ERC FUNDED PROJECTS

I propose to pursue two emerging Force Microscopy techniques that allow measuring structural properties below the surface of the specimen. Whereas Force Microscopy (most commonly known under the name AFM) is usually limited to measuring the surface topography and surface properties of a specimen, I will demonstrate that Force Microscopy can achieve true 3D images of the structure of the cell nucleus. In Ultrasound Force Microscopy, an ultrasound wave is launched from below towards the surface of the specimen. After the sound waves interact with structures beneath the surface of the specimen, the local variations in the amplitude and phase shift of the ultrasonic surface motion is collected by the Force Microscopy tip. Previously, measured 2D maps of the surface response have shown that the surface response is sensitive to structures below the surface. In this project I will employ miniature AFM cantilevers and nanotube tips that I have already developed in my lab. This will allow me to quickly acquire many such 2D maps at a much wider range of ultrasound frequencies and from these 2D maps calculate the full 3D structure below the surface. I expect this technique to have a resolving power better than 10 nm in three dimensions as far as 2 microns below the surface. In parallel I will introduce a major improvement to a technique based on Nuclear Magnetic Resonance (NMR). Magnetic Resonance Force Microscopy measures the interaction of a rotating nuclear spin in the field gradient of a magnetic Force Microscopy tip. However, these forces are so small that they pose an enormous challenge. Miniature cantilevers and nanotube tips, in combination with additional innovations in the detection of the cantilever motion, can overcome this problem. I expect to be able to measure the combined signal of 100 proton spins or fewer, which will allow me to measure proton densities with a resolution of 5 nm, but possibly even with atomic resolution.

1 794 960 €

Start date: 2008-08-01, End date: 2013-07-31

The sub-cellular processes that control the most critical aspects of life occur in three-dimensions (3D), and are intrinsically dynamic. While super-resolution microscopy has revolutionized cellular imaging in recent years, our current capability to observe the dynamics of life on the nanoscale is still extremely limited, due to inherent trade-offs between spatial, temporal and spectral resolution using existing approaches. We propose to develop and demonstrate an optical microscopy methodology that would enable live sub-cellular observation in unprecedented detail. Making use of multicolor 3D point-spread-function (PSF) engineering, a technique I have recently developed, we will be able to simultaneously track multiple markers inside live cells, at high speed and in five-dimensions (3D, time, and color). Multicolor 3D PSF engineering holds the potential of being a uniquely powerful method for 5D tracking. However, it is not yet applicable to live-cell imaging, due to significant bottlenecks in optical engineering and signal processing, which we plan to overcome in this project. Importantly, we will also demonstrate the efficacy of our method using a challenging biological application: real-time visualization of chromatin dynamics - the spatiotemporal organization of DNA. This is a highly suitable problem due to its fundamental importance, its role in a variety of cellular processes, and the lack of appropriate tools for studying it. The project is divided into 3 aims: 1. Technology development: diffractive-element design for multicolor 3D PSFs. 2. System design: volumetric tracking of dense emitters. 3. Live-cell measurements: chromatin dynamics. Looking ahead, here we create the imaging tools that pave the way towards the holy grail of chromatin visualization: dynamic observation of the 3D positions of the ~3 billion DNA base-pairs in a live human cell. Beyond that, our results will be applicable to numerous 3D micro/nanoscale tracking applications.

1 802 500 €

Start date: 2018-11-01, End date: 2023-10-31

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

We propose to elucidate the structural design principles of naturally occurring antibody complementarity-determining regions (CDRs) and to computationally design novel antibody functions. Antibodies represent the most versatile known system for molecular recognition. Research has yielded many insights into antibody design principles and promising biotechnological and pharmaceutical applications. Still, our understanding of how CDRs encode specific loop conformations lags far behind our understanding of structure-function relationships in non-immunological scaffolds. Thus, design of antibodies from first principles has not been demonstrated. We propose a computational-experimental strategy to address this challenge. We will: (a) characterize the design principles and sequence elements that rigidify antibody CDRs. Natural antibody loops will be subjected to computational modeling, crystallography, and a combined in vitro evolution and deep-sequencing approach to isolate sequence features that rigidify loop backbones; (b) develop a novel computational-design strategy, which uses the >1000 solved structures of antibodies deposited in structure databases to realistically model CDRs and design them to recognize proteins that have not been co-crystallized with antibodies. For example, we will design novel antibodies targeting insulin, for which clinically useful diagnostics are needed. By accessing much larger sequence/structure spaces than are available to natural immune-system repertoires and experimental methods, computational antibody design could produce higher-specificity and higher-affinity binders, even to challenging targets; and (c) develop new strategies to program conformational change in CDRs, generating, e.g., the first allosteric antibodies. These will allow targeting, in principle, of any molecule, potentially revolutionizing how antibodies are generated for research and medicine, providing new insights on the design principles of protein functional sites.

1 499 930 €

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

In mammals, gene dosage of X-chromosomal genes is equalized between sexes by random inactivation of either one of the two X chromosomes in female cells. In the initial phase of X chromosome inactivation (XCI), a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome (Xi). Xist is an X-encoded gene that plays a crucial role in the XCI process. At the start of XCI Xist expression is up-regulated and Xist RNA accumulates on the future Xi thereby initiating silencing in cis. Recent work performed in my laboratory indicates that the counting and initiation process is directed by a stochastic mechanism, in which each X chromosome has an independent probability to be inactivated. We also found that this probability is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of XCI. With a BAC screen we recently identified X-encoded RNF12 to be a dose-dependent activator of XCI. Expression of RNF12 correlates with Xist expression, and a heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells. The presence of a small proportion of cells that still initiate XCI, in Rnf12+/- cells, also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI in mouse and human, and to search for additional XCI-activators. We will also attempt to establish the role of different inhibitors of XCI, including CTCF and the pluripotency factors OCT4, SOX2 and NANOG. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation of X-linked diseases that are affected by XCI.

1 500 000 €

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

My proposal seeks to explain the complex interplay between genetic and environmental causes of individual variation in substance use and the risk for abuse. Substance use is common. Substances like nicotine and cannabis have well-known negative health consequences, while alcohol and caffeine use may be both beneficial and detrimental, depending on quantity and frequency of use. Twin studies (including my own) demonstrated that both heritable and environmental factors play a role. My proposal on substance use (nicotine, alcohol, cannabis and caffeine) is organized around several key objectives: 1. To unravel the complex contribution of genetic and environmental factors to substance use by using extended twin family designs; 2. To identify and confirm genes and gene networks involved in substance use by using DNA-variant data; 3. To explore gene expression patterns with RNA data in substance users versus non-users; 4. To investigate biomarkers in substance users versus non-users using blood or urine; 5. To unravel relation between substance use and health by linking twin-family data to national medical databases. To realize these aims I will use the extensive resources of the Netherlands Twin Register (NTR); including both the longitudinal phenotype database and the biological samples. I have been involved in data collection, coordination of data collection and analyzing NTR data since 1999. With my comprehensive experience in data collection, data analyses and my knowledge in the field of behavior genetics and addiction research I will be able to successfully lead this cutting-edge project. Additional data crucial for the project will be collected by my team. Large samples will be available for this study and state-of-the art methods will be used to analyze the data. All together, my project will offer powerful approaches to unravel the complex interaction between genetic and environmental causes of individual differences in substance use and the risk for abuse.

