ERC FUNDED PROJECTS

"Two-dimensional (2D) nanosheets, which possess a high degree of anisotropy with nanoscale thickness and infinite length in other dimensions, hold enormous promise as a novel class of ultrathin 2D nanomaterials with various unique functionalities and properties, and exhibit great potential in energy storage and conversion systems that are substantially different from their respective 3D bulk forms. Here I propose a strategy for the synthesis and processing of various 2D nanosheets across a broad range of inorganic, organic and polymeric materials with molecular-level or thin thickness through both the top-down exfoliation of layered materials and the bottom-up assembly of available molecular building blocks. Further, I aim to develop the synthesis of various 2D-nanosheet based composite materials with thickness of less than 100 nm and the assembly of 2D nanosheets into novel hierarchal superstrucutures (like aerogels, spheres, porous particles, nanotubes, multi-layer films). The structural features of these 2D nanomaterials will be controllably tailored by both the used layered precursors and processing methodologies. The consequence is that I will apply and combine defined functional components as well as assembly protocols to create novel 2D nanomaterials for specific purposes in energy storage and conversion systems. Their unique characters will include the good electrical conductivity, excellent mechanical flexibility, high surface area, high chemical stability, fast electron transport and ion diffusion etc. Applications will be mainly demonstrated for the construction of lithium ion batteries (anode and cathode), supercapacitors (symmetric and asymmetric) and fuel cells. As the key achievements, I expect to establish the delineation of reliable structure-property relationships and improved device performance of 2D nanomaterials."

1 500 000 €

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

The paradigm of the structure-function relationship in proteins is outdated. Biological macromolecules and supramolecular assemblies are highly dynamic objects. Evidence that their motions are of utmost importance to their functions is regularly identified. The understanding of the physical chemistry of biological processes at an atomic level has to rely not only on the description of structure but also on the characterization of molecular motions. The investigation of protein motions will be undertaken with a very innovative methodological approach in nuclear magnetic resonance relaxation. In order to widen the ranges of frequencies at which local motions in proteins are probed, we will first use and develop new techniques for a prototype shuttle system for the measurement of relaxation at low fields on a high-field NMR spectrometer. Second, we will develop a novel system: a set of low-field NMR spectrometers designed as accessories for high-field spectrometers. Used in conjunction with the shuttle, this system will offer (i) the sensitivity and resolution (i.e. atomic level information) of a high-field spectrometer (ii) the access to low fields of a relaxometer and (iii) the ability to measure a wide variety of relaxation rates with high accuracy. This system will benefit from the latest technology in homogeneous permanent magnet development to allow a control of spin systems identical to that of a high-resolution probe. This new apparatus will open the way to the use of NMR relaxation at low fields for the refinement of protein motions at an atomic scale. Applications of this novel approach will focus on the bright side of protein dynamics: (i) the largely unexplored dynamics of intrinsically disordered proteins, and (ii) domain motions in large proteins. In both cases, we will investigate a series of diverse protein systems with implications in development, cancer and immunity.

1 462 080 €

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

Parkinson’s disease (PD) is the second most common neurodegenerative disorder primarily caused by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN). Despite the advances in gene discovery associated with PD, the knowledge of the PD pathogenesis is largely limited to the involvement of these genes in the generic cell death pathways, and why degeneration is specific to DA neurons and why the degeneration is progressive remain enigmatic. Broad goal of our work is therefore to elucidate the mechanisms underlying specific and progressive DA neuron degeneration in PD. Our new Drosophila model of PD ⎯Fer2 gene loss-of-function mutation⎯ is unusually well suited to address these questions. Fer2 mutants exhibit specific and progressive death of brain DA neurons as well as severe locomotor defects and short life span. Strikingly, the death of DA neuron is initiated in a small cluster of Fer2-expressing DA neurons and subsequently propagates to Fer2-negative DA neurons. We therefore propose a novel two-step model of the neurodegeneration in PD: primary cell death occurs in a specific subset of dopamindegic neurons that are genetically defined, and subsequently the failure of the neuronal connectivity triggers and propagates secondary cell death to remaining DA neurons. In this research, we will test this hypothesis and investigate the underlying molecular mechanisms. This will be the first study to examine circuit-dependency in DA neuron degeneration. Our approach will use a combination of non-biased genomic techniques and candidate-based screening, in addition to the powerful Drosophila genetic toolbox. Furthermore, to test this hypothesis beyond the Drosophila model, we will establish new mouse models of PD that exhibit progressive DA neuron degeneration. Outcome of this research will likely revolutionize the understanding of PD pathogenesis and open an avenue toward the discovery of effective therapy strategies against PD.

1 518 960 €

Start date: 2013-06-01, End date: 2018-05-31

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

It was early predicted by M. Green and coeval colleagues that dividing the solar spectrum into narrow ranges of colours is the most efficient manner to convert solar energy into electrical power. Multijunction solar cells are the current solution to this challenge, which have reached over 30% conversion efficiencies by stacking 3 junctions together. However, the large fabrication costs and time hinders their use in everyday life. It has been shown that highly mismatched alloy (HMA) materials provide a powerful playground to achieve at least 3 different colour absorption regions that enable optimised energy conversion with just one junction. Combining HMA-based junctions with standard Silicon solar cells will rocket solar conversion efficiency at a reduced price. To turn this ambition into marketable devices, several efforts are still needed and few challenges must be overcome. 4SUNS is a revolutionary approach for the development of HMA materials on Silicon technology, which will bring highly efficient multi-colour solar cells costs below current multijunction devices. The project will develop the technology of HMA materials on Silicon via material synthesis opening a new technology for the future. The understanding and optimization of highly mismatched alloy materials-using GaAsNP alloy- will provide building blocks for the fabrication of laboratory-size 4-colours/2-junctions solar cells. Using a molecular beam epitaxy system, 4SUNS will grow 4-colours/2-junctions structure as well as it will manufacture the final devices. Structural and optoelectronic characterizations will carry out to determine the quality of the materials and the solar cells characteristic to obtain a competitive product. These new solar cells are competitive products to breakthrough on the solar energy sector solar cells and allowing Europe to take leadership on high efficiency solar cells.

1 499 719 €

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

Crucial processes within cells depend on specific non-covalent interactions which mediate the assembly of proteins and other biomolecules. Deriving structural information to understand the function of these complex systems is the primary goal of Structural Biology. In this application, the recently developed LILBID method (Laser Induced Liquid Bead Ion Desorption) will be optimized for investigation of macromolecular complexes with a mass accuracy two orders of magnitude better than in 1st generation spectrometers. Controlled disassembly of the multiprotein complexes in the mass spectrometric analysis while keeping the 3D structure intact, will allow for the determination of complex stoichiometry and connectivity of the constituting proteins. Methods for such controlled disassembly will be developed in two separate units of the proposed LILBID spectrometer, in a collision chamber and in a laser dissociation chamber, enabling gas phase dissociation of protein complexes and removal of excess water/buffer molecules. As a third unit, a chamber allowing determination of ion mobility (IM) will be integrated to determine collisional cross sections (CCS). From CCS, unique information regarding the spatial arrangement of proteins in complexes or subcomplexes will then be obtainable from LILBID. The proposed design of the new spectrometer will offer fundamentally new possibilities for the investigation of non-covalent RNA, soluble and membrane protein complexes, as well as broadening the applicability of non-covalent MS towards supercomplexes.

1 264 477 €

Start date: 2014-02-01, End date: 2019-01-31

What is responsible for the emergence of homochirality, the almost exclusive use of one enantiomer over its mirror image? And what led to the evolution of life’s homochiral biopolymers, DNA/RNA, proteins and lipids, where all the constituent monomers exhibit the same handedness? Based on in-situ observations and laboratory studies, we propose that this handedness occurs when chiral biomolecules are synthesized asymmetrically through interaction with circularly polarized photons in interstellar space. The ultimate goal of this project will be to demonstrate how the diverse set of heterogeneous enantioenriched molecules, available from meteoritic impact, assembles into homochiral pre-biopolymers, by simulating the evolutionary stages on early Earth. My recent research has shown that the central chiral unit of RNA, ribose, forms readily under simulated comet conditions and this has provided valuable new insights into the accessibility of precursors of genetic material in interstellar environments. The significance of this project arises due to the current lack of experimental demonstration that amino acids, sugars and lipids can simultaneously and asymmetrically be synthesized by a universal physical selection process. A synergistic methodology will be developed to build a unified theory for the origin of all chiral biological building blocks and their assembly into homochiral supramolecular entities. For the first time, advanced analyses of astrophysical-relevant samples, asymmetric photochemistry triggered by circularly polarized synchrotron and laser sources, and chiral amplification due to polymerization processes will be combined. Intermediates and autocatalytic reaction kinetics will be monitored and supported by quantum calculations to understand the underlying processes. A unified theory on the asymmetric formation and self-assembly of life’s biopolymers is groundbreaking and will impact the whole conceptual foundation of the origin of life.

