTE proposes an integrated approach to address such multiple factors in which different innovative methodologies are implemented, aiming at developing tissue-like substitutes with enhanced in vivo functionality. Several ground-breaking advances are expected to be achieved, including: i) improved methodologies for isolation and expansion of sub-populations of stem cells derived from not so explored sources such as adipose tissue and amniotic fluid; ii) radically new methods to monitor human stem cells behaviour in vivo; iii) new macromolecules isolated from renewable resources, especially from marine origin; iv) combinations of liquid volumes mingling biomaterials and distinct stem cells, generating hydrogel beads upon adequate cross-linking reactions; v) optimised culture of the produced beads in adequate 3D bioreactors and a novel selection method to sort the beads that show a (pre-defined) positive biological reading; vi) random 3D arrays validated by identifying the natural polymers and cells composing the positive beads; v) 2D arrays of selected hydrogel spots for brand new in vivo tests, in which each spot of the implanted chip may be evaluated within the living animal using adequate imaging methods; vi) new porous scaffolds of the best combinations formed by particles agglomeration or fiber-based rapid-prototyping. The ultimate goal of this proposal is to develop breakthrough research specifically focused on the above mentioned key issues and radically innovative approaches to produce and scale-up new tissue engineering strategies that are both industrially and clinically relevant, by mastering the inherent complexity associated to the correct selection among a great number of combinations of possible biomaterials, stem cells and culturing conditions.

2 320 000 €

Start date: 2013-05-01, End date: 2018-04-30

Cloud computing is being increasingly adopted by individuals, organizations, and governments. However, as the computations that are offloaded to the cloud expand to societal-critical services, the dependability requirements of cloud services become much higher, and we need to ensure that the infrastructure that supports these services is ready to meet these requirements. In particular, this proposal tackles the challenges that arise from two distinctive characteristic of the cloud infrastructure. The first is that non-crash faults, despite being considered highly unlikely by the designers of traditional systems, become commonplace at the scale and complexity of the cloud infrastructure. We argue that the current ad-hoc methods for handling these faults are insufficient, and that the only principled approach of assuming Byzantine faults is too pessimistic. Therefore, we call for a new systematic approach to tolerating non-crash, non-adversarial faults. This requires the definition of a new fault model, and the construction of a series of building blocks and key protocol elements that enable the construction of fault-tolerant cloud services. The second issue is that to meet their scalability requirements, cloud services spread their state across multiple data centers, and direct users to the closest one. This raises the issue that not all operations can be executed optimistically, without being aware of concurrent operations over the same data, and thus multiple levels of consistency must coexist. However, this puts the onus of reasoning about which behaviors are allowed under such a hybrid consistency model on the programmer of the service. We propose a systematic solution to this problem, which includes a novel consistency model that allows for developing highly scalable services that are fast when possible and consistent when necessary, and a labeling methodology to guide the programmer in deciding which operations can run at each consistency level.

1 076 084 €

Start date: 2012-10-01, End date: 2018-01-31

Flows of complex fluids, such as many biological fluids and most synthetic fluids, are common in our daily life and are very important from an industrial perspective. Because of their inherent nonlinearity, the flow of complex viscoelastic fluids often leads to counterintuitive and complex behaviour and, above critical conditions, can prompt flow instabilities even under low Reynolds number conditions which are entirely absent in the corresponding Newtonian fluid flows. The primary goal of this project is to substantially expand the frontiers of our current knowledge regarding the mechanisms that lead to the development of such purely-elastic flow instabilities, and ultimately to understand the transition to so-called “elastic turbulence”, a turbulent-like phenomenon which can arise even under inertialess flow conditions. This is an extremely challenging problem, and to significantly advance our knowledge in such important flows these instabilities will be investigated in a combined manner encompassing experiments, theory and numerical simulations. Such a holistic approach will enable us to understand the underlying mechanisms of those instabilities and to develop accurate criteria for their prediction far in advance of what we could achieve with either approach separately. A deep understanding of the mechanisms generating elastic instabilities and subsequent transition to elastic turbulence is crucial from a fundamental point of view and for many important practical applications involving engineered complex fluids, such as the design of microfluidic mixers for efficient operation under inertialess flow conditions, or the development of highly efficient micron-sized energy management and mass transfer systems. This research proposal will create a solid basis for the establishment of an internationally-leading research group led by the PI studying flow instabilities and elastic turbulence in complex fluid flows.

994 110 €

Start date: 2012-10-01, End date: 2018-01-31

The 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 non-invasive 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.

