ERC FUNDED PROJECTS

One’s ability to remember visual material such as objects, faces, and spatial locations over a short period of time declines with age. The proposed research will examine whether these deficits are explained by a reduction in visual working memory (VWM) capacity, or an impairment in one’s ability to maintain, or ‘bind’ appropriate associations among pieces of related information. In this project successful binding is operationally defined as the proper recall or recognition of objects that are defined by the conjunction of multiple visual features. While tests of long-term memory have demonstrated that, despite preserved memory for isolated features, older adults have more difficulty remembering conjunctions of features, no research has yet investigated analogous age related binding deficits in VWM. This is a critical oversight because, given the current state of the science, it is unknown whether these deficits are specific to the long-term memory system, or if they originate in VWM. The project interweaves three strands of research that each investigate whether older adults have more difficulty creating, maintaining, and updating bound multi-feature object representations than younger adults. This theoretical program of enquiry will provide insight into the cognitive architecture of VWM and how this system changes with age, and its outcomes will have wide ranging multi-disciplinary applications in applied theory and intervention techniques that may reduce the adverse consequences of aging on memory.

500 000 €

Start date: 2008-09-01, End date: 2011-08-31

DNA replication represents a dangerous moment in the life of the cell as endogenous and exogenous events challenge genome integrity by interfering with the progression, stability and restart of the replication fork. Failure to protect stalled forks or to process the replication fork appropriately contribute to the pathological mechanisms giving rise to cancer, therefore an understanding of the intricate mechanisms that ensure fork integrity can provide targets for new chemotherapeutic assays. Smc5-Smc6 is a multi-subunit complex with a poorly understood function in DNA replication and repair. One of its subunits, Nse2, is able to promote the addition of a small ubiquitin-like protein modifier (SUMO) to specific target proteins. Recent work has revealed that the Smc5-Smc6 complex is required for the progression of replication forks through damaged DNA and is recruited de novo to forks that undergo collapse. In addition, Smc5-Smc6 mediate repair of DNA breaks by homologous recombination between sister-chromatids. Thus, Smc5-Smc6 is anticipated to promote recombinational repair at stalled/collapsed replication forks. My laboratory proposes to develop molecular techniques to study replication at the level of single replication forks. We will employ these assays to identify and dissect the function of factors involved in replication fork stability and repair. We will place an emphasis on the study of the Smc5-Smc6 complex in these processes because of its potential roles in recombination-dependent fork repair and restart. We also propose to identify novel Nse2 substrates involved in DNA repair using yeast model systems. Specifically, we will address the following points: (1) Development of assays for analysis of factors involved in stabilisation, collapse and re-start of single-forks, (2) Analysis of the roles of Smc5-Smc6 in fork biology using developed techniques, (3) Isolation and functional analysis of novel Nse2 substrates.

893 396 €

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

The vast majority of our knowledge about how the brain encodes information has been obtained from recordings of one or few neurons at a time or from global mapping methods such as fMRI. These approaches have left unexplored how neuronal activity is distributed in space and time within a cortical column and how hundreds of neurons interact to process sensory information. By taking advantage of the most recent advances in two-photon microscopy, the proposed project addresses two broad aims, with a particular focus on the function and development of primary visual cortex: 1) to understand how cortical neuronal networks encode visual information, and 2) to understand how they become specialised for sensory processing during postnatal development. For the first aim, we will use in vivo two-photon calcium imaging to record activity simultaneously from hundreds of neurons in visual cortex while showing different visual stimuli to anaesthetised mice. This approach enables us for the first time to characterise in detail how individual neurons and neuronal subsets interact within a large cortical network in response to artificial and natural stimuli. Genetically-encoded fluorescent proteins expressed in distinct cell-types will inform us how excitatory and inhibitory neurons interact to shape population responses during vision. For the second aim, the same approach will be used to describe the maturation of cortical network function after the onset of vision and to assess the role of visual experience in this process. We will additionally use Channelrhodopsin-2, a genetic tool for remote control of action potential firing, to examine the role of correlated neuronal activity on establishment of functional cortical circuits. Together, this work will bring us closer to unravelling how sensory coding emerges on the level of neuronal networks.