1 500 000 €

Start date: 2019-04-01, End date: 2024-03-31

A persistent challenge in unravelling mechanisms that regulate memory function is how to bridge the gap between inter-molecular dynamics of single proteins, activity of individual synapses and emerging properties of neuronal circuits. The prototype condition of disintegrating neuronal circuits is Alzheimer’s Disease (AD). Since the early time of Alois Alzheimer at the turn of the 20th century, scientists have been searching for a molecular entity that is in the roots of the cognitive deficits. Although diverse lines of evidence suggest that the amyloid-beta peptide (Abeta) plays a central role in synaptic dysfunctions of AD, several key questions remain unresolved. First, endogenous Abeta peptides are secreted by neurons throughout life, but their physiological functions are largely unknown. Second, experience-dependent physiological mechanisms that initiate the changes in Abeta composition in sporadic, the most frequent form of AD, are unidentified. And finally, molecular mechanisms that trigger Abeta-induced synaptic failure and memory decline remain elusive. To target these questions, I propose to develop an integrative approach to correlate structure and function at the level of single synapses in hippocampal circuits. State-of-the-art techniques will enable the simultaneous real-time visualization of inter-molecular dynamics within signalling complexes and functional synaptic modifications. Utilizing FRET spectroscopy, high-resolution optical imaging, electrophysiology, molecular biology and biochemistry we will determine the casual relationship between ongoing neuronal activity, temporo-spatial dynamics and molecular composition of Abeta, structural rearrangements within the Abeta signalling complexes and plasticity of single synapses and whole networks. The proposed research will elucidate fundamental principles of neuronal circuits function and identify critical steps that initiate primary synaptic dysfunctions at the very early stages of sporadic AD.

2 000 000 €

Start date: 2011-12-01, End date: 2017-09-30

Clouds play a key role in the climate system. Small anthropogenic perturbations of the cloud system potentially have large radiative effects. Aerosols perturb the global radiation budget directly, by scattering and absorption, as well as indirectly, by the modification of cloud properties and occurrence. The applicability of traditional conceptual models of indirect aerosol effects to convective clouds is disputed as cloud dynamics complicates the picture. Strong evidence for numerous aerosol effects on convection has been established in individual disciplines: through remote sensing and in-situ observations as well as by cloud resolving and global modelling. However, a coherent scientific view of the effects of aerosols on convection has yet to be established. The primary objective of ACCLAIM is to recast the effects of aerosols on convective clouds as basis for improved global estimates of anthropogenic climate effects. Specific objectives include: i) to unravel the governing principles of aerosol effects on convective clouds; ii) provide quantitative constraints on satellite-retrieved relationships between convective clouds and aerosols; and ultimately iii) to enable global climate models to represent the full range of anthropogenic climate perturbations and quantify the climate response to aerosol effects on convective clouds. I have developed the research strategy of ACCLAIM to overcome disciplinary barriers in this frontier research area and seek five years of funding to establish an interdisciplinary, physics focused, research group consisting of two PostDocs, two PhD students and myself. ACCLAIM will be centred around global aerosol-convection climate modelling studies, complemented by research constraining aerosol-convection interactions through remote sensing and a process focused research strand, advancing fundamental understanding and global model parameterisations through high resolution aerosol-cloud modelling in synergy with in-situ observations.

1 429 243 €

Start date: 2011-09-01, End date: 2017-02-28

"How are actions initiated by the human brain when there is no external sensory cue or other immediate imperative? How do subtle ongoing interactions within the brain and between the brain, body, and sensory context influence the spontaneous initiation of action? How should we approach the problem of trying to identify the neural events that cause spontaneous voluntary action? Much is understood about how the brain decides between competing alternatives, leading to different behavioral responses. But far less is known about how the brain decides "when" to perform an action, or "whether" to perform an action in the first place, especially in a context where there is no sensory cue to act such as during foraging. This project seeks to open a new chapter in the study of spontaneous voluntary action building on a novel hypothesis recently introduced by the applicant (Schurger et al, PNAS 2012) concerning the role of ongoing neural activity in action initiation. We introduce brain-behavior forecasting, the converse of movement-locked averaging, as an approach to identifying the neurodynamic states that commit the motor system to performing an action "now", and will apply it in the context of information foraging. Spontaneous action remains a profound mystery in the brain basis of behavior, in humans and other animals, and is also central to the problem of asynchronous intention-detection in brain-computer interfaces (BCIs). A BCI must not only interpret what the user intends, but also must detect "when" the user intends to act, and not respond otherwise. This remains the biggest challenge in the development of high-performance BCIs, whether invasive or non-invasive. This project will take a systematic and collaborative approach to the study of spontaneous self-initiated action, incorporating computational modeling, neuroimaging, and machine learning techniques towards a deeper understanding of voluntary behavior and the robust asynchronous detection of decisions-to-act."

1 338 130 €

Start date: 2015-10-01, End date: 2020-09-30

The brain evolves, develops, and operates in the context of animal movements. As a consequence, fundamental brain functions such as spatial perception and motor control critically depend on the precise knowledge of the ongoing body motion. An accurate internal estimate of self-movement is thought to emerge from sensorimotor integration; nonetheless, which circuits perform this internal estimation, and exactly how motor-sensory coordination is implemented within these circuits are basic questions that remain to be poorly understood. There is growing evidence suggesting that, during locomotion, motor-related and visual signals interact at early stages of visual processing. In mammals, however, it is not clear what the function of this interaction is. Recently, we have shown that a population of Drosophila optic-flow processing neurons —neurons that are sensitive to self-generated visual flow, receives convergent visual and walking-related signals to form a faithful representation of the fly’s walking movements. Leveraging from these results, and combining quantitative analysis of behavior with physiology, optogenetics, and modelling, we propose to investigate circuit mechanisms of self-movement estimation during walking. We will:1) use cell specific manipulations to identify what cells are necessary to generate the motor-related activity in the population of visual neurons, 2) record from the identified neurons and correlate their activity with specific locomotor parameters, and 3) perturb the activity of different cell-types within the identified circuits to test their role in the dynamics of the visual neurons, and on the fly’s walking behavior. These experiments will establish unprecedented causal relationships among neural activity, the formation of an internal representation, and locomotor control. The identified sensorimotor principles will establish a framework that can be tested in other scenarios or animal systems with implications both in health and disease.

1 500 000 €

Start date: 2017-11-01, End date: 2022-10-31

Our affective and motivational state is important for our decisions, actions and quality of life. Many pathological conditions affect this state. For example, addictive drugs are hyperactivating the reward system and trigger a strong motivation for continued drug intake, whereas many somatic and psychiatric diseases lead to an aversive state, characterized by loss of motivation. I will study specific neural circuits and mechanisms underlying reward and aversion, and how pathological signaling in these systems can trigger relapse in drug addiction. Given the important role of the dopaminergic neurons in the midbrain for many aspects of reward signaling, I will study how synaptic plasticity in these cells, and in their target neurons in the striatum, contribute to relapse in drug seeking. I will also study the circuits underlying aversion. Little is known about these circuits, but my hypothesis is that an important component of aversion is signaled by a specific neuronal population in the brainstem parabrachial nucleus, projecting to the central amygdala. We will test this hypothesis and also determine how this aversion circuit contributes to the persistence of addiction and to relapse. To dissect this complicated system, I am developing new genetic methods for manipulating and visualizing specific functional circuits in the mouse brain. My unique combination of state-of-the-art competence in transgenics and cutting edge knowledge in the anatomy and functional organization of the circuits behind reward and aversion should allow me to decode these systems, linking discrete circuits to behavior. Collectively, the results will indicate how signals encoding aversion and reward are integrated to control addictive behavior and they may identify novel avenues for treatment of drug addiction as well as aversion-related symptoms affecting patients with chronic inflammatory conditions and cancer.

1 500 000 €

Start date: 2010-10-01, End date: 2015-09-30

The rise of atmospheric O2 ~2,500 million years ago is one of the most profound transitions in Earth's history. Yet, despite its central role in shaping Earth's surface environment, the cause for the rise of O2 remains poorly understood. Tight coupling between the O2 cycle and the biogeochemical cycles of redox-active elements, such as C, Fe and S, implies radical changes in these cycles before, during and after the rise of O2. These changes, too, are incompletely understood, but have left valuable information encoded in the geological record. This information has been qualitatively interpreted, leaving many aspects of the rise of O2, including its causes and constraints on ocean chemistry before and after it, topics of ongoing research and debate. Here, I outline a research program to address this fundamental question in geochemical Earth systems evolution. The inherently interdisciplinary program uniquely integrates laboratory experiments, numerical models, geological observations, and geochemical analyses. Laboratory experiments and geological observations will constrain unknown parameters of the early biogeochemical cycles, and, in combination with field studies, will validate and refine the use of paleoenvironmental proxies. The insight gained will be used to develop detailed models of the coupled biogeochemical cycles, which will themselves be used to quantitatively understand the events surrounding the rise of O2, and to illuminate the dynamics of elemental cycles in the early oceans. This program is expected to yield novel, quantitative insight into these important events in Earth history and to have a major impact on our understanding of early ocean chemistry and the rise of O2. An ERC Starting Grant will enable me to use the excellent experimental and computational facilities at my disposal, to access the outstanding human resource at the Weizmann Institute of Science, and to address one of the major open questions in modern geochemistry.