1 491 964 €

Start date: 2011-12-01, End date: 2017-05-31

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

In a typical learning problem one tries to approximate an unknown function by a function from a given class using random data, sampled according to an unknown measure. In this project we will be interested in parameters that govern the complexity of a learning problem. It turns out that this complexity is determined by the geometry of certain sets in high dimension that are connected to the given class (random coordinate projections of the class). Thus, one has to understand the structure of these sets as a function of the dimension - which is given by the cardinality of the random sample. The resulting analysis leads to many theoretical questions in Asymptotic Geometric Analysis, Probability (most notably, Empirical Processes Theory) and Combinatorics, which are of independent interest beyond the application to Learning Theory. Our main goal is to describe the role of various complexity parameters involved in a learning problem, to analyze the connections between them and to investigate the way they determine the geometry of the relevant high dimensional sets. Some of the questions we intend to tackle are well known open problems and making progress towards their solution will have a significant theoretical impact. Moreover, this project should lead to a more complete theory of learning and is likely to have some practical impact, for example, in the design of more efficient learning algorithms.

750 000 €

Start date: 2009-03-01, End date: 2014-02-28

This research proposal explores the political economy of international development assistance (aid) directed towards social expenditures, examined through the lens of a particular financial quandary that has been ignored in the literature despite having important economic and political repercussions. The quandary is that aid cannot be directly spent on expenditures denominated in domestic currency. Instead, aid needs to be first converted into domestic currency whereas the foreign exchange provided is used for other purposes, resulting in a process prone to complex politics regarding domestic monetary policy and spending commitments. The implications require a serious rethink of many of the accepted premises in the political economy of aid and related literatures. It is urgent to engage in this rethinking given tensions between two dynamics in the current global political economy: a tightening financial cycle facing developing countries versus an increasing emphasis in international development agendas of directing aid towards social expenditures. The financial quandary might exacerbate these tensions, restricting recipient government policy space despite donor commitments of respecting national ownership. The proposed research examines these implications through the emerging social protection agenda among donors, which serves as an ideal policy case given that social protection expenditures are almost entirely based on domestic currency. This will be researched through a mixed-method comparative case study of six developing countries, combining quantitative analysis of balance of payments and financing constraints with qualitative process tracing based on elite interviews and documentary research. The objective is to re-orient our thinking on these issues for a deeper appreciation of the systemic political and economic challenges facing global redistribution towards poorer countries, particularly with respect to the forthcoming Sustainable Development Goals.

1 459 529 €

Start date: 2015-05-01, End date: 2020-04-30

In most European countries social insurance programs, like welfare, unemployment insurance and disability insurance are characterized by low reemployment rates. Therefore, governments spend huge amounts of money on active labour market programs, which should help individuals in finding work. Recent surveys indicate that programs which aim at intensifying job search behaviour are much more effective than schooling programs for improving human capital. A second conclusion from these surveys is that despite the size of the spendings on these programs, evidence on its effectiveness is limited. This research proposal aims at developing an economic framework that will be used to evaluate the effectiveness of popular programs like offering reemployment bonuses, fraud detection, workfare and job search monitoring. The main innovation is that I will combine economic theory with recently developed econometric techniques and detailed administrative data sets, which have not been explored before. While most of the literature only focuses on short-term outcomes, the available data allow me to also consider the long-term effectiveness of programs. The key advantage of an economic model is that I can compare the effectiveness of the different programs, consider modifications of programs and combinations of programs. Furthermore, using an economic model I can construct profiling measures to improve the targeting of programs to subsamples of the population. This is particularly relevant if the effectiveness of programs differs between individuals or depends on the moment in time the program is offered. Therefore, the results from this research will not only be of scientific interest, but will also be of great value to policymakers.

550 000 €

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

"The first decade of Algorithmic Mechanism Design (AMD) concentrated, very successfully, on the design of truthful mechanisms for the allocation of resources among agents with private preferences. Truthful mechanisms are ones that incentivize rational users to report their preferences truthfully. Truthfulness, however, for all its theoretical appeal, suffers from several inherent limitations, mainly its high communication and computation complexities. It is not surprising, therefore, that practical applications forego truthfulness and use simpler mechanisms instead. Simplicity in itself, however, is not sufficient, as any meaningful mechanism should also have some notion of fairness; otherwise agents will stop using it over time. In this project I plan to develop an innovative AMD theoretical framework that will go beyond truthfulness and focus instead on the natural themes of simplicity and fairness, in addition to computational tractability. One of my primary goals will be the design of simple and fair poly-time mechanisms that perform at near optimal levels with respect to important economic objectives such as social welfare and revenue. To this end, I will work toward providing precise definitions of simplicity and fairness and quantifying the effects of these restrictions on the performance levels that can be obtained. A major challenge in the evaluation of non-truthful mechanisms is defining a reasonable behavior model that will enable their evaluation. The success of this project could have a broad impact on Europe and beyond, as it would guide the design of natural mechanisms for markets of tens of billions of dollars in revenue, such as online advertising, or sales of wireless frequencies. The timing of this project is ideal, as the AMD field is now sufficiently mature to lead to a breakthrough and at the same time young enough to be receptive to new approaches and themes."

1 394 600 €

Start date: 2013-11-01, End date: 2018-10-31

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

Life on earth is sustained by the process that converts sunlight energy into chemical energy: photosynthesis. This process is operating near the boundary between life and death: if the absorbed energy exceeds the capacity of the metabolic reactions, it can result in photo-oxidation events that can cause the death of the organism. Over-excitation is happening quite often: oxygenic organisms are exposed to (drastic) changes in environmental conditions (light intensity, light quality and temperature), which influence the physical (light-harvesting) and chemical (enzymatic reactions) parts of the photosynthetic process to a different extent, leading to severe imbalances. However, daily experience tells us that plants are able to deal with most of these situations, surviving and happily growing. How do they manage? The photosynthetic membrane is highly flexible and it is able to change its supramolecular organization and composition and even the function of some of its components on a time scale as fast as a few seconds, thereby regulating the light-harvesting capacity. However, the structural/functional changes in the membrane are far from being fully characterized and the molecular mechanisms of their regulation are far from being understood. This is due to the fact that all these mechanisms require the simultaneous presence of various factors and thus the system should be analyzed at a high level of complexity; however, to obtain molecular details of a very complex system as the thylakoid membrane in action has not been possible so far. Over the last years we have developed and optimized a range of methods that now allow us to take up this challenge. This involves a high level of integration of biological and physical approaches, ranging from plant transformation and in vivo knock out of individual pigments to ultrafast-spectroscopy in a mix that is rather unique for my laboratory and will allow us to unravel the photoprotective mechanisms in algae and plants.