1 699 320 €

Start date: 2012-11-01, End date: 2017-10-31

Open angle glaucoma (OAG) is the second leading cause of world blindness. Treatments involving topically applied pressure-reducing medications or surgery targeting ocular drainage channels are effective, although significant complications exist. We propose to address the hypothesis that it is possible to develop a radical approach to management of intraocular pressure employing an AAV-mediated system for increasing the permeability of Schlemm’s canal endothelial cells (SCEC), based on published supportive data from this laboratory showing that RNAi-mediated down regulation of mRNA encoding components of tight junctions of neuronal vascular endothelia induces increased cell permeability, a process which has been used to validate a procedure for acute treatment of neuronal edema. While tight junctions of neuronal vascular endothelial cells have been extensively studied and comprise of a series of up to 30 protein components, less is known of the organization of adherence mechanisms of SCEC, although electron- and immunofluorescence microscopy show the presence of tight junctions. We propose a comprehensive analysis of tight junction protein expression in SCEC in vitro. In vivo studies will involve introduction of AAV vectors into the anterior chamber of the eye in rodent models of elevated IOP. The vectors will be designed to express shRNAs targeting a variety of tight junction transcripts expressed in SCEC using an inducible system. The effect of RNAi-mediated increase in the permeability of SCEC will be assessed using aqueous humour outflow measurement methods and we will also explore the utility of high resolution and diffusion-weighted MRI for this purpose, which may prove to be a simpler, non-invasive and clinically relevant method. This research will provide further fundamental insights into the mechanisms of ocular pressure maintenance and could provide benefit to those patients not responsive to conventional means of therapy.

2 499 838 €

Start date: 2013-04-01, End date: 2018-09-30

Novel artificial materials (photonic crystals (PCs), negative index materials (NIMs), and plasmonics) enable the realization of innovative EM properties unattainable in naturally existing materials. These materials, called metamaterials (MMs), have been in the foreground of scientific interest in the last ten years. However, many serious obstacles must be overcome before the impressive possibilities of MMs, especially in the optical regime, become real applications. The present project combines NIMs, PCs, and aspects of plasmonics in a unified way in order to promote the development of functional MMs, and mainly functional optical MMs (OMMs). It identifies the main obstacles, proposes specific approaches to deal with them, and intends to study unexplored capabilities of OMMs. The project objectives are: (a) Design and realization of 3d OMMs, and achieve new metasurface designs applying Babinet’s principle. (b) Understanding and reducing the losses in OMM by incorporating gain and EM induced transparency (EIT). (c) Achieving highly efficient PC nanolasers and surface plasmons (SPs) lasers. (d) Use chiral MMs and SPs to reduce and manipulate Casimir forces, and (e) Using MMs, combined with nonlinear materials, for THz generation, and tunable response.(f)Calculate electron- phonon scattering and edge collisions in graphene and in graphene-based molecules. The unifying link in all these objectives is the endowment of photons with novel properties through imaginative use of EM-field / artificial-matter interactions. Some of these objectives seem almost certainly realizable; others are more risky but with higher reward if accomplished; some are directed towards new specific applications, while others explore new physical reality. The accomplishment of those objectives requires novel ideas, advanced computational techniques, nanofabrication approaches, and testing. The broad expertise of the PI and his team, and their pioneering contributions to NIMs, PCs, and plasmonics qualifies them for facing the challenges and ensuring the maximum possible success of the project.

2 100 000 €

Start date: 2013-03-01, End date: 2019-02-28

Predicting the electron and spin transport properties of organic crystals is a formidable theoretical challenge as these are determined both by the electronic structure of the individual molecules and by the morphology of the crystal. Quest's research program seeks at developing a fully quantitative theory for electron and spin transport in organic crystals, which does not rely on external parameters and can be applied to materials underpinning a multitude of applications, ranging from organic electronics, to spintronics, to energy. In particular we aim at combining state of the art density functional theory with advanced quantum transport methods and Monte Carlo simulations. We will then construct a hierarchical computational protocol enabling us to evaluate electron and spin transport across different length scales at finite temperature, including effects originating from external fields (electric and magnetic). Our developed tools will form a software package to be distributed freely to academia.

1 492 728 €

Start date: 2012-12-01, End date: 2018-11-30

Vegetation 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 high-reactivity 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 ecology 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.