1 472 690 €

Start date: 2013-09-01, End date: 2018-08-31

This project will develop the principles required to enable bond-modifying redox catalysis based on aluminium by preparing and studying new Al(I) compounds capable of reversible oxidative addition. Catalytic processes are involved in the synthesis of 75 % of all industrially produced chemicals, but most catalysts involved are based on precious metals such as rhodium, palladium or platinum. These metals are expensive and their supply limited and unstable; there is a significant need to develop the chemistry of non-precious metals as alternatives. On toxicity and abundance alone, aluminium is an attractive candidate. Furthermore, recent work, including in our group, has demonstrated that Al(I) compounds can perform a key step in catalytic cycles - the oxidative addition of E-H bonds. In order to realise the significant potential of Al(I) for transition-metal style catalysis we urgently need to: - establish the principles governing oxidative addition and reductive elimination reactivity in aluminium systems. - know how the reactivity of Al(I) compounds can be controlled by varying properties of ligand frameworks. - understand the onward reactivity of oxidative addition products of Al(I) to enable applications in catalysis. In this project we will: - Study mechanisms of oxidative addition and reductive elimination of a range of synthetically relevant bonds at Al(I) centres, establishing the principles governing this fundamental reactivity. - Develop new ligand frameworks to support of Al(I) centres and evaluate the effect of the ligand on oxidative addition/reductive elimination at Al centres. - Investigate methods for Al-mediated functionalisation of organic compounds by exploring the reactivity of E-H oxidative addition products with unsaturated organic compounds.

1 493 679 €

Start date: 2017-03-01, End date: 2022-02-28

Alkenones are algal lipids that have been used for decades to reconstruct quantitative past sea surface temperature. Although alkenones are being discovered in an increasing number of lake sites worldwide, only two terrestrial temperature records have been reconstructed so far. The development of this research field is limited by the lack of interdisciplinary research that combines modern biological and ecological algal research with the organic geochemical techniques needed to develop a quantitative biomarker (or molecular fossil) for past lake temperatures. More research is needed for alkenones to become a widely used tool for reconstructing past terrestrial temperature change. The early career Principal Investigator has discovered a new lake alkenone-producing species of haptophyte algae that produces alkenones in high abundances both in the environment and in laboratory cultures. This makes the new species an ideal organism for developing a culture-based temperature calibration and exploring other potential environmental controls. In this project, alkenone production will be manipulated, and monitored using state-of-the-art photobioreactors with real-time detectors for cell density, light, and temperature. The latest algal culture and isolation techniques that are used in microalgal biofuel development will be applied to developing the lake temperature proxy. The objectives will be achieved through the analysis of 90 new Canadian lakes to develop a core-top temperature calibration across a large latitudinal and temperature gradient (Δ latitude = 5°, Δ spring surface temperature = 9°C). The results will be used to assess how regional palaeo-temperature (Uk37), palaeo-moisture (δDwax) and palaeo-evaporation (δDalgal) respond during times of past global warmth (e.g., Medieval Warm Period, 900-1200 AD) to find an accurate analogue for assessing future drought risk in the interior of Canada.

940 883 €

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

Methane, a key greenhouse gas, is cycled by microorganisms via two pathways, aerobically and anaerobically. Research on the marine methane cycle has mainly concentrated on anaerobic processes. Recent biomarker work has provided compelling evidence that aerobic methane oxidation (AMO) can play a more significant role in cycling methane emitted from sediments than previously considered. AMO, however, is not well studied requiring novel proxies that can be applied to the sedimentary record. A group of complex lipids biosynthesised by aerobic methanotrophs known as aminobacteriohopanepolyols represent an ideal target for developing such poxies. Recently BHPs have been identified in a wide range of modern and recent environments including a continuous record from the Congo deep sea fan spanning the last 1.2 million years. In this integrated study, the regulation and expression of BHP will be investigated and calibrated against environmental variables including temperature, pH, salinity and, most importantly, methane concentrations. The work program has three complementary strands. (1) Pure culture and sedimentary microcosm experiments providing an approximation to natural conditions. (2) Calibration of BHP signatures in natural marine settings (e.g. cold seeps, mud volcanoes, pockmarks) against measured methane gradients. (3) Application of this novel approach to the marine sedimentary record to approximate methane fluxes in the past, explore the age and bathymetric limits of this novel molecular proxy, and identify and potentially 14C date palaeo-pockmarks structures. Crucial to the success is also the refinement of the analytical protocols to improve both accuracy and sensitivity, using a more sensitive analytical instrument (triple-quadrupole mass spectrometer).

1 496 392 €

Start date: 2010-11-01, End date: 2016-04-30

"I propose a structured multidisciplinary research programme that seeks to combine advanced materials, such as metal oxides and organics, with novel fabrication methods to develop devices for application in: (1) large area electronics, (2) integrated nanoelectronics and (3) sensors. At the heart of this programme lies the development of novel oxide semiconductors. These will be synthesised from solution using precursors. Chemical doping via physical blending will be explored for the tuning of the electronic properties of these compounds. This simple approach will enable the rapid development of a library of materials far beyond those accessible by traditional methods. Oxides will then be combined with inorganic/organic dielectrics to demonstrate low power transistors. Ultimate target for application area (1) is the development of transistors with hole/electron mobilities exceeding 20/200 cm^2/Vs respectively. For application area (2) I will combine the precursor formulations with advanced scanning thermochemical nanolithography. A heated atomic force microscope tip will be used for the local chemical conversion of the precursor to oxide with sub-50 nm resolution. This will enable patterning of nanostructures with desirable shape and size. Sequential patterning of semi/conductive layers combined with SAM dielectrics would enable fabrication of nano-sized devices and circuits. For application area (3), research effort will focus on novel hybrid phototransistors. Use of different light absorbing organic dyes functionalised onto the oxide channel will be explored as a mean for developing high sensitivity phototransistors and full colour sensing arrays. Organic dyes will also be combined with nano-sized transistors to demonstrate integrated nano-scale optoelectronics. The unique combination of bottom-up and top-down strategies adopted in this project will lead to the development of novel high performance devices with a host of existing and new applications."

1 497 798 €

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

The goal of crystal engineering is the design of functional crystalline materials in which the arrangement of basic structural building blocks imparts desired properties. The engineering of organic molecular crystals has, to date, relied largely on empirical rules governing the intermolecular association of functional groups in the solid state. However, many materials properties depend intricately on the complete crystal structure, i.e. the unit cell, space group and atomic positions, which cannot be predicted solely using such rules. Therefore, the development of computational methods for crystal structure prediction (CSP) from first principles has been a goal of computational chemistry that could significantly accelerate the design of new materials. It is only recently that the necessary advances in the modelling of intermolecular interactions and developments in algorithms for identifying all relevant crystal structures have come together to provide predictive methods that are becoming reliable and affordable on a timescale that could usefully complement an experimental research programme. The principle aim of the proposed work is to establish the use of state-of-the-art crystal structure prediction methods as a means of guiding the discovery and design of novel molecular materials. This research proposal both continues the development of the computational methods for CSP and, by developing a computational framework for screening of potential molecules, develops the application of these methods for materials design. The areas on which we will focus are organic molecular semiconductors with high charge carrier mobilities and, building on our recently published results in Nature [1], the development of porous organic molecular materials. The project will both deliver novel materials, as well as improvements in the reliability of computational methods that will find widespread applications in materials chemistry. [1] Nature 2011, 474, 367-371.

1 499 906 €

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

Within a 12 month period, 20% of adults will meet criteria for one or more clinical anxiety disorders (ADs). These disorders are hugely disruptive, placing an emotional burden on individuals and their families. While both cognitive behavioural therapy and pharmacological treatment are widely viewed as effective strategies for managing ADs, systematic review of the literature reveals that only 30–45% of patients demonstrate a marked response to treatment (anxiety levels being reduced into the nonaffected range). In addition, a significant proportion of initial responders relapse after treatment is discontinued. There is hence a real and marked need to improve upon current approaches to AD treatment. One possible avenue for improving response rates is through optimizing initial treatment selection. Specifically, it is possible that certain individuals might respond better to cognitive interventions while others might respond better to pharmacological treatment. Recently it has been suggested that there may be two or more distinct biological pathways disrupted in anxiety. If this is the case, then specification of these pathways may be an important step in predicting which individuals are likely to respond to which treatment. Few studies have focused upon this issue and, in particular, upon identifying neural markers that might predict response to cognitive (as opposed to pharmacological) intervention. The proposed research aims to address this. Specifically, it tests the hypothesis that there are at least two mechanisms disrupted in ADs, one entailing amygdala hyper-responsivity to cues that signal threat, the other impoverished recruitment of frontal regions that support cognitive and emotional regulation. Two series of functional magnetic resonance imaging experiments will be conducted. These will investigate differences in amygdala and frontal function during (a) attentional processing and (b) fear conditioning. Initial clinical experiments will investigate whether Generalised Anxiety Disorder and Specific Phobia involve differing degrees of disruption to frontal versus amygdala function during these tasks. This work will feed into training studies, the goal being to characterize AD patient subgroups that benefit from cognitive training.