1 080 000 €

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

Bacterial dehalorespiration is a microbial respiratory process in which halogenated hydrocarbons, from natural or anthropogenic origin, act as terminal electron acceptors. This leads to effective dehalogenation of these compounds, and as such their degradation and detoxification. The bacterial species, their enzymes and other components responsible for this unusual metabolism have only recently been identified. Unlocking the full potential of this process for bioremediation of persistent organohalides, such as polychlorinated biphenyls (PCBs) and tetrachloroethene, requires detailed understanding of the underpinning biochemistry. However, the regulation, mechanism and structure of the reductive dehalogenase (the enzyme responsible for delivering electrons to the halogenated substrates) are poorly understood. This ambitious proposal seeks to study representatives of the distinct reductive dehalogenase classes as well as key elements of the associated regulatory systems. Our group has been at the forefront of studying the biochemistry underpinning transcriptional regulation of dehalorespiration, providing detailed insights in the protein CprK at the atomic level. However, it is now apparent that only a subset of dehalogenases are regulated by CprK homologues with little known about the other regulators. In addition, studies on the reductive dehalogenases have been hampered by the inability to purify sufficient quantities. Using an interdisciplinary, biophysical approach focused around X-ray crystallography, enzymology and molecular biology, combined with novel reductive dehalogenase production methods, we aim to provide a detailed understanding and identification of the structural elements crucial to reductive dehalogenase mechanism and regulation. At the same time, we aim to apply the knowledge gathered and study the feasibility of generating improved dehalorespiratory components for biosensing or bioremediation applications through laboratory assisted evolution.

1 148 522 €

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

Understanding the mechanisms underlying the initiation and regulation of transcription remains one of the most fundamental questions in biology. Much of what we know about the transcription process was inferred from experiments on a handful of genes. As these experiments are not realistically scalable, corresponding computational methods building on these findings have emerged; however, these are not accurate enough for annotation of genomes. The limitations reflect that we have no accurate universal model describing transcription initiation; to a large extent, our understanding is based on case stories. Recently, high-throughput methods have been developed to chart the TSS landscape with nucleotide resolution. Using these data, I have dissected promoters at nucleotide level and found patterns that explain the transcription initiation rate for individual nucleotides. The objective for this work is to extend this to the first universal model for how cells select core promoters and associated TSSs. This will have two counterparts: i)prediction of TSSs from DNA sequence given a region of accessible DNA, and ii)prediction of DNA accessibility based on DNA sequences and dynamic epigenetic factors. Such a model will be a corner stone of future experimental and computational transcriptome and gene regulation studies.

812 399 €

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

To what extent can international institutions learn? What factors determine whether such institutions develop capacities for self-awareness and endogenous institutional change? This project investigates these questions in the context of the European Union (EU). Specifically, it examines the dramatic expansion in security missions led by the EU since 2003, a capacity that many observers doubted was even possible for the EU. To explain this change in institutional behaviour, the project intends to develop a theory of institutional learning to analyze the EU’s instigation and implementation of 16 security operations in various regions under the auspices of the European Security and Defence Policy (ESDP). In addition, with these missions the EU has shown a growing capacity to innovate in security affairs, using a unique civilian crisis management (CCM) capacity linked to security sector reform and other EU policy tools, including the ESDP, the Common Foreign and Security Policy (CFSP), and the European Neighbourhood Policy (ENP). These changes demand further examination in light of not only the growing ambitions of the EU itself but also in terms of the increasing demands for security assistance placed on a variety of IOs, such as the UN, NATO, and the OSCE. The initial phase of the project will focus on four key ESDP operations as detailed case studies – Macedonia, the Palestinian Authority, the Democratic Republic of the Congo, and Bosnia-Hercegovina – to explain this innovation. Following the investigation of these representative cases, the later stages of the project will examine more recent EU security operations in hopes of developing a general theory of EU institutional learning in the area of foreign/security/defence policy. The project also hopes to generalize beyond this theory to other EU policy domains and, potentially, other IOs at the regional and global levels. In doing so the findings could have major implications for global governance.