1 696 961 €

Start date: 2011-12-01, End date: 2017-11-30

The role of intestinal bacteria in human health and disease has been intensively studied; however the viral composition of the microbiome, the virome, remains largely unknown. As many of the viruses are bacteriophages, they are expected to be a major factor shaping the human microbiome. The dynamics of the virome during early life, its interaction with host and environmental factors, is likely to have profound effects on human physiology. Therefore it is extremely timely to study the virome in depth and on a wide scale. This ERC project aims at understanding how the gut virome develops during the first year of life and how that relates to the composition of the bacterial microbiome. In particular, we will determine which intrinsic and environmental factors, including genetics and the mother’s microbiome and diet, interact with the virome in shaping the early gut microbiome ecosystem. In a longitudinal study of 1,000 newborns followed at 7 time points from birth till age 12 months, I will investigate: (1) the composition and evolution of the virome and bacterial microbiome in the first year of life; (2) the role of factors coming from the mother and from the host genome on virome and bacterial microbiome development and their co-evolution; and (3) the role of environmental factors, like infectious diseases, vaccinations and diet habits, on establishing the virome and overall microbiome composition during the first year of life. This project will provide crucial knowledge about composition and maturation of the virome during the first year of life, and its symbiotic relation with the bacterial microbiome. This longitudinal dataset will be instrumental for identification of microbiome markers of diseases and for the follow up analysis of the long-term effect of microbiota maturation later in life. Knowledge of the role of viruses in shaping the microbiota may promote future directions for manipulating the human gut microbiota in health and disease.

1 499 881 €

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

Natural selection is supposed to keep lethal alleles (dysfunctional or deleted copies of crucial genes) in check. Yet, in a balanced lethal system the frequency of lethal alleles is inflated. Because two forms of a chromosome carry distinct lethal alleles that are reciprocally compensated for by functional genes on the alternate chromosome form, both chromosome forms – and in effect their linked lethal alleles – are required for survival. The inability of natural selection to purge balanced lethal systems appears to defy evolutionary theory. How do balanced lethal systems originate and persist in nature? I suspect the answer to this pressing but neglected research question can be found in the context of supergenes in a balanced polymorphism – a current, hot topic in evolutionary biology. Chromosome rearrangements can lock distinct beneficial sets of alleles (i.e. supergenes) on two chromosome forms by suppressing recombination. Now, balancing selection would favour possession of both supergenes. However, as a consequence of suppressed recombination, unique lethal alleles could become fixed on each supergene, with natural selection powerless to prevent collapse of the arrangement into a balanced lethal system. I aim to explain the evolution of balanced lethal systems in nature. As empirical example I will use chromosome 1 syndrome, a balanced lethal system observed in newts of the genus Triturus. My research team will: Reconstruct the genomic architecture of this balanced lethal system at its point of origin [PI project]; Conduct comparative genomics with related, unaffected species [PhD project]; Determine gene order of the two supergenes involved [Postdoc project I]; and Model the conditions under which this balanced lethal system could theoretically have evolved [Postdoc project II]. Solving the paradox of chromosome 1 syndrome will allow us to understand balanced lethal systems in general and address the challenges they pose to evolutionary theory.

1 499 869 €

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

Cancer is the leading cause of death in the Western world and the second cause of death worldwide. Despite advances in medical research, 30% of cancer patients are prescribed a medication the tumor does not respond to, or, alternatively, drugs that induce adverse side effects patients' cannot tolerate. Nanotechnologies are becoming impactful therapeutic tools, granting tissue-targeting and cellular precision that cannot be attained using systems of larger scale. In this proposal, I plan to expand far beyond the state-of-the-art and develop a conceptually new approach in which diagnostic nanoparticles are designed to retrieve drug-sensitivity information from malignant tissue inside the body. The ultimate goal of this program is to be able to predict, ahead of time, which treatment will be best for each cancer patient – an emerging field called personalized medicine. This interdisciplinary research program will expand our understandings and capabilities in nanotechnology, cancer biology and medicine. To achieve this goal, I will engineer novel nanotechnologies that autonomously maneuver, target and diagnose the various cells that compose the tumor microenvironment and its disseminated metastasis. Each nanometric system will contain a miniscule amount of a biologically-active agent, and will serve as a nano lab for testing the activity of the agents inside the tumor cells. To distinguish between system to system, and to grant single-cell sensitivity in vivo, nanoparticles will be barcoded with unique DNA fragments. We will enable nanoparticle' deep tissue penetration into primary tumors and metastatic microenvironments using enzyme-loaded particles, and study how different agents, including small-molecule drugs, proteins and RNA, interact with the malignant and stromal cells that compose the cancerous microenvironments. Finally, we will demonstrate the ability of barcoded nanoparticles to predict adverse, life-threatening, side effects, in a personalized manner.

1 499 250 €

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

The goal of this proposal is to develop and promote Bayesian hypothesis tests for social scientists. By and large, social scientists have ignored the Bayesian revolution in statistics, and, consequently, most social scientists still assess the veracity of experimental effects using the same methodology that was used by their advisors and the advisors before them. This state of affairs is undesirable: social scientists conduct groundbreaking, innovative research only to analyze their results using methods that are old-fashioned or even inappropriate. This imbalance between the science and the statistics has gradually increased the pressure on the field to change the way inferences are drawn from their data. However, three requirements need to be fulfilled before social scientists are ready to adopt Bayesian tests of hypotheses. First, the Bayesian tests need to be developed for problems that social scientists work with on a regular basis; second, the Bayesian tests need to be default or objective; and, third, the Bayesian tests need to be available in a user-friendly computer program. This proposal seeks to make major progress on all three fronts. Concretely, the projects in this proposal build on recent developments in the field of statistics and use the default Jeffreys-Zellner-Siow priors to compute Bayesian hypothesis tests for regression, correlation, the t-test, and different versions of analysis of variance (ANOVA). A similar approach will be used to develop Bayesian hypothesis tests for logistic regression and the analysis of contingency tables, as well as for popular latent process methods such as factor analysis and structural equation modeling. We aim to implement the various tests in a new computer program, Bayes-SPSS, with a similar look and feel as the frequentist spreadsheet program SPSS (i.e., Statistical Package for the Social Sciences). Together, these projects may help revolutionize the way social scientists analyze their data.

1 498 286 €

Start date: 2012-05-01, End date: 2017-04-30

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

A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size. A fundamental challenge of pancreas biology is to understand and manipulate the determinants of beta cell mass. The homeostatic maintenance of adult beta cell mass relies largely on replication of differentiated beta cells, but the triggers and signaling pathways involved remain poorly understood. Here I propose to investigate the physiological and molecular mechanisms that control beta cell replication. First, novel transgenic mouse tools will be used to isolate live replicating beta cells and to examine the genetic program of beta cell replication in vivo. Information gained will provide insights into the molecular biology of cell division in vivo. Additionally, these experiments will address critical unresolved questions in beta cell biology, for example whether duplication involves transient dedifferentiation. Second, genetic and pharmacologic tools will be used to dissect the signaling pathways controlling the entry of beta cells to the cell division cycle, with emphasis on the roles of glucose and insulin, the key physiological input and output of beta cells. The expected outcome of these studies is a detailed molecular understanding of the homeostatic maintenance of beta cell mass, describing how beta cell function is linked to beta cell number in vivo. This may suggest new targets and concepts for pharmacologic intervention, towards the development of regenerative therapy strategies in diabetes. More generally, the experiments will shed light on one of the greatest mysteries of developmental biology, namely how organs achieve and maintain their correct size.