1 708 407 €

Start date: 2011-04-01, End date: 2016-08-31

Linear Parameter-Varying (LPV) systems are flexible mathematical models capable of representing Nonlinear (NL)/Time-Varying (TV) dynamical behaviors of complex physical systems (e.g., wafer scanners, car engines, chemical reactors), often encountered in engineering, via a linear structure. The LPV framework provides computationally efficient and robust approaches to synthesize digital controllers that can ensure desired operation of such systems - making it attractive to (i) high-tech mechatronic, (ii) automotive and (iii) chemical-process applications. Such a framework is important to meet with the increasing operational demands of systems in these industrial sectors and to realize future technological targets. However, recent studies have shown that, to fully exploit the potential of the LPV framework, a number of limiting factors of the underlying theory ask a for serious innovation, as currently it is not understood how to (1) automate exact and low-complexity LPV modeling of real-world applications and how to refine uncertain aspects of these models efficiently by the help of measured data, (2) incorporate control objectives directly into modeling and to develop model reduction approaches for control, and (3) how to see modeling & control synthesis as a unified, closed-loop system synthesis approach directly oriented for the underlying NL/TV system. Furthermore, due to the increasingly cyber-physical nature of applications, (4) control synthesis is needed in a plug & play fashion, where if sub-systems are modified or exchanged, then the control design and the model of the whole system are only incrementally updated. This project aims to surmount Challenges (1)-(4) by establishing an innovative revolution of the LPV framework supported by a software suite and extensive empirical studies on real-world industrial applications; with a potential to ensure a leading role of technological innovation of the EU in the high-impact industrial sectors (i)-(iii).

1 493 561 €

Start date: 2017-09-01, End date: 2022-08-31

Novel sophisticated technologies that exploit the laws of quantum physics form a cornerstone for the future well-being, economic growth and security of Europe. Here photonic devices have gained a prominent position because the absorption, emission, propagation or storage of a photon is a process that can be harnessed at a fundamental level and render more practical ways to use light for such applications. However, the interaction of light with single quantum systems under ambient conditions is typically very weak and difficult to control. Furthermore, there are quantum phenomena occurring in matter at nanometer length scales that are currently not well understood. These deficiencies have a direct and severe impact on creating a bridge between quantum physics and photonic device technologies. aQUARiUM, precisely address the issue of controlling and enhancing the interaction between few photons and rolled-up nanostructures with ability to be deployed in practical applications. With aQUARiUM, we will take epsilon (permittivity)-near-zero (ENZ) metamaterials into quantum nanophotonics. To this end, we will integrate quantum emitters with rolled-up waveguides, that act as ENZ metamaterial, to expand and redefine the range of light-matter interactions. We will explore the electromagnetic design freedom enabled by the extended modes of ENZ medium, which “stretches” the effective wavelength inside the structure. Specifically, aQUARiUM is built around the following two objectives: (i) Enhancing light-matter interactions with single emitters (Enhance) independent of emitter position. (ii) Enabling collective excitations in dense emitter ensembles (Collect) coherently connect emitters on nanophotonic devices to obtain coherent emission. aQUARiUM aims to create novel light-sources and long-term entanglement generation and beyond. The envisioned outcome of aQUARiUM is a wholly new photonic platform applicable across a diverse range of areas.

1 499 431 €

Start date: 2019-01-01, End date: 2023-12-31

The bottom-up assembly of tissue from cellular building blocks constitutes a promising, yet highly challenging approach to engineer complex tissues. The challenge lies in controlling cell-cell interactions, which determine how cells organize with respect to each other, how they work together and consequently whether such a multicellular architecture will be functional. The limited spatial and temporal control over cell-cell interactions current biological and chemical approaches provide severely restricts bottom-up tissue engineering. Here, I propose a new way to control cell-cell interactions. I aim to regulate cell-cell interactions with visible light using proteins that reversibly homo- or heterodimerize under blue or red light. These photoswitchable cell-cell interactions provide sustainable, non-invasive, dynamic and reversible control over cell-cell interactions with unprecedented spatial and temporal resolution. First of all, we will focus on various light dependent protein interactions to mediate cell-cell contacts. The detailed characterization (strength, dynamics, interaction modes and orthogonality) of these new photoswitchable cell-cell interactions will provide the framework for the bottom-up construction of tissue-like structures. Secondly, we will use these photoswitchable cell-cell interactions to assemble cells into multicellular architectures with predictable and programmable organization. The dynamic and reversible nature of the photoswitchable contacts will allow us to locally alter interactions at any point in time, to rearrange and obtain asymmetric multicellular structures, which are typical of tissues. Finally, we will also explore how the photoswitchable cell-cell interactions alter cell behavior and signaling. Ultimately, this will pave the way for the bottom-up assembly of multicellular architectures, enabling us to control precisely and dynamically their organization in space and time as well as regulate how cells work together.

1 937 000 €

Start date: 2018-07-01, End date: 2023-06-30

Supramolecular polymers are of major interest in the field of self assembly with a promising outlook in areas of viscosity modification, compartmentalized architectures, bio-conjugates and drug-delivery applications. They are dynamic macromolecular materials prepared by simple mixing of relatively small components bearing complementary or self-complementary recognition motifs. A major limitation in the field, however, has been access to synthetic systems capable of undergoing self assembly in an aqueous environment. This research proposal develops well-defined, self-organizing macromolecular structures that will overcome this limitation by focusing on systems that rely on several non-covalent interactions occurring in concert rather than on single interactions alone. The envisioned supramolecular polymers and bio-conjugates are designed as dynamic water-soluble smart materials, whose architectures can be controlled and exhibit reversibility upon exposure to external stimuli such as electrochemical, temperature or pH changes. Molecular recognition events occurring between functional handles on both synthetic and bio-polymers will be investigated in order to control the formation of desired functional architectures through stoichiometrically controlled complexation. Preparation of synthetic core motifs to assemble discrete peptide aggregates such as the dimeric through hexameric oligomers of amyloid-beta(40/42) will lead to structural elucidation and insight into several peptide misfolding pathologies like Alzheimer&apos;s or Parkinson&apos;s disease.

1 700 000 €

Start date: 2009-11-01, End date: 2015-10-31

Despite considerable efforts aimed at prevention and treatment, the prevalence of obesity and type 2 diabetes has increased at an alarming rate worldwide over recent decades. Given the urgent need to develop safe and efficient anti-obesity drugs, the scientific community has to intensify efforts to better understand the mechanisms involved in the pathogenesis of obesity. Based on human genome-wide association studies and targeted mouse mutagenesis models, it has recently emerged that the brain controls most aspects of systemic metabolism and that obesity may be a brain disease. I have recently shown that like neurons, astrocytes also respond to circulating nutrients, and they cooperate with neurons to efficiently regulate energy metabolism. So far, the study of brain circuits controlling energy balance has focused on neurons, ignoring the presence and role of astrocytes. Importantly, our studies were the first to describe that exposure to a high-fat, highsugar (HFHS) diet triggers hypothalamic astrogliosis prior to significant body weight gain, indicating a potentially important role in promoting obesity. Overall, my recent findings suggest a novel model in which astrocytes are actively involved in the central nervous system (CNS) control of metabolism, likely including active crosstalk between astrocytes and neurons. To test this hypothetical model, I propose to develop a functional understanding of astroglia-neuronal communication in the CNS control of metabolism focusing on: 1) dissecting the ability of astrocytes to release gliotransmitters to neurons, 2) assessing how astrocytes respond to neuronal activity, and 3) determining if HFHS-induced astrogliosis interrupts this crosstalk and contributes to the development of obesity and type 2 diabetes. These studies aim to uncover the molecular underpinnings of astrocyte-neuron inputs regulating metabolism in health and disease so as to inspire and enable novel therapeutic strategies to fight diabetes and obesity.

1 499 938 €

Start date: 2018-01-01, End date: 2022-12-31

Despite more than fifty years of scientific progress since Richard Feynman's 1959 vision for nanotechnology, there is only one way to manipulate individual atoms in materials: scanning tunneling microscopy. Since the late 1980s, its atomically sharp tip has been used to move atoms over clean metal surfaces held at cryogenic temperatures. Scanning transmission electron microscopy, on the other hand, has been able to resolve atoms only more recently by focusing the electron beam with sub-atomic precision. This is especially useful in the two-dimensional form of hexagonally bonded carbon called graphene, which has superb electronic and mechanical properties. Several ways to further engineer those have been proposed, including by doping the structure with substitutional heteroatoms such as boron, nitrogen, phosphorus and silicon. My recent discovery that the scattering of the energetic imaging electrons can cause a silicon impurity to move through the graphene lattice has revealed a potential for atomically precise manipulation using the Ångström-sized electron probe. To develop this into a practical technique, improvements in the description of beam-induced displacements, advances in heteroatom implantation, and a concerted effort towards the automation of manipulations are required. My project tackles these in a multidisciplinary effort combining innovative computational techniques with pioneering experiments in an instrument where a low-energy ion implantation chamber is directly connected to an advanced electron microscope. To demonstrate the power of the method, I will prototype an atomic memory with an unprecedented memory density, and create heteroatom quantum corrals optimized for their plasmonic properties. The capability for atom-scale engineering of covalent materials opens a new vista for nanotechnology, pushing back the boundaries of the possible and allowing a plethora of materials science questions to be studied at the ultimate level of control.