2 259 366 €

Start date: 2013-05-01, End date: 2018-04-30

Static program analysis is a fundamental computing challenge. We have recently demonstrated significant advantages from expressing analyses for Java declaratively, in the Datalog language. This means that the algorithm is in a form that resembles a pure logical specification, rather than a step-by-step definition of the execution. The declarative specification does not merely cover the main logic of the algorithm, but its entire implementation, including the handling of complex semantic features (such as native methods, reflection, threads) of the Java language. Surprisingly, the declarative specification can be made to execute up to an order of magnitude faster than the dominant pre-existing implementations of the same algorithms. Armed with this past experience, the SPADE project aims to develop a next-generation approach to the design and declarative implementation of static program analyses. This will include a) a substantially more flexible notion of context-sensitive analysis, which allows context to vary according to introspective observations; b) a flow-sensitive analysis framework that can be used as the basis for dataflow analysis; c) an approach to producing parallel implementations of analyses by exploiting the parallelism inherent in the declarative specification; d) an exploration of adapting analysis logic to multiple languages and paradigms, including C (using the LLVM infrastructure), functional languages (e.g., Scheme), and dynamic languages (notably, Javascript); e) client analyses algorithms (e.g., may-happen-in-parallel, bug finding analyses such as race and atomicity-violation detectors, etc.) expressed modularly over the underlying substrate of points-to analysis. The work will have applications to multiple languages and a variety of analyses. Concretely, our precise and scalable analysis algorithms will enhance optimizing compilers, program analyzers for error detection, and program understanding tools.

1 042 616 €

Start date: 2013-01-01, End date: 2019-03-31

"One of the most important developments in the communication microelectronics in the last decade was the invention and popularization of “Digital RF”. It transforms the radio frequency (RF) analog functionality of a wireless transceiver into digitally-intensive implementations that operate in time-domain. They are best realized in mainstream nanometer-scale CMOS technologies and easily integrated with digital processors. As a result, RF transceivers based on this new approach now enjoy significant benefits. Consequently, the RF transceivers based on this architecture are now the majority of the 1.5 billion mobile handsets produced annually. The invention and development of “Digital RF” was pioneered in the last decade by this applicant at Texas Instruments in Dallas, Texas, USA. Despite having published over 130 scientific papers, that industrial research focus has been mainly limited to the highest volume segment of the wireless communications market: low-cost GSM/EDGE cellular phones and Bluetooth radios. Unfortunately, that low-cost low-data-rate market segment has already reached the saturation. The fastest growing segments of the wireless communications are now: high-data-rate “smart phones”, ultra-low-power wireless sensor network devices, antenna-array and millimeter-wave transceivers, where the original “Digital RF” approach could not be readily exploited. The goal of this proposal is to revisit and exploit the fundamental theory of the time-domain operation of RF and analog circuits. This way the broad area of the wireless communications, as well as analog and mixed-signal electronics in general, can be transformed for the ready realization in the advanced CMOS technology. This is expected to revolutionize the entire research field to even a larger extent than the “Digital RF” breakthrough in low-cost low-data-rate radios pioneered by this applicant in the last decade."

1 497 000 €

Start date: 2012-09-01, End date: 2017-08-31

Genomic integrity is essential for accurate gene expression and epigenetic inheritance. On the other hand, a prolonged transcriptional arrest can challenge genome stability, contributing to genetic and epigenetic defects and the mechanisms of ageing and disease. Here we aim to identify the molecular mechanisms that couple transcriptional arrest to chromatin alteration and repair. We wish to explore the idea that transcription suppresses cellular toxicity and preserves genetic and epigenetic inheritance. Towards these goals our work will be focused on: 1. Deciphering the molecular events impinging on the manner cells respond when the progress of a transcribing RNA polymerase II is blocked. 2. Exploring a novel, so far unanticipated function of key players of the transcription-associated repair pathways, such as the Cockayne Syndrome (CS) proteins, not related to repair. 3. Understanding the role of transcription in chemotherapeutic-driven toxicity. 4. Investigating novel post-translational modifications of CS and determining their function. These objectives will be addressed using advanced proteomics and genome wide technologies in combination with biochemical and cellular techniques in normal human cells and a large battery of patient-derived cell lines. Our rational is that better understanding of CS function will help reach our ultimate goal, which is to identify the regulatory cascades involved in the interplay between genomic stability and transcription. The novel key idea put forward in this proposal is that active transcription itself directly contributes to genome integrity. While the role of DNA damage-driven transcription blockage in promoting repair is well established, the protective role of active transcription in genome stability is entirely unexplored. If successful, the proposed studies may help reveal the underlying causes of related disorders and explain their clinical features.

1 500 000 €

Start date: 2012-11-01, End date: 2018-10-31