1 445 000 €

Start date: 2010-09-01, End date: 2015-08-31

Massive stars play many key roles in Astrophysics. As COSMIC ENGINES they transformed the pristine Universe left after the Big Bang into our modern Universe. We use massive stars, their explosions and products as COSMIC PROBES to study the conditions in the distant Universe and the extreme physics inaccessible at earth. Models of massive stars are thus widely applied. A central common assumption is that massive stars are non-rotating single objects, in stark contrast with new data. Recent studies show that majority (70% according to our data) will experience severe interaction with a companion (Sana, de Mink et al. Science 2012). I propose to conduct the most ambitious and extensive exploration to date of the effects of binarity and rotation on the lives and fates of massive stars to (I) transform our understanding of the complex physical processes and how they operate in the vast parameter space and (II) explore the cosmological implications after calibrating and verifying the models. To achieve this ambitious objective I will use an innovative computational approach that combines the strength of two highly complementary codes and seek direct confrontation with observations to overcome the computational challenges that inhibited previous work. This timely project will provide the urgent theory framework needed for interpretation and guiding of observing programs with the new facilities (JWST, LSST, aLIGO/VIRGO). Public release of the model grids and code will ensure wide impact of this project. I am in the unique position to successfully lead this project because of my (i) extensive experience modeling the complex physical processes, (ii) leading role in introducing large statistical simulations in the massive star community and (iii) direct involvement in surveys that will be used in this project.

1 926 634 €

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

Meta-materials, best known for their extraordinary properties (e.g. negative stiffness), are halfway from both materials and structures: their unusual properties are direct results of their complex 3D structures. This project introduces a new class of meta-materials called meta-biomaterials. Meta-biomaterials go beyond meta-materials by adding an extra dimension to the complex 3D structure, i.e. complex and precisely controlled surface nano-patterns. The 3D structure gives rise to unprecedented or rare combination of mechanical (e.g. stiffness), mass transport (e.g. permeability, diffusivity), and biological (e.g. tissue regeneration rate) properties. Those properties optimize the distribution of mechanical loads and the transport of nutrients and oxygen while providing geometrical shapes preferable for tissue regeneration (e.g. higher curvatures). Surface nano-patterns communicate with (stem) cells, control their differentiation behavior, and enhance tissue regeneration. There is one important problem: meta-biomaterials cannot be manufactured with current technology. 3D printing can create complex shapes while nanolithography creates complex surface nano-patterns down to a few nanometers but only on flat surfaces. There is, however, no way of combining complex shapes with complex surface nano-patterns. The groundbreaking nature of this project is in solving that deadlock using the Origami concept (the ancient Japanese art of paper folding). In this approach, I first decorate flat 3D-printed sheets with nano-patterns. Then, I apply Origami techniques to fold the decorated flat sheet and create complex 3D shapes. The sheet knows how to self-fold to the desired structure when subjected to compression, owing to pre-designed joints, crease patterns, and thickness/material distributions that control its mechanical instability. I will demonstrate the added value of meta-biomaterials in improving bone tissue regeneration using in vitro cell culture assays and animal models

1 499 600 €

Start date: 2016-02-01, End date: 2021-01-31

Programmable biomolecular circuits have received increasing attention in recent years as the scope of chemistry expands from the synthesis of individual molecules to the construction of chemical networks that can perform sophisticated functions such as logic operations and feedback control. Rationally engineered biomolecular circuits that robustly execute higher-order spatiotemporal behaviours typically associated with intracellular regulatory functions present a unique and uncharted platform to systematically explore the molecular logic and physical design principles of the cell. The experience gained by in-vitro construction of artificial cells displaying advanced system-level functions deepens our understanding of regulatory networks in living cells and allows theoretical assumptions and models to be refined in a controlled setting. This proposal combines elements from systems chemistry, in-vitro synthetic biology and micro-engineering and explores generic strategies to investigate the molecular logic of biology’s regulatory circuits by applying a physical chemistry-driven bottom-up approach. Progress in this field requires 1) proof-of-principle systems where in-vitro biomolecular circuits are designed to emulate characteristic system-level functions of regulatory circuits in living cells and 2) novel experimental tools to operate biochemical networks under out-of-equilibrium conditions. Here, a comprehensive research program is proposed that addresses these challenges by engineering three biochemical model systems that display elementary signal transduction and information processing capabilities. In addition, an open microfluidic droplet reactor is developed that will allow, for the first time, high-throughput analysis of biomolecular circuits encapsulated in water-in-oil droplets. An integral part of the research program is to combine the computational design of in-vitro circuits with novel biochemistry and innovative micro-engineering tools.

1 887 180 €

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

Brain-inspired (neuromorphic) computing has recently demonstrated advancements in pattern and image recognition as well as classification of unstructured (big) data. However, the volatility and energy required for neuromorphic devices presented to date significantly complicate the path to achieve the interconnectivity and efficiency of the brain. In previous work, recently published in Nature Materials, the PI has demonstrated a low-cost solution to these drawbacks: an organic artificial synapse as a building-block for organic neuromorphics. The conductance of this single synapse can be accurately tuned by controlled ion injection in the conductive polymer, which could trigger unprecedented low-energy analogue computing. Hence, the major challenge in the largely unexplored field of organic neuromorphics, is to create an interconnected network of these synapses to obtain a true neuromorphic array which will not only be exceptionally pioneering in materials research for neuromorphics and machine-learning, but can also be adopted in a multitude of vital medical research devices. BIOMORPHIC will develop a unique brain-inspired organic lab-on-a-chip in which microfluidics integrated with sensors, collecting characteristics of biological cells, will serve as input to the neuromorphic array. BIOMORPHIC will combine modular microfluidics and machine-learning to develop a novel platform for low-cost lab-on-a-chip devices capable of on-chip cell classification. In particular, BIOMORPHIC will focus on the detection of circulating tumour cells (CTC). Current methods for the detection of cancer are generally invasive, whereas analysing CTCs in blood offers a highly desired alternative. However, accurately detecting and isolating these cells remains a challenge due to their low prevalence and large variability. The strength of neuromorphics precisely lies in finding patterns in such variable data, which will result in a ground-breaking CTC classification lab-on-a-chip.

1 498 726 €

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

"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 objective of this project is to design and develop biocatalytic cascades, using purified enzymes in vitro, as well as biosynthetic pathways in whole cell microbial organisms. These biocatalytic cascades and biosynthetic pathways will be developed for the synthesis of chiral and achiral amines that are of particular interest for the chemical industry. The amine functionality will be introduced using amine dehydrogenases (AmDHs) as biocatalysts in the pivotal core enzymatic step. AmDHs are a new class of enzymes that have recently been obtained by protein engineering of wild-type amino acid dehydrogenases. However, only two AmDHs have been generated so far and, moreover, they show a limited substrate scope. Therefore protein engineering will be undertaken in order to expand the substrate scope of the already existing AmDHs. In addition, novel AmDHs will be generated starting from different wild-type amino acid dehydrogenases as scaffolds, whose amino acid and DNA sequences are available in databases, literature, libraries, etc. In particular, protein engineering will be focused on the specific chemical targets that are the objectives of the designed biocatalytic cascades and in addition, screening for more diverse substrates will also be carried out. Finally, the AmDHs will be used in combination with other enzymes such as alcohol dehydrogenases, oxidases, alkane monooxygenases, etc., to deliver variously functionalised amines and derivatives as final products with elevated yields, perfect chemo- regio- and stereoselectivity, enhanced atom efficiency and minimum environmental impact. Such an approach will be realised through the design of new pathways that will convert inexpensive starting materials from renewable resources, encompassing the internal recycling of redox equivalents, the use of inorganic ammonia as nitrogen source and, if necessary, only molecular oxygen as the innocuous additional oxidant. Water will be the sole by-product.