1 497 202 €

Start date: 2017-10-01, End date: 2022-09-30

Atomic scale defects play a key role in determining the behaviour of all crystalline materials, profoundly modifying mechanical, thermal and electrical properties. Many current technological applications make do with phenomenological descriptions of these effects; yet myriad intriguing questions about the fundamental link between defect structure and material function remain. Transmission electron microscopy revolutionised the study of atomic scale defects by enabling their direct imaging. The novel coherent X-ray diffraction techniques developed in this project promise a similar advancement, making it possible to probe the strain fields that govern defect interactions in 3D with high spatial resolution (<10 nm). They will allow us to clarify the effect of impurities and retained gas on dislocation strain fields, shedding light on opportunities to engineer dislocation properties. The exceptional strain sensitivity of coherent diffraction will enable us to explore the fundamental mechanisms governing the behaviour of ion-implantation-induced point defects that are invisible to TEM. While we concentrate on dislocations and point defects, the new techniques will apply to all crystalline materials where defects are important. Our characterisation of defect structure will be combined with laser transient grating measurements of thermal transport changes due to specific defect populations. This unique multifaceted perspective of defect behaviour will transform our ability to devise modelling approaches linking defect structure to material function. Our proof-of-concept results highlight the feasibility of this ambitious research project. It opens up a vast range of exciting possibilities to gain a deep, fundamental understanding of atomic scale defects and their effect on material function. This is an essential prerequisite for exploiting and engineering defects to enhance material properties.

1 610 231 €

Start date: 2017-03-01, End date: 2022-02-28

At every moment in time, the brain receives a vast amount of sensory information about the environment. This makes attention, the process by which we select currently relevant stimuli for processing and ignore irrelevant input, a fundamentally important brain function. Studies in primates have yielded a detailed description of how attention to a stimulus modifies the responses of neuronal ensembles in visual cortex, but how this modulation is produced mechanistically in the circuit is not well understood. Neuronal circuits comprise a large variety of neuron types, and to gain mechanistic insights, and to treat specific diseases of the nervous system, it is crucial to characterize the contribution of different identified cell types to information processing. Inhibition supplied by a small yet highly diverse set of interneurons controls all aspects of cortical function, and the central hypothesis of this proposal is that differential modulation of genetically-defined interneuron types is a key mechanism of attention in visual cortex. To identify the interneuron types underlying attentional modulation and to investigate how this, in turn, affects computations in the circuit we will use an innovative multidisciplinary approach combining genetic targeting in mice with cutting-edge in vivo 2-photon microscopy-based recordings and selective optogenetic manipulation of activity. Importantly, a key set of experiments will test whether the observed neuronal mechanisms are causally involved in attention at the level of behavior, the ultimate readout of the computations we are interested in. The expected results will provide a detailed, mechanistic dissection of the neuronal basis of attention. Beyond attention, selection of different functional states of the same hard-wired circuit by modulatory input is a fundamental, but poorly understood, phenomenon in the brain, and we predict that our insights will elucidate similar mechanisms in other brain areas and functional contexts.

1 466 505 €

Start date: 2014-02-01, End date: 2019-01-31

Embedded Control software plays a critical role in many safety-critical applications. For instance, modern vehicles use interacting software and hardware components to control steering and braking. Control software forms the main core of autonomous transportation, power networks, and aerospace. These applications are examples of cyber-physical systems (CPS), where distributed software systems interact tightly with spatially distributed physical systems with complex dynamics. CPS are becoming ubiquitous due to rapid advances in computation, communication, and memory. However, the development of core control software running in these systems is still ad hoc and error-prone and much of the engineering costs today go into ensuring that control software works correctly. In order to reduce the design costs and guaranteeing its correctness, I aim to develop an innovative design process, in which the embedded control software is synthesized from high-level correctness requirements in a push-button and formal manner. Requirements for modern CPS applications go beyond conventional properties in control theory (e.g. stability) and in computer science (e.g. protocol design). Here, I propose a compositional methodology for automated synthesis of control software by combining compositional techniques from computer science (e.g. assume-guarantee rules) with those from control theory (e.g. small-gain theorems). I will leverage decomposition and abstraction as two key tools to tackle the design complexity, by either breaking the design object into semi-independent parts or by aggregating components and eliminating unnecessary details. My project is high-risk because it requires a fundamental re-thinking of design techniques till now studied in separate disciplines. It is high-gain because a successful method for automated synthesis of control software will make it finally possible to develop complex yet reliable CPS applications while considerably reducing the engineering cost.

1 470 800 €

Start date: 2019-02-01, End date: 2024-01-31

Learning and memory are the basis of our behaviour and mental well-being. Understanding the mechanisms of structural and cellular plasticity in defined neuronal circuits in vivo will be crucial to elucidate principles of circuit-specific memory formation and their relation to changes in neuronal ensemble dynamics. Structural plasticity studies were technically limited to cortex, excluding deep brain areas like the amygdala, and mainly focussed on the input site (dendritic spines), whilst the plasticity of the axon initial segment (AIS), a neuron’s site of output generation, was so far not studied in vivo. Length and location of the AIS are plastic and strongly affects a neurons spike output. However, it remains unknown if AIS plasticity regulates neuronal activity upon learning in vivo. We will combine viral expression of AIS live markers and genetically-encoded Ca2+-sensors with novel deep brain imaging techniques via gradient index (GRIN) lenses to investigate how AIS location and length are regulated upon associative learning in amygdala circuits in vivo. Two-photon time-lapse imaging of the AIS of amygdala neurons upon fear conditioning will help us to track learning-driven AIS location dynamics. Next, we will combine miniature microscope imaging of neuronal activity in freely moving animals with two-photon imaging to link AIS location, length and plasticity to the intrinsic activity as well as learning-related response plasticity of amygdala neurons during fear learning and extinction in vivo. Finally, we will test if AIS plasticity is a general cellular plasticity mechanisms in brain areas afferent to the amygdala, e.g. thalamus. Using a combination of two-photon and miniature microscopy imaging to map structural dynamics of defined neural circuits in the amygdala and its thalamic input areas will provide fundamental insights into the cellular mechanisms underlying sensory processing upon learning and relate network level plasticity with the cellular level.

1 475 475 €

Start date: 2018-12-01, End date: 2023-11-30

Next generation sequencing (NGS) is revolutionizing all fields of biological research but it fails to extract the full range of information associated with genetic material and is lacking in its ability to resolve variations between genomes. The high degree of genome variation exhibited both on the population level as well as between genetically “identical” cells (even in the same organ) makes genetic and epigenetic analysis on the single cell and single genome level a necessity. Chromosomes may be conceptually represented as a linear one-dimensional barcode. However, in contrast to a traditional binary barcode approach that considers only two possible bits of information (1 & 0), I will use colour and molecular structure to expand the variety of information represented in the barcode. Like colourful beads threaded on a string, where each bead represents a distinct type of observable, I will label each type of genomic information with a different chemical moiety thus expanding the repertoire of information that can be simultaneously measured. A major effort in this proposal is invested in the development of unique chemistries to enable this labelling. I specifically address three types of genomic variation: Variations in genomic layout (including DNA repeats, structural and copy number variations), variations in the patterns of chemical DNA modifications (such as methylation of cytosine bases) and variations in the chromatin composition (including nucleosome and transcription factor distributions). I will use physical extension of long DNA molecules on surfaces and in nanofluidic channels to reveal this information visually in the form of a linear, fluorescent “barcode” that is read-out by advanced imaging techniques. Similarly, DNA molecules will be threaded through a nanopore where the sequential position of “bulky” molecular groups attached to the DNA may be inferred from temporal modulation of an ionic current measured across the pore.