1 019 264 €

Start date: 2008-05-01, End date: 2013-04-30

What impact do forecasts have on political action? How are they communicated, perceived and used in order to prevent harmful events in the future? There are few policy areas as dependent on good forecasts as efforts aimed at preventing intra-state violent conflicts. Both practitioners and scholars agree that early, appropriate and sustained action on the part of various international players can help to avoid or at least alleviate many of the harmful consequences. Preventing the outbreak of such conflicts has increasingly become a priority objective of the European Union and its most influential member states. But there is a curious gap in the literature with respect to the exact linkage between early warning and political response: under what conditions do forecasts of impending conflicts lead to political action? The first objective of the project is to better understand the interplay of communication and political perception of early warnings about impending intra-state armed conflict. In a second step, the project will compare the findings about early warnings regarding armed conflict to insights about the impact of forecasts in other policy-areas such as adjusting to impending environmental and economic crises. Thus, the project aims to contribute to improving public policy by analysing the interplay of forecasting, advocacy and preventive decision-making.

754 077 €

Start date: 2008-09-01, End date: 2011-10-31

This project develops new theories and constructs new datasets to understand the determinants of net and gross foreign assets, the trade balance and the exchange rate. It also quantifies their respective roles in the dynamics of countries’ external deficits. In previous work, I constructed a database of US foreign assets and liabilities to analyse the sustainability of US current account deficits. I propose to build on this work along four related lines. First, I will generalize the analysis to other countries, contrasting the external balance sheets of large financially developed economies (US, UK) with those of small open economies (Canada, Australia). I will compare the historical role of the UK as a world banker to the current position of the US in the international monetary system. I will construct disaggregated databases of foreign assets at market value for these countries. Second, I will develop new theories of portfolio investment where international wealth transfers and predictable excess returns play a key role. These elements are rarely incorporated in open economy models but are essential for realism. I will develop and calibrate a new class of portfolio balance models compatible with the macroeconomic stylized facts on capital flows to study how countries’ capacity to accumulate foreign debt depends on changes in portfolio preferences (e.g. erosion of home bias). Third, I will use a disaggregated database of international investment positions of institutional investors to test for portfolio rebalancing at the microeconomic level. This exceptional database should also provide insights on the international propagation of financial crises. I will link the magnitude of price drops of given equities in crisis times to the institutional and geographical characteristics of their holders. Fourth, I will extend the methodology developed to analyze external adjustment to the issue of fiscal adjustment and twin deficits.

1 340 000 €

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

Inhibitory interneurons function as modulators of local circuit excitability. Their properties are of fundamental importance for normal brain function therefore understanding how these cells are generated during development may provide insight into neurodevelopmental disorders such as epilepsy and schizophrenia, in which interneuron defects have been implicated. Inhibitory GABAergic interneurons of the cerebral cortex (pallium) are generated from proliferating subpallial precursors during development and migrate extensively to populate the cortex. The aim of this proposal is to identify genetic pathways and signalling systems that underlie cortical interneuron migration and integration into functional neuronal circuits. Distinct interneuron subtypes are generated from the two most prominent neuroepithelial stem cell pools in the subpallium: the medial ganglionic eminence (MGE) and the lateral/caudal ganglionic eminence (LGE/CGE). We will genetically tag and purify interneurons originating from these precursors in order to examine their transcriptomes and identify factors involved in specification and migration. We will use Cre-lox fate mapping in transgenic mice to label specific sub-populations of neural stem cells and their differentiated progeny in the embryonic telencephalon. This will allow us to determine whether subdomains of the MGE or LGE/CGE neuroepithelium generate interneurons with distinct neurochemical phenotypes and/or characteristic migratory properties. Electrical activity and/or neurotransmitter receptor activation can act in concert with genetic programs to promote precursor proliferation, neuronal differentiation as well as neuronal migration. We will use gain-of-function and loss-of-function approaches to examine the role of neurotransmitters and neuropeptides at early stages of interneuron migration to the cortex.

1 250 000 €

Start date: 2008-07-01, End date: 2014-08-31