1 497 270 €

Start date: 2015-05-01, End date: 2020-04-30

A fundamental feature of language is that it allows us to reproduce what others have said. It is traditionally assumed that there are two ways of doing this: direct discourse, where you preserve the original speech act verbatim, and indirect discourse, where you paraphrase it in your own words. In accordance with this dichotomy, linguists have posited a number of universal characteristics to distinguish the two modes. At the same time, we are seeing more and more examples that seem to fall somewhere in between. I reject the direct indirect distinction and replace it with a new paradigm of blended discourse. Combining insights from philosophy and linguistics, my framework has only one kind of speech reporting, in which a speaker always attempts to convey the content of the reported words from her own perspective, but can quote certain parts verbatim, thereby effectively switching to the reported perspective. To explain why some languages are shiftier than others, I hypothesize that a greater distance from face-to-face communication, with the possibility of extra- and paralinguistic perspective marking, necessitated the introduction of an artificial direct indirect separation. I test this hypothesis by investigating languages that are closely tied to direct communication: Dutch child language, as recent studies hint at a very late acquisition of the direct indirect distinction; Dutch Sign Language, which has a special role shift marker that bears a striking resemblance to the quotational shift of blended discourse; and Ancient Greek, where philologists have long been observing perspective shifts. In sum, my research combines a new philosophical insight on the nature of reported speech with formal semantic rigor and linguistic data from child language experiments, native signers, and Greek philology.

677 254 €

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

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

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

1 344 853 €

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

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

1 500 000 €

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

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

This project is an interdisciplinary study of the role of indigenous knowledge in the making of science. Situated at the intersection of history and anthropology, its main research objective is to understand the transformation of information and practices of South American indigenous peoples into a body of knowledge that became part of the Western scholarly canon. It aims to explore, by means of a distinctive case-study, how European science is constructed in intercultural settings. This project takes the book Historia Naturalis Brasiliae (HNB), published in 1648 by Piso and Marcgraf, as its central focus. The HNB is the first product of the encounter between early modern European scholarship and South American indigenous knowledge. In an encyclopedic format, it brings together information about the natural world, linguistics, and geography of South America as understood and experienced by indigenous peoples as well as enslaved Africans. Its method of construction embodies the intercultural connections that shaped practices of knowledge production in colonial settings across the globe, and is the earliest example of such in South America. With my research team, I will investigate how indigenous knowledge was appropriated and transformed into European science by focusing on ethnobotanics, ethnozoology, and indigenous material culture. Since the HNB and its associated materials are kept in European museums and archives, this project is timely and relevant in light of the growing concern for the democratization of heritage. The current debate about the societal role of publicly-funded cultural institutions across Europe argues for the importance of multi-vocality in cultural and political processes. This project proposes a more inclusive interpretation and use of the materials in these institutions and thereby sets an example of how European heritage institutions can use their historical collections to reconnect the past with present-day societal concerns.

1 475 565 €

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

Belief systems research is vital for understanding democratic politics, extremism, and political decision-making. What is the basic structure of belief systems? Clear answers to this fundamental question are not forthcoming. This is due to flaws in the conceptualization of belief systems. The state-of-the-art treats a belief system as a theoretical latent variable that causes people’s responses on attitudes and values relevant to the belief system. This approach cannot assess a belief system because it cannot assess the network of connections between the beliefs–attitudes and values–that make up the system; it collapses across them and the interrelationships are lost. The Belief Systems Project conceptualizations belief systems as systems of interconnecting attitudes and values. I conceptualize attitudes and values as interactive nodes in a network that are analysed with network analyses. With these conceptual and empirical tools, I can understand the structure and dynamics of the belief system and will be able to avoid theoretical pitfalls common in belief system assessments. This project will move belief systems research beyond the state-of-the-art in four ways by: 1. Mapping the structure of systems of attitudes and values, something that is not possible using current methods. 2. Answering classic questions about central concepts and clustering of belief systems. 3. Modeling within-person belief systems and their variations, so that I can make accurate predictions about partisan motivated reasoning. 4. Testing how external and internal pressures (e.g., feelings of threat) change the underlying structure and dynamics of belief systems. Using survey data from around the world, longitudinal panel studies, intensive longitudinal designs, experiments, and text analyses, I will triangulate on the structure of political belief systems over time, between countries, and within individuals.

1 496 944 €

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

Transcription in single cells is a stochastic process that arises from the random collision of molecules, resulting in heterogeneity in gene expression in cell populations. This heterogeneity in gene expression influences cell fate decisions and disease progression. Interestingly, gene expression variability is not the same for every gene: noise can vary by several orders of magnitude across transcriptomes. The reason for this transcript-specific behavior is that genes are not transcribed in a continuous fashion, but can show transcriptional bursting, with periods of gene activity followed by periods of inactivity. The noisiness of a gene can be tuned by changing the duration and the rate of switching between periods of activity and inactivity. Even though transcriptional bursting is conserved from bacteria to yeast to human cells, the origin and regulators of bursting remain largely unknown. Here, I will use cutting-edge single-molecule RNA imaging techniques to directly observe and measure transcriptional bursting in living yeast cells. First, bursting properties will be quantified at different endogenous and mutated genes to evaluate the contribution of cis-regulatory promoter elements on bursting. Second, the role of trans-regulatory complexes will be characterized by dynamic depletion or gene-specific targeting of transcription regulatory proteins and observing changes in RNA synthesis in real-time. Third, I will develop a new technology to visualize the binding dynamics of single transcription factor molecules at the transcription site, so that the stability of upstream regulatory factors and the RNA output can directly be compared in the same cell. Finally, I will examine the phenotypic effect of different bursting patterns on organismal fitness. Overall, these approaches will reveal how bursting is regulated at the molecular level and how different bursting patterns affect the heterogeneity and fitness of the organism.

1 950 775 €

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

Modern cryptography has deeply rooted connections with computational complexity theory and other areas of computer science. This proposal suggests to explore several {\em new connections} between questions in cryptography and questions from other domains, including computational complexity, coding theory, and even the natural sciences. The project is expected to broaden the impact of ideas from cryptography on other domains, and on the other hand to benefit cryptography by applying tools from other domains towards better solutions for central problems in cryptography.