1 627 600 €

Start date: 2013-10-01, End date: 2018-09-30

There is an apparent lack of non-metallic 2D-matrials for the construction of electronic devices, as only five materials of the “graphene family” are known: graphene, hBN, BCN, fluorographene, and graphene oxide – none of them with a narrow bandgap close to commercially used silicon. This ERC-StG proposal, BEGMAT, outlines a strategy for design, synthesis, and application of layered, functional materials that will go beyond this exclusive club. These materials “beyond graphene” (BEG) will have to meet – like graphene – the following criteria: (1) The BEG-materials will feature a transfer of crystalline order from the molecular (pm-range) to the macroscopic level (cm-range), (2) individual, free-standing layers of BEG-materials can be addressed by mechanical or chemical exfoliation, and (3) assemblies of different BEG-materials will be stacked as van der Waals heterostructures with unique properties. In contrast to the existing “graphene family”, (4) BEG-materials will be constructed in a controlled way by covalent organic chemistry in a bottom-up approach from abundant precursors free of metals and critical raw materials (CRMs). Moreover – and unlike – many covalent organic frameworks (COFs), (5) BEG-materials will be fully aromatic, donor-acceptor systems to ensure that electronic properties can be addressed on macroscopic scale. The potential to make 2D materials “beyond graphene” is a great challenge to chemical bond formation and material design. In 2014 the applicant has demonstrated the feasibility of the concept to expand the “graphene family” with triazine-based graphitic carbon, a compound highlighted as an “emerging competitor for the miracle material” graphene. Now, the PI has the opportunity to build a full-scale research program on layered functional materials that offers unique insights into controlled, covalent linking-chemistry, and that addresses practicalities in device manufacture, and structure-properties relationships.

1 362 538 €

Start date: 2016-08-01, End date: 2021-07-31

The selective functionalization of C-H and C=C bonds remains a formidable unsolved problem, owing to their inert nature. Novel alkane and alkene oxidation reactions exhibiting good and/or unprecedented selectivities will have a big impact on bulk and fine chemistry by opening novel methodologies that will allow removal of protection-deprotection sequences, thus streamlining synthetic strategies. These goals are targeted in this project via design of iron and manganese catalysts inspired by structural elements of the active site of non-heme enzymes of the Rieske Dioxygenase family. Selectivity is pursued via rational design of catalysts that will exploit substrate recognition-exclusion phenomena, and control over proton and electron affinity of the active species. Moreover, these catalysts will employ H2O2 as oxidant, and will operate under mild conditions (pressure and temperature). The fundamental mechanistic aspects of the catalytic reactions, and the species implicated in C-H and C=C oxidation events will also be studied with the aim of building on the necessary knowledge to design future generations of catalysts, and provide models to understand the chemistry taking place in non-heme iron and manganese-dependent oxygenases.

1 299 998 €

Start date: 2009-11-01, End date: 2015-10-31

The use of renewable feedstocks by the chemical industry is fundamental due to both the depletion of fossil resources and the increasing pressure of environmental concerns. Biomass can act as a sustainable source of organic industrial chemicals; however, the establishment of a renewable chemical industry that is economically competitive with the present oil-based one requires the development of new processes to convert biomass-derived compounds into useful industrial materials following the principles of green chemistry. To achieve these goals, developments in several fields including heterogeneous catalysis are needed. One of the ways to accelerate the discovery of new potentially active, selective and stable catalysts is the massive use of computational chemistry. Recent advances have demonstrated that Density Functional Theory coupled to ab initio thermodynamics, transition state theory and microkinetic analysis can provide a full view of the catalytic phenomena. The aim of the present project is thus to employ these well-tested computational techniques to the development of a theoretical framework that can accelerate the identification of new catalysts for the conversion of biomass derived target compounds into useful chemicals. Since compared to petroleum-based materials-biomass derived ones are multifuncionalized, the search for new catalytic materials and processes has a strong requirement in the selectivity of the chemical transformations. The main challenges in the project are related to the high functionalization of the molecules, their liquid nature and the large number of potentially competitive reaction paths. The requirements of specificity and selectivity in the chemical transformations while keeping a reasonably flexible framework constitute a major objective. The work will be divided in three main work packages, one devoted to the properties of small molecules or fragments containing a single functional group; the second addresses competition in multiple functionalized molecules; and third is dedicated to the specific transformations of two molecules that have already been identified as potential platform generators. The goal is to identify suitable candidates that could be synthetized and tested in the Institute facilities.

1 496 200 €

Start date: 2010-10-01, End date: 2015-09-30

The overall objective of the proposal is to develop enabling chemical technologies to address two important problems in biology: detect in a nondestructive fashion gene expression or microRNA sequences in vivo and, secondly, study the role of multivalency and spatial organization in carbohydrate recognition. Both of these projects exploit the programmable pre-organization of peptide nucleic acid (PNA) to induce a chemical reaction in the first case or modulate a ligand-receptor interaction in the second case. For nucleic acid detection, a DNA or RNA fragment will be utilized to bring two PNA fragments bearing reactive functionalities in close proximity thereby promoting a reaction. Two types of reactions are proposed, the first one to release a fluorophore for imaging purposes and the second one to release a drug as an “intelligent” therapeutic. If affinities are programmed such that hybridization is reversible, the template can work catalytically leading to large amplifications. As a proof of concept, this method will be used to measure the transcription level of genes implicated in stem cell differentiation and detect mutations in oncogenes. For the purpose of studying multivalent carbohydrate ligand architectures, the challenge of chemical synthesis has been a limiting factor. A supramolecular approach is proposed herein where different arrangements of carbohydrates can be displayed in a well organized fashion by hybridizing PNA-tagged carbohydrates to DNA templates. This will be used not only to control the distance between multiple ligands or to create combinatorial arrangements of hetero ligands but also to access more complex architectures such as Hollyday junctions. The oligosaccharide units will be prepared using de novo organoctalytic reactions. This technology will be first applied to probe the recognition events between HIV and dendritic cells which promote HIV infection.

1 249 980 €

Start date: 2008-07-01, End date: 2013-06-30

Recent intensive research on the laser spectroscopy of neutral gas-phase biomolecules has yielded a detailed picture of their structures and conformational preferences away from the complications of the bulk environment. In contrast, work on ionic systems has been sparse despite the fact that many important molecular groups are charged under physiological conditions. To address this probelm, we have developed a custom-built laser spectrometer, which incorporates a distincitive electrospray ionisation (ESI) cluster ion source, dedicated to producing biological anions (ATP,oligonucleotides) and their microsolvated clusters for structural characterization. Many previous laser spectrometers with ESI sources have suffered from producing &quot;hot&quot; congested spectra as the ions were produced at ambient temperatures. This is a particularly serious limitation for spectroscopic studies of biomolecules, since these systems can possess high internal energies due tothe presence of numerous low frequency modes. Our spectrometer overcomes this problem by exploiting the newly developed physics technique of &quot;buffer gas cooling&quot; to produce cold ESI molecular ions. In this proposal, we now seek to exploit the new laser-spectrometer to perform detailed spectroscopic interrogations of ESI generated biomolecular anions and clusters. In addition to traditional ion-dissociation spectroscopies, we propose to develop two new laser spectroscopy techniques (Two-color tuneable IR spectroscopy and Dipole-bound excited state spectroscopy) to give the broadest possible structural characterizations of the systems of interest. Studies will focus on ATP/GTP-anions, olignonucleotides, and sulphated and carboxylated sugars. These methodologies will provide a general approach for performing temperature-controlled spectroscopic characterizations of isolated biological ions, with measurements on the corresponding micro-solvated clusters providing details of how the molecules are perturbed by solvent.

1 250 000 €

Start date: 2008-10-01, End date: 2015-06-30

This ERC-StG proposal, BIOMOF, outlines a dual strategy for the growth and processing of porous metal-organic framework (MOF) materials, inspired by the interfacial interactions that characterise highly controlled biomineralisation processes. The aim is to prepare MOF (bio)-composite materials of hierarchical structure and multi-modal functionality to address key societal challenges in healthcare, catalysis and energy. In order for MOFs to reach their full potential, a transformative approach to their growth, and in particular their processability, is required since the insoluble macroscopic micron-sized crystals resulting from conventional syntheses are unsuitable for many applications. The BIOMOF project defines chemically flexible routes to MOFs under mild conditions, where the added value with respect to wide-ranging experimental procedures for the growth and processing of crystalline controllably nanoscale MOF materials with tunable structure and functionality that display significant porosity for wide-ranging applications is extremely high. Theme 1 exploits protein vesicles and abundant biopolymer matrices for the confined growth of soluble nanoscale MOFs for high-end biomedical applications such as cell imaging and targeted drug delivery, whereas theme 2 focuses on the cost-effective preparation of hierarchically porous MOF composites over several length scales, of relevance to bulk industrial applications such as sustainable catalysis, separations and gas-storage. This diverse yet complementary range of applications arising simply from the way the MOF is processed, coupled with the versatile structural and physical properties of MOFs themselves indicates strongly that the BIOMOF concept is a powerful convergent new approach to applied materials chemistry.

1 492 970 €

Start date: 2010-11-01, End date: 2015-10-31

We are largely unaware of our own motives. Understanding our motives can be reduced to knowing how we form goals and these goals translate into behavior. Goals can be defined as pleasurable situations that we particularly value and that we intend to reach. Recent investigation in the emerging field of neuro-economics has put forward a neuronal network constituting a brain valuation system (BVS). We wish to build a more comprehensive account of motivational processes, investigating not only valuation and choice but also effort (how much energy we would spend to attain a goal). More specifically, our aims are to better describe 1) how the brain assigns values to various objects and actions, 2) how values depend on parameters such as reward magnitude, probability, delay and cost, 3) how values are affected by social contexts, 4) how values are modified through learning and 5) how values influence the brain systems (perceptual, cognitive and motor) that underpin behavioral performance. To these aims, we would combine three approaches: 1) human cognitive neuroscience, which is central as we ultimately wish to understand ourselves, as well as human pathological conditions where motivation is either deficient (apathy) or out of control (compulsion), 2) primate neurophysiology, which is essential to describe information processing at the single-unit level and to derive causality by observing behavioral consequences of brain manipulations, 3) computational modeling, which is mandatory to link quantitatively the different descriptions levels (single-unit recordings, local field potentials, regional BOLD signal, vegetative manifestations and motor outputs). A bayesian framework will be developed to infer from experimental measures the subjects prior beliefs and value functions. We believe that our team, bringing together three complementary perspectives on motivation within a clinical environment, would represent a unique education and research center in Europe.

1 346 000 €

Start date: 2011-03-01, End date: 2016-08-31

"In the course of biomineralization, organisms produce a large variety of functional biogenic crystals that exhibit fascinating mechanical, optical, magnetic and other characteristics. More specifically, when living organisms grow crystals they can effectively control polymorph selection as well as the crystal morphology, shape, and even atomic structure. Materials existing in nature have extraordinary and specific functions, yet the materials employed in nature are quite different from those engineers would select. I propose to emulate specific strategies used by organisms in forming structural biogenic crystals, and to apply these strategies biomimetically so as to form new structural materials with new properties and characteristics. This bio-inspired approach will involve the adoption of three specific biological strategies. We believe that this procedure will open up new ways to control the structure and properties of smart materials. The three bio-inspired strategies that we will utilize are: (i) to control the short-range order of amorphous materials, making it possible to predetermine the polymorph obtained when they transform from the amorphous to the succeeding crystalline phase; (ii) to control the morphology of single crystals of various functional materials so that they can have intricate and curved surfaces and yet maintain their single-crystal nature; (iii) to entrap organic molecules into single crystals of functional materials so as to tailor and manipulate their electronic structure. The proposed research has significant potential for opening up new routes for the formation of novel functional materials. Specifically, it will make it possible for us (1) to produce single, intricately shaped crystals without the need to etch, drill or polish; (2) to control the short-range order of amorphous materials and hence the polymorph of the successive crystalline phase; (3) to tune the band gap of semiconductors via incorporation of tailored bio-molecules."

1 500 000 €

Start date: 2013-09-01, End date: 2018-08-31

The standard variational principles (VPs) are cornerstones of quantum mechanics, and one can hardly overestimate their usefulness as tools for generating approximations to the time-independent and time-dependent Schröodinger equations. The aim of the proposal is to study and apply a generalization of these, the bivariational principles (BIVPs), which arise naturally when one does not assume a priori that the system Hamiltonian is Hermitian. This unconventional approach may have transformative impact on development of ab initio methodology, both for electronic structure and dynamics. The first objective is to establish the mathematical foundation for the BIVPs. This opens up a whole new axis of method development for ab initio approaches. For instance, it is a largely ignored fact that the popular traditional coupled cluster (TCC) method can be neatly formulated with the BIVPs, and TCC is both polynomially scaling with the number of electrons and size-consistent. No “variational” method enjoys these properties simultaneously, indeed this seems to be incompatible with the standard VPs. Armed with the BIVPs, the project aims to develop new and understand existing ab initio methods. The second objective is thus a systematic multireference coupled cluster theory (MRCC) based on the BIVPs. This is in itself a novel approach that carries large potential benefits and impact. The third and last objective is an implementation of a new coupled-cluster type method where the orbitals are bivariational parameters. This gives a size-consistent hierarchy of approximations to multiconfiguration Hartree--Fock. The PI's broad contact with and background in scientific disciplines such as applied mathematics and nuclear physics in addition to quantum chemistry increases the feasibility of the project.

1 499 572 €

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

The study of synthetic molecular networks is of fundamental importance for understanding the organizational principles of biological systems and may well be the key to unraveling the origins of life. In addition, such systems may be useful for parallel synthesis of molecules, implementation of catalysis via multi-step pathways, and as media for various applications in nano-medicine and nano-electronics. We have been involved recently in developing peptide-based replicating networks and revealed their dynamic characteristics. We argue here that the structural information embedded in the polypeptide chains is sufficiently rich to allow the construction of peptide 'Systems Chemistry', namely, to facilitate the use of replicating networks as cell-mimetics, featuring complex dynamic behavior. To bring this novel idea to reality, we plan to take a unique holistic approach by studying such networks both experimentally and via simulations, for elucidating basic-principles and towards applications in adjacent fields, such as molecular electronics. Towards realizing these aims, we will study three separate but inter-related objectives: (i) design and characterization of networks that react and rewire in response to external triggers, such as light, (ii) design of networks that operate via new dynamic rules of product formation that lead to oscillations, and (iii) exploitation of the molecular information gathered from the networks as means to control switching and gating in molecular electronic devices. We believe that achieving the project's objectives will be highly significant for the development of the arising field of Systems Chemistry, and in addition will provide valuable tools for studying related scientific fields, such as systems biology and molecular electronics.

1 500 000 €

Start date: 2010-10-01, End date: 2015-09-30

Brain-Computer Interfaces (BCIs) are communication systems that enable users to send commands to computers through brain signals only, by measuring and processing these signals. Making computer control possible without any physical activity, BCIs have promised to revolutionize many application areas, notably assistive technologies, e.g., for wheelchair control, and human-machine interaction. Despite this promising potential, BCIs are still barely used outside laboratories, due to their current poor reliability. For instance, BCIs only using two imagined hand movements as mental commands decode, on average, less than 80% of these commands correctly, while 10 to 30% of users cannot control a BCI at all. A BCI should be considered a co-adaptive communication system: its users learn to encode commands in their brain signals (with mental imagery) that the machine learns to decode using signal processing. Most research efforts so far have been dedicated to decoding the commands. However, BCI control is a skill that users have to learn too. Unfortunately how BCI users learn to encode the commands is essential but is barely studied, i.e., fundamental knowledge about how users learn BCI control is lacking. Moreover standard training approaches are only based on heuristics, without satisfying human learning principles. Thus, poor BCI reliability is probably largely due to highly suboptimal user training. In order to obtain a truly reliable BCI we need to completely redefine user training approaches. To do so, I propose to study and statistically model how users learn to encode BCI commands. Then, based on human learning principles and this model, I propose to create a new generation of BCIs which ensure that users learn how to successfully encode commands with high signal-to-noise ratio in their brain signals, hence making BCIs dramatically more reliable. Such a reliable BCI could positively change human-machine interaction as BCIs have promised but failed to do so far.

1 498 751 €

Start date: 2017-07-01, End date: 2022-06-30

The core function of all brains is to compute the current state of the world, compare it to the desired state of the world and select motor programs that drive behavior minimizing any mismatch. The circuits underlying these functions are the key to understand brains in general, but so far they are completely unknown. Three problems have hindered progress: 1) The animal’s desired state of the world is rarely known. 2) Most studies in simple models have focused on sensory driven, reflex-like processes, and not considered self-initiated behavior. 3) The circuits underlying complex behaviors in vertebrates are widely distributed, containing millions of neurons. With this proposal I aim at overcoming these problems using insects, whose tiny brains solve the same basic problems as our brains but with 100,000 times fewer cells. Moreover, the central complex, a single conserved brain region consisting of only a few thousand neurons, is crucial for sensory integration, motor control and state-dependent modulation, essentially being a ‘brain in the brain’. To simplify the problem further I will focus on navigation behavior. Here, the desired and actual states of the world are equal to the desired and current headings of the animal, with mismatches resulting in compensatory steering. I have previously shown how the central complex encodes the animal’s current heading. Now I will use behavioral training to generate animals with highly defined desired headings, and correlate neural activity with the animal’s ‘intentions’ and actions - at the level of identified neurons. To establish the involved conserved core circuitry valid across insects I will compare species with distinct lifestyles. Secondly, I will reveal how these circuits have evolved to account for each species’ unique ecology. The proposed work will provide a coherent framework to study key concepts of fundamental brain functions in unprecedented detail - using a single, conserved, but flexible neural circuit.

1 500 000 €

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

We are currently witnessing a paradigm shift in our understanding of human brain function, moving towards a clearer description of cortical processing. Sensory systems are no longer considered as 'passively recording' but rather as dynamically anticipating and adapting to the rapidly changing environment. These new ideas are encompassed in the predictive coding framework, and indeed in a unifying theory of the brain (Friston, 2010). In terms of brain computation, a predictive model is created in higher cortical areas and communicated to lower sensory areas through feedback connections. Based on my pioneering research I propose experiments that are capable of ‘brain-reading’ cortical feedback– which would contribute invaluable data to theoretical frameworks. The proposed research project will advance our understanding of ongoing brain activity, contextual processing, and cortical feedback - contributing to what is known about general cortical functions. By providing new insights as to the information content of cortical feedback, the proposal will fill one of the most important gaps in today’s knowledge about brain function. Friston’s unifying theory of the brain (Friston, 2010) and contemporary models of the predictive-coding framework (Hawkins and Blakeslee, 2004;Mumford, 1992;Rao and Ballard, 1999) assign feedback processing an essential role in cortical processing. Compared to feedforward information processing, our knowledge about feedback processing is in its infancy. The proposal introduces parametric and explorative brain reading designs to investigate this feedback processing. The chief goal of my proposal will be precision measures of cortical feedback, and a more ambitious objective is to read mental images and inner thoughts.