1 459 703 €

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

This project focuses on the appropriation of the Old Testament by early Christian interpreters of the Bible. A historical approach, not commonly adopted in the study of biblical interpretation, will enable us to study how this process contributed to the formation of distinctive Christian identities within the multicultural society of the late Roman principate and early Byzantine rule. The exegetes of this period were to a great extent responsible for the creation of a distinctive, sophisticated, and uncompromising discourse—a ‘totalising Christian discourse’, which determines Christian identities up to this day. In two projects, carried out by three researchers, we will make cross sections of the relevant material. It was allegorizing interpretation that enabled exegetes belonging to the so-called School of Alexandria to recognize Christ everywhere in the Old Testament, and thus to appropriate it and make it useful to the Church. Thus the Song of Songs was no longer considered an earthly love song, but was said to describe Christ’s love for the Church. Exegetes associated with the School of Antioch opposed to this kind of approach. They are often described as literalists. The traditional understanding of the distinctions between the two schools needs to be broadened and corrected by a picture of the actual practice of their hermeneutics. In my view the Antiochene opposition was brought about by the fact that pagan and ‘heretic’ critics did not accept the Alexandrian use of allegory. My innovative hypothesis is related to the central role played by the letters of the apostle Paul in the Antiochene reaction against Alexandria. For the Antiochenes, the use of Paul became an alternative means to bridge the gap between the two Testaments. Instead of a book in which every jot and tittle referred to Christ through allegory, the Antiochenes came to view the Old Testament as an amalgamation of moral lessons that agreed with Paul's teaching.

655 309 €

Start date: 2008-09-01, End date: 2013-12-31

"Heart failure is a serious clinical disorder that represents the primary cause of hospitalization and death in Europe and the United States. There is a dire need for new paradigms and therapeutic approaches for treatment of this devastating disease. The heart responds to mechanical load and various extracellular stimuli by hypertrophic growth and sustained pathological hypertrophy is a major clinical predictor of heart failure. A variety of stress-responsive signaling pathways promote cardiac hypertrophy, but the precise mechanisms that link these pathways to cardiac disease are only beginning to be unveiled. Signal transduction is traditionally concentrated on the protein coding part of the genome, but it is now appreciated that the protein coding part of the genome only constitutes 1.5% of the genome. RNA based mechanisms may provide a more complete understanding of the fundamentals of cellular signaling. As a proof-of-principle, we focus on a principal hypertrophic signaling cascade, cardiac calcineurin/NFAT signaling. Here we will establish that microRNAs are intimately interwoven with this signaling cascade, influence signaling strength by unexpected upstream mechanisms. Secondly, we will firmly establish that microRNA target genes critically contribute to genesis of heart failure. Third, the surprising stability of circulating microRNAs has opened the possibility to develop the next generation of biomarkers and provide unexpected mechanisms how genetic information is transported between cells in multicellular organs and fascilitate inter-cellular communication. Finally, microRNA-based therapeutic silencing is remarkably powerful and offers opportunities to specifically intervene in pathological signaling as the next generation heart failure therapeutics. CALMIRS aims to mine the wealth of these RNA mechanisms to enable the development of next generation RNA based signal transduction biology, with surprising new diagnostic and therapeutic opportunities."

1 499 528 €

Start date: 2013-02-01, End date: 2018-01-31

Introduction: The ability of a cancer cell to invade into the surrounding tissue is the main feature of malignant cancer progression. Diffuse Intrinsic Pontine Glioma (DIPG) is a paediatric high-grade brain tumour with no chance of survival due to its highly invasive nature. Goal: By combining state-of-the-art imaging and transcriptomics, we aim to identify and target the key mechanisms driving the highly invasive growth of DIPG. Technology advances: Two unique single cell resolution imaging techniques that we have recently developed will be implemented: Large-scale Single-cell Resolution 3D imaging (LSR-3D) that allows visualization of complete tumour specimens and intravital microscopy using a cranial imaging window that allows imaging of tumour cell behaviour in living mice. In addition, we will apply a technique of live imaging Patch-seq to perform behaviour studies together with single cell RNA profiling. Expected results: Using a glioma murine model in which the disease is induced in neonates and a new embryonic model based on in utero electroporation, we expect to gain knowledge on the progression of DIPG in maturing brain. LSR-3D imaging on human and murine specimens will provide insight into the cellular tumour composition and its integration in the neuroglial network. With intravital imaging, we will characterize invasive cancer cell behaviour and functional connections with healthy brain cells. In combination with Patch-seq, we will identify transcriptional program(s) specific to invasive behaviour. Altogether, we expect to identify novel key players in cancer invasion and assess their potential to prevent DIPG progression.  Future perspective: With the studies proposed, we will gain fundamental insights into the cancer cell invasion mechanisms that govern DIPG which may provide new potential therapeutic target(s) for this dismal disease. Overall, the knowledge and advanced technologies obtained here will be of great value for the tumour biology field.

1 500 000 €

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

The metabolism of cancer cells is altered to meet cellular requirements for growth, providing novel means to selectively target tumorigenesis. While extensively studied, our current view of cancer cellular metabolism is fundamentally limited by lack of information on variability in metabolic activity between distinct subcellular compartments and cells. We propose to develop a spatio-temporal fluxomics approach for quantifying metabolic fluxes in the cytoplasm vs. mitochondria as well as their cell-cycle dynamics, combining mass-spectrometry based isotope tracing with cell synchronization, rapid cellular fractionation, and computational metabolic network modelling. Spatio-temporal fluxomics will be used to revisit and challenge our current understanding of central metabolism and its induced adaptation to oncogenic events – an important endeavour considering that mitochondrial bioenergetics and biosynthesis are required for tumorigenesis and accumulating evidences for metabolic alterations throughout the cell-cycle. Our preliminary results show intriguing oscillations between oxidative and reductive TCA cycle flux throughout the cell-cycle. We will explore the extent to which cells adapt their metabolism to fulfil the changing energetic and anabolic demands throughout the cell-cycle, how metabolic oscillations are regulated, and their benefit to cells in terms of thermodynamic efficiency. Spatial flux analysis will be instrumental for investigating glutaminolysis - a ‘hallmark’ metabolic adaptation in cancer involving shuttling of metabolic intermediates and cofactors between mitochondria and cytoplasm. On a clinical front, our spatio-temporal fluxomics analysis will enable to disentangle oncogene-induced flux alterations, having an important tumorigenic role, from artefacts originating from population averaging. A comprehensive view of how cells adapt their metabolism due to oncogenic mutations will reveal novel targets for anti-cancer drugs.

1 481 250 €

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

Clouds and precipitation play a crucial role in the Earth's energy balance, global atmospheric circulation and the water cycle. Despite their importance, clouds still pose the largest uncertainty in climate research. I propose a new approach for studying anthropogenic effects on cloud fields and rain, tackling the challenge from both scientific ends: reductionism and systems approach. We will develop a novel research approach using observations and models interactively that will allow us to “peel apart” detailed physical processes. In parallel we will develop a systems view of cloud fields looking for Emergent Behavior rising out of the complexity, as the end result of all of the coupled processes. Better understanding of key processes on a detailed (reductionist) manner will enable us to formulate the important basic rules that control the field and to look for emergence of the overall effects. We will merge ideas and methods from four different disciplines: remote sensing and radiative transfer, cloud physics, pattern recognition and computer vision and ideas developed in systems approach. All of this will be done against the backdrop of natural variability of meteorological systems. The outcomes of this work will include fundamental new understanding of the coupled surface-aerosol-cloud-precipitation system. More importantly this work will emphasize the consequences of human actions on the environment, and how we change our climate and hydrological cycle as we input pollutants and transform the Earth’s surface. This work will open new horizons in cloud research by developing novel methods and employing the bulk knowledge of pattern recognition, complexity, networking and self organization to cloud and climate studies. We are proposing a long-term, open-ended program of study that will have scientific and societal relevance as long as human-caused influences continue, evolve and change.