1 494 714 €

Start date: 2012-12-01, End date: 2017-11-30

Our ability to think, to memorize and focus our thoughts depends on acetylcholine signaling in the brain. The loss of cholinergic signalling in for instance Alzheimer’s disease strongly compromises these cognitive abilities. The traditional view on the role of cholinergic input to the neocortex is that slowly changing levels of extracellular acetylcholine (ACh) mediate different arousal states. This view has been challenged by recent studies demonstrating that rapid phasic changes in ACh levels at the scale of seconds are correlated with focus of attention, suggesting that these signals may mediate defined cognitive operations. Despite a wealth of anatomical data on the organization of the cholinergic system, very little understanding exists on its functional organization. How the relatively sparse input of cholinergic transmission in the prefrontal cortex elicits such a profound and specific control over attention is unknown. The main objective of this proposal is to develop a causal understanding of how cellular mechanisms of fast acetylcholine signalling are orchestrated during cognitive behaviour. In a series of studies, I have identified several synaptic and cellular mechanisms by which the cholinergic system can alter neuronal circuitry function, both in cortical and subcortical areas. I have used a combination of behavioral, physiological and genetic methods in which I manipulated cholinergic receptor functionality in prefrontal cortex in a subunit specific manner and found that ACh receptors in the prefrontal cortex control attention performance. Recent advances in optogenetic and electrochemical methods now allow to rapidly manipulate and measure acetylcholine levels in freely moving, behaving animals. Using these techniques, I aim to uncover which cholinergic neurons are involved in fast cholinergic signaling during cognition and uncover the underlying neuronal mechanisms that alter prefrontal cortical network function.

1 499 242 €

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

My lab's work ranges from basic science, querying brain plasticity and sensory integration, to technological developments, allowing the blind to be more independent and even “see” using sounds and touch similar to bats and dolphins (a.k.a. Sensory Substitution Devices, SSDs), and back to applying these devices in research. We propose that, with proper training, any brain area or network can change the type of sensory input it uses to retrieve behaviorally task-relevant information within a matter of days. If this is true, it can have far reaching implications also for clinical rehabilitation. To achieve this, we are developing several innovative SSDs which encode the most crucial aspects of vision and increase their accessibility the blind, along with targeted, structured training protocols both in virtual environments and in real life. For instance, the “EyeMusic”, encodes colored complex images using pleasant musical scales and instruments, and the “EyeCane”, a palm-size cane, which encodes distance and depth in several directions accurately and efficiently. We provide preliminary but compelling evidence that following such training, SSDs can enable almost blind to recognize daily objects, colors, faces and facial expressions, read street signs, and aiding mobility and navigation. SSDs can also be used in conjunction with (any) invasive approach for visual rehabilitation. We are developing a novel hybrid Visual Rehabilitation Device which combines SSD and bionic eyes. In this set up, the SSDs is used in training the brain to “see” prior to surgery, in providing explanatory signal after surgery and in augmenting the capabilities of the bionic-eyes using information arriving from the same image. We will chart the dynamics of the plastic changes in the brain by performing unprecedented longitudinal Neuroimaging, Electrophysiological and Neurodisruptive approaches while individuals learn to ‘see’ using each of the visual rehabilitation approaches suggested here.

1 499 900 €

Start date: 2013-09-01, End date: 2018-08-31

Current control applications necessitate the treatment of systems with multiple interconnected components, rather than the traditional single component paradigm that has been studied extensively. The individual subsystems may need to fulfil different and possibly conflicting specifications in a real-time manner. At the same time, they may need to fulfill coupled constraints that are defined as relations between their states. Towards this end, the need for methods for decentralized control at the continuous level and planning at the task level becomes apparent. We aim here towards unification of these two complementary approaches. Existing solutions rely on a top down centralized approach. We instead consider here a decentralized, bottom-up solution to the problem. The approach relies on three layers of interaction. In the first layer, agents aim at coordinating in order to fulfil their coupled constraints with limited communication exchange of their state information and design of appropriate feedback controllers; in the second layer, agents coordinate in order to mutually satisfy their discrete tasks through exchange of the corresponding plans in the form of automata; in the third and most challenging layer, the communication exchange for coordination now includes both continuous state and discrete plan/abstraction information. The results will be demonstrated in a scenario involving multiple (possibly human) users and multiple robots. The unification will yield a completely decentralized system, in which the bottom up approach to define tasks, the consideration of coupled constraints and their combination towards distributed hybrid control and planning in a coordinated fashion require for new ways of thinking and approaches to analysis and constitute the proposal a beyond the SoA and groundbreaking approach to the fields of control and computer science.

1 498 729 €

Start date: 2015-03-01, End date: 2020-02-29

C-H activations and related reactions can potentially revolutionize the way organic molecules are made and allow a more efficient use of earth's natural resources. Despite the rapid progress of the last couple of years, many problems like limited scope, extreme reaction conditions (temperature, excess of reagents) or low reactivities and selectivities remain in many cases. In this comprehensive proposal containing a number of projects and work packages, we want to develope new C-H activation methods 1) for the efficient synthesis of heterocycles, 2) for the activation of unactivated C(sp3)-H bonds, 3) by employing newly designed Fe-NHC complexes and 4) demonstrating the application of C-H activation for the functionalization of metal-organic frameworks (MOFs). The realization of these goals would render organic synthesis greener and more efficient and would have an impact on the preparation of compounds in academia and industry.

1 499 400 €

Start date: 2010-12-01, End date: 2015-11-30

Whether and where clouds consist of liquid water, ice or both (i.e. their thermodynamic phase distribution), has major impacts on the clouds’ dynamical development, their radiative properties, their efficiency to form precipitation, and their impacts on the atmospheric environment. Cloud ice formation in the temperature range between 0 and -37°C is initiated by aerosol particles acting as heterogeneous ice nuclei and propagates through the cloud via a multitude of microphysical processes. Enormous progress has been made in recent years concerning the understanding and model parameterization of primary ice formation. In addition, high-resolution atmospheric models with complex cloud microphysics schemes can now be employed for realistic case studies of clouds. Finally, new retrieval schemes for the cloud (top) phase have recently been developed for various satellites, including passive polar orbiting and geostationary sensors, which provide a good spatial and temporal coverage and a long data record. We propose here to merge the bottom-up, forward modeling approach for the cloud phase distribution with the top-down view of satellites. C2Phase will conduct systematic closure studies for variables related to the cloud phase distribution such as the cloud ice area fraction, its distribution as function of temperature and its temporal evolution, with a focus on Europe. For this, we will (1) use clustering techniques to separate different cloud regimes in model and satellite data, (2) explore the parameters and processes which the simulated phase distribution is most sensitive to, (3) investigate whether closure is reached between state-of-the art cloud resolving models and satellite observations, and how this closure can be improved by consistent and physically justified changes in microphysical parameterizations, and (4) use our results to improve the representation of mixed-phase clouds in weather and climate models and to quantify the impacts of these improvements.

1 499 549 €

Start date: 2017-04-01, End date: 2022-03-31

The Earth's climate system contains a highly complex interplay of numerous components, such as atmospheric greenhouse gases, ice sheets, and ocean circulation. Due to nonlinearities and feedbacks, changes to the system can result in rapid transitions to radically different climate states. In light of rising greenhouse gas levels there is an urgent need to better understand climate at such tipping points. Reconstructions of profound climate changes in the past provide crucial insight into our climate system and help to predict future changes. However, all proxies we use to reconstruct past climate depend on assumptions that are in addition increasingly uncertain back in time. A new kind of temperature proxy, the carbonate ‘clumped isotope’ thermometer, has great potential to overcome these obstacles. The proxy relies on thermodynamic principles, taking advantage of the temperature-dependence of the binding strength between different isotopes of carbon and oxygen, which makes it independent of other variables. Yet, widespread application of this technique in paleoceanography is currently prevented by the required large sample amounts, which are difficult to obtain from ocean sediments. If applied to the minute carbonate shells preserved in the sediments, this proxy would allow robust reconstructions of past temperatures in the surface and deep ocean, as well as global ice volume, far back in time. Here I propose to considerably decrease sample amount requirements of clumped isotope thermometry, building on recent successful modifications of the method and ideas for further analytical improvements. This will enable my group and me to thoroughly ground-truth the proxy for application in paleoceanography and for the first time apply it to aspects of past climate change across major climate transitions in the past, where clumped isotope thermometry can immediately contribute to solving long-standing first-order questions and allow for major progress in the field.

1 877 209 €

Start date: 2015-08-01, End date: 2020-07-31