1 428 169 €

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

"Combinatorics, and its interplay with geometry, has fascinated our ancestors as shown by early stone carvings in the Neolithic period. Modern combinatorics is motivated by the ubiquity of its structures in both pure and applied mathematics. The work of Hochster and Stanley, who realized the relation of enumerative questions to commutative algebra and toric geometry made a vital contribution to the development of this subject. Their work was a central contribution to the classification of face numbers of simple polytopes, and the initial success lead to a wealth of research in which combinatorial problems were translated to algebra and geometry and then solved using deep results such as Saito's hard Lefschetz theorem. As a caveat, this also made branches of combinatorics reliant on algebra and geometry to provide new ideas. In this proposal, I want to reverse this approach and extend our understanding of geometry and algebra guided by combinatorial methods. In this spirit I propose new combinatorial approaches to the interplay of curvature and topology, to isoperimetry, geometric analysis, and intersection theory, to name a few. In addition, while these subjects are interesting by themselves, they are also designed to advance classical topics, for example, the diameter of polyhedra (as in the Hirsch conjecture), arrangement theory (and the study of arrangement complements), Hodge theory (as in Grothendieck's standard conjectures), and realization problems of discrete objects (as in Connes embedding problem for type II factors). This proposal is supported by the review of some already developed tools, such as relative Stanley--Reisner theory (which is equipped to deal with combinatorial isoperimetries), combinatorial Hodge theory (which extends the ``K\""ahler package'' to purely combinatorial settings), and discrete PDEs (which were used to construct counterexamples to old problems in discrete geometry)."

1 337 200 €

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

Amines are crucially important classes of chemicals, widely present in pharmaceuticals, agrochemicals and surfactants. Yet, surprisingly, a systematic approach to obtaining this essential class of compounds from renewables has not been realized to date. The aim of this proposal is to enable chemical pathways for the production of amines through alcohols from renewable resources, preferably lignocellulose waste. Two key scientific challenges will be addressed: The development of efficient cleavage reactions of complex renewable resources by novel heterogeneous catalysts; and finding new homogeneous catalyst based on earth-abundant metals for the atom-economic coupling of the derived alcohol building blocks directly with ammonia as well as possible further functionalization reactions. The program is divided into 3 interrelated but not mutually dependent work packages, each research addressing a key challenge in their respective fields, these are: WP1: Lignin conversion to aromatics; WP2: Cellulose-derived platform chemicals to aromatic and aliphatic diols and solvents. WP3: New iron-based homogeneous catalysts for the direct, atom-economic C-O to C-N transformations. The approach taken will embrace the inherent complexity present in the renewable feedstock. A unique balance between cleavage and coupling pathways will allow to access chemical diversity in products that is necessary to achieve economic competitiveness with current fossil fuel-based pathways and will permit rapid conversion to higher value products such as functionalized amines that can enter the chemical supply chain at a much later stage than bulk chemicals derived from petroleum. The proposed high risk-high gain research will push the frontiers of sustainable and green chemistry and reach well beyond state of the art in this area. This universal, flexible and iterative approach is anticipated to give rise to a variety of similar systems targeting diverse product outcomes starting from renewables.

1 500 000 €

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

Social-science explanations for rising wage inequality have reached a dead end. Most economists argue that computerization has been primarily responsible, while on the other side of the argument are sociologists and political scientists who stress the role of political forces in the evolution process of wages. I would like to use my knowledge and experience to come up with an original theory on the complex dynamics between technology and politics in order to solve two unsettled questions regarding the role of computerization in rising wage inequality: First, how can computerization, which diffused simultaneously in rich countries, explain the divergent inequality trends in Europe and the United States? Second, what are the mechanisms behind the well-known observed positive correlation between computers and earnings? To answer the first question, I develop a new institutional agenda stating that politics, broadly defined, mitigates the effects of technological change on wages by stimulating norms of fair pay and equity. To answer the second question, I propose a truly novel perspective that conceptualizes the earnings advantage that derives from computerization around access to and control of information on the production process. Capitalizing on this new perspective, I develop a new approach to measuring computerization to capture the form of workers’ interaction with computers at work, and build a research strategy for analysing the effect of computerization on wages across countries and workplaces, and over time. This research project challenges the common understanding of technology’s role in producing economic inequality, and would thereby significantly impact all of the abovementioned disciplines, which are debating over the upswing in wage inequality, as well as public policy, which discusses what should be done to confront the resurgence of income inequality.

1 495 091 €

Start date: 2016-09-01, End date: 2021-08-31

The promise of nanoscience stems from the fundamentally new behavior that emerges at the nanoscale. Here, we propose to explore, control and exploit one of the most dramatic aspects of this unusual behavior: quantum entanglement of spins. Our nanoscale system of choice is an array of semiconductor quantum dots that each contain one single electron. Thanks to a string of recent breakthroughs, it is now possible to initialize, coherently manipulate and read out the spin state of one such electron, and to couple it coherently to a spin in a neighboring dot. Today, we are at the brink of a new era in this field, in which entanglement will play the central part. The primary goal of this proposal, therefore, is to experimentally demonstrate that electron spins in quantum dots can really be entangled, and to control this entanglement in time. We will then use this capability to implement various quantum information protocols such as quantum algorithms and teleportation, which intrinsically rely on entanglement to realize tasks that are classically impossible. In order to push the level of coherent control to its limits, we will suppress fluctuations in the normally uncontrolled spin environment, and pursue novel quantum dot technologies which offer an intrinsically ‘quiet’ environment. Our long-term dream is to demonstrate that the accuracy threshold for fault-tolerant quantum computation can be reached in this system, which would permit quantum coherence and entanglement to be preserved indefinitely. This research is presently very much at the stage of exploratory research and is bound to produce surprising and unexpected outcomes. Furthermore, we are convinced that pushing the frontier of quantum control in nanoscale devices has a real potential to lead to future quantum technologies.

1 296 000 €

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

The formation of plant organs (leaves, roots, flowers) depends on the activity of stem cells (SC), located in stem cell niches (meristems) together with adjoining organizer cells (OC) that prevent SC differentiation. Despite their importance, SC and OC have been poorly described at molecular and cellular level and mechanisms for their coordinated specification are only partially understood. We study the specification of the very first SC and OC for the root in the early Arabidopsis embryo where cell divisions are almost invariant and, in the absence of cell motility, highly predictable. Previously we have established a central role for the transcription factor MONOPTEROS (MP) in OC specification and we have recently found that MP also controls SC specification. Hence, MP offers a unique entry point into studying the genomic and cellular reprogramming that underlies coordinated SC and OC specification. Our recent identification of MP target genes has shown that its function in SC specification is cell-autonomous, while MP-dependent OC specification involves a mobile transcription factor. In recent years we have developed a set of resources to systematically study embryonic root meristem initiation, and are now in a unique position to answer the following questions in this ERC project: 1. What transcriptional reprogramming underlies the first specification of SC and OC in the plant embryo? 2. What cellular changes follow from transcriptional reprogramming and mediate elongation and asymmetric division of SC and OC? 3. What is the mechanism of directional protein transport that ensures spatiotemporal coordination between SC and OC? The project will provide genome-wide insight in the cellular reprogramming underlying the coordinated formation of a multicellular structure. Finally, this work will shed light on mechanisms of stem cell and stem cell niche formation.

1 499 070 €

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

Understanding how values of different options that lead to choice are represented in the brain is a basic scientific question with far reaching implications. I recently showed that by the mere-association of a cue and a button press we could influence preferences of snack food items up to two months following a single training session lasting less than an hour. This novel behavioural change manipulation cannot be explained by any of the current learning theories, as external reinforcement was not used in the process, nor was the context of the decision changed. Current choice theories focus on goal directed behaviours where the value of the outcome guides choice, versus habit-based behaviours where an action is repeated up to the point that the value of the outcome no longer guides choice. However, in this novel task training via the involvement of low-level visual, auditory and motor mechanisms influenced high-level choice behaviour. Thus, the far-reaching goal of this project is to study the mechanism, by which low-level sensory, perceptual and motor neural processes underlie value representation and change in the human brain even in the absence of external reinforcement. I will use behavioural, eye-gaze and functional MRI experiments to test how low-level features influence the neural representation of value. I will then test how they interact with the known striatal representation of reinforced behavioural change, which has been the main focus of research thus far. Finally, I will address the basic question of dynamic neural plasticity and if neural signatures during training predict long term success of sustained behavioural change. This research aims at a paradigmatic shift in the field of learning and decision-making, leading to the development of novel interventions with potential societal impact of helping those suffering from health-injuring behaviours such as addictions, eating or mood disorders, all in need of a long lasting behavioural change.

1 500 000 €

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

This project revisits a major question in world history: how can we explain the continuity of the Chinese Empire. Moving beyond the comparison of early world empires (China and Rome) to explain the different courses Chinese and European history have taken, this project aims to assess the importance of political communication in the maintenance of empire in the last millennium. The core questions are twofold: 1) How can the continuity of empire in the Chinese case be best explained? 2) Does the nature and extent of political communication networks, measured through the frequency and multiplexity of information exchange ties, play a critical role in the reconstitution and maintenance of empire? Its methodology is based on the conviction that an investigation of the nature and extent of political communication in imperial Chinese society should include a systematic quantitative and qualitative analysis of the rich commentary on current affairs in correspondence and notebooks. By combining multi-faceted digital analyses of relatively large corpora of texts with an intellectually ambitious research agenda, this project will both radically transform our understanding of the history of Chinese political culture and inspire wide-ranging methodological innovation across the humanities.

1 432 797 €

Start date: 2012-04-01, End date: 2017-08-31

How animal communication systems evolve is a fundamental question in ecology and evolution and crucial for our understanding of adaptation and speciation. I will make use of the process of urbanization to address how communication signals adapt to changes in the sensory environment. I will focus on the impact of noise and light pollution on acoustic communication of Neotropical frogs and address the following questions: 1) How do senders, such as a male frog, adjust their signals to altered sensory environments? I will assess plasticity and heritability of signal divergence found between urban and forest populations of the tungara frog. 2) How do signals evolve in response to direct (via sender) and indirect (via receivers) selection pressures? I will expose forest sites to noise and light pollution, parse out importance of multiple selection pressures and carry out experimental evolution using artificial phenotypes. 3) What are the evolutionary consequences of signal divergence? I will assess inter-and-intra sexual responses to signal divergence between urban and forest populations. 4) Can we predict how species adapt their signals to the sensory environment? I will use a trait-based comparative approach to study signal divergence among closely related species with known urban populations. Our state-of-the-art automated sender-receiver system allows for experimental evolution using long-lived species and opens new ways to study selection pressures operating on animal behaviour under real field conditions. Our expected results will provide crucial insight into the early stages of signal divergence that may ultimately lead to reproductive isolation and speciation.

1 500 000 €

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

Coherence of law is created in the writings of legal scholars who systematize rules and principles of law. Their pursuit of coherence is vital for the effectiveness of legal systems. However, coherence of law has almost not been analysed in a systematic, empirical way. The project will therefore develop a methodology that will address coherence across forms (‘sources’) of law (legislation, legal scholarship, case law, customs), across themes (e.g. criminal law and contracts) and across authors, and which will additionally encompass interaction with societal demand and contextual factors. The methodology will be ground-breaking because it will disentangle the concept of coherence into measurable modes of interconnectedness, weighing them together so as to assess (in)coherence at the level of the legal system. This methodology will constitute a stepping stone for a new field of dynamic coherence of law created through legal scholarship that will ultimately improve the quality of law. It will be founded on academic writings on law from the early modern period (ca. 1500 - ca. 1800) that concern the theme of collateral rights, that is, those rights facilitating expropriation of the assets of debtors in case of their default. Indications are that the impact of rules on collateral rights hinged on coherence as established in legal writings, and that in the period mentioned legal coherence for this theme was increasing. Coherence in development will be traced in the interpretations of legal scholars following on from interactions between scholarly writings, local law (bylaws, judgments) and commercial practice (contracts). Connections of rules and principles found will be presented in frames of analysis that cluster them along variables of context, time and source of law. The combination of legal analysis with a broad scope of coherence (cross-source, context-driven) will build bridges across gaps now existing between the different disciplines that study law.

1 495 625 €

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

We will unravel the origin of cosmic magnetic fields, the physics of particle acceleration in dilute plasmas, and the nature of AGN feedback with state-of-the-art radio telescopes. With the enormous gains in sensitivity, survey speed, and resolution of these telescopes – combined with recent breakthroughs that correct for phased-arrays and the Earth’s distorting ionosphere – we can now take the next big step in this field. Cosmic web filaments and galaxy clusters are the Universe’s largest structures. Clusters grow by a sequence of mergers, generating shock waves and turbulence which heat the cluster plasma. In merging clusters, cosmic rays are accelerated to extreme energies, producing Mpc-size diffuse synchrotron emitting sources. However, these acceleration processes are still poorly understood. Clusters are also heated by AGN feedback from radio galaxies, but the total energy input by feedback and its evolution over cosmic time are unknown. We will construct the largest low-frequency sample of galaxy clusters to (1) establish how particles are accelerated in cluster plasmas, (2) quantify how the cosmic ray content scales with cluster mass, (3) determine the importance of AGN fossil plasma in the acceleration processes, (4) characterize current and past episodes of AGN feedback, and (5) determine the evolution of feedback up to the epoch of cluster formation (z=1-2). These results will be essential to understand cluster formation and its associated energy budget. As in clusters, cosmic web accretion shocks should also accelerate particles producing radio emission. Based on the deepest low-frequency images ever produced, we will (5) carry out the first studies of these giant accelerators, opening up a new window on the elusive warm-hot intergalactic medium, where many of the cosmic baryons reside. Even more important, (6) we aim to obtain measurements of the intergalactic magnetic field, providing key constraints on the origin of our Universe’s magnetic fields.

1 487 755 €

Start date: 2019-09-01, End date: 2024-08-31