ERC FUNDED PROJECTS

Chronic lung diseases are increasing in prevalence with over 65 million patients worldwide. Lung transplantation remains the only potential option at end-stage disease. Around 4000 patients receive lung transplants annually with more awaiting transplantation, including 1000 patients in Europe. New options to increase available tissue for lung transplantation are desperately needed. An exciting new research area focuses on generating lung tissue ex vivo using bioengineering approaches. Scaffolds can be generated from synthetic or biologically-derived (acellular) materials, seeded with cells and grown in a bioreactor prior to transplantation. Ideally, scaffolds would be seeded with cells derived from the transplant recipient, thus obviating the need for long-term immunosuppression. However, functional regeneration has yet to be achieved. New advances in 3D printing and 3D bioprinting (when cells are printed) indicate that this once thought of science-fiction concept might finally be mature enough for complex tissues, including lung. 3D bioprinting addresses a number of concerns identified in previous approaches, such as a) patient heterogeneity in acellular human scaffolds, b) anatomical differences in xenogeneic sources, c) lack of biological cues on synthetic materials and d) difficulty in manufacturing the complex lung architecture. 3D bioprinting could be a reproducible, scalable, and controllable approach for generating functional lung tissue. The aim of this proposal is to use custom 3D bioprinters to generate constructs mimicking lung tissue using an innovative approach combining primary cells, the engineering reproducibility of synthetic materials, and the biologically conductive properties of acellular lung (hybrid). We will 3D bioprint hybrid murine and human lung tissue models and test gas exchange, angiogenesis and in vivo immune responses. This proposal will be a critical first step in demonstrating feasibility of 3D bioprinting lung tissue.

1 499 975 €

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

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

In this project we will push the limits of microscale ultrasound-based technology to gain access to diagnostically important rare constituents of blood within minutes from blood draw. To meet the demands for shorter time from sampling to result in healthcare there is an increased interest to shift from heavy centralized lab equipment to point-of-care tests and patient self-testing. Key challenges with point-of-care equipment is to enable simultaneous measurement of many parameters at a reasonable cost and size of equipment. Therefore, microscale technologies that can take in small amounts of blood and output results within minutes are sought for. In addition, the high precision and potential for multi-stage serial processing offered by such microfluidic methods opens up for fast and automated isolation of rare cell populations, such as circulating tumor cells, and controlled high-throughput size fractionation of sub-micron biological particles, such as platelets, pathogens and extracellular vesicles. To achieve effective and fast separation of blood components we will expose blood to acoustic radiation forces in a flow-through format. By exploiting a newly discovered acoustic body force, that stems from local variations the acoustic properties of the cell suspension, we can generate self-organizing configurations of the blood cells. We will tailor and tune the acoustic cell-organization in novel ways by time modulation of the acoustic field, by altering the acoustic properties of the fluid by solute molecules, and by exploiting a novel concept of sound interaction with thermal gradients. The project will render new fundamental knowledge regarding the acoustic properties of single cells and an extensive theoretical framework for the response of cells in any aqueous medium, bounding geometry and sound field, potentially leading to new diagnostic methods.

1 999 720 €

Start date: 2019-11-01, End date: 2024-10-31

Synthetic biology is an emerging discipline that offers powerful tools to control and manipulate fundamental processes in living matter. We propose to develop and apply such tools to modify the genetic code of cultured mammalian cells and bacteria with the aim to study the role of lysine acetylation in the regulation of metabolism and in cancer development. Thousands of lysine acetylation sites were recently discovered on non-histone proteins, suggesting that acetylation is a widespread and evolutionarily conserved post translational modification, similar in scope to phosphorylation and ubiquitination. Specifically, it has been found that most of the enzymes of metabolic processes—including glycolysis—are acetylated, implying that acetylation is key regulator of cellular metabolism in general and in glycolysis in particular. The regulation of metabolic pathways is of particular importance to cancer research, as misregulation of metabolic pathways, especially upregulation of glycolysis, is common to most transformed cells and is now considered a new hallmark of cancer. These data raise an immediate question: what is the role of acetylation in the regulation of glycolysis and in the metabolic reprogramming of cancer cells? While current methods rely on mutational analyses, we will genetically encode the incorporation of acetylated lysine and directly measure the functional role of each acetylation site in cancerous and non-cancerous cell lines. Using this methodology, we will study the structural and functional implications of all the acetylation sites in glycolytic enzymes. We will also decipher the mechanism by which acetylation is regulated by deacetylases and answer a long standing question – how 18 deacetylases recognise their substrates among thousands of acetylated proteins? The developed methodologies can be applied to a wide range of protein families known to be acetylated, thereby making this study relevant to diverse research fields.

1 499 375 €

Start date: 2016-07-01, End date: 2021-06-30

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

1 500 000 €

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

Our tissues are constantly renewed by stem cells. Over time, stem cells accumulate cellular damage that will compromise renewal and results in aging. As stem cells can divide asymmetrically, segregation of harmful factors to the differentiating daughter cell could be one possible mechanism for slowing damage accumulation in the stem cell. However, current evidence for such mechanisms comes mainly from analogous findings in yeast, and studies have concentrated only on few types of cellular damage. I hypothesize that the chronological age of a subcellular component is a proxy for all the damage it has sustained. In order to secure regeneration, mammalian stem cells may therefore specifically sort old cellular material asymmetrically. To study this, I have developed a novel strategy and tools to address the age-selective segregation of any protein in stem cell division. Using this approach, I have already discovered that stem-like cells of the human mammary epithelium indeed apportion chronologically old mitochondria asymmetrically in cell division, and enrich old mitochondria to the differentiating daughter cell. We will investigate the mechanisms underlying this novel phenomenon, and its relevance for mammalian aging. We will first identify how old and young mitochondria differ, and how stem cells recognize them to facilitate the asymmetric segregation. Next, we will analyze the extent of asymmetric age-selective segregation by targeting several other subcellular compartments in a stem cell division. Finally, we will determine whether the discovered age-selective segregation is a general property of stem cell in vivo, and it's functional relevance for maintenance of stem cells and tissue regeneration. Our discoveries may open new possibilities to target aging associated functional decline by induction of asymmetric age-selective organelle segregation.

1 500 000 €

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

Agriculture employs the majority of the labor force in many developing countries, particularly in Sub-Saharan Africa. Increasing efficiency of agricultural production is a crucial step to foster economic development. Limited access to both input and output markets is widely considered a major obstacle to technology adoption and, in turn, to agricultural productivity. In this proposal, I outline a research program that focuses on improving farmers’ market access in East Africa. The research builds on the expertise I have developed on these topics over the last ten years. The research program consists of three related projects. In Project A, we will use a randomized experiment to evaluate the impact of a holistic approach to improve market access: contract farming. The prevalence of contract farming arrangements in the developing world is growing. However, so far, there is no experimental evidence on their impact. We have established a partnership with a large contract farming company in Kenya, which has agreed to randomize the order in which it will expand to new villages. In Project B, we will study how to increase demand for crop insurance among smallholders. Building on previous successful experimental work, we will test i) whether offering pay-at-harvest insurance, as opposed to upfront premium pay, raises take-up, ii) which behavioral mechanisms may drive such response, and iii) whether pay-at-harvest can foster sustained insurance demand over multiple crop seasons. In Project C, we will combine parcel-level proprietary data for three decades that we obtained from a large agribusiness company with land registry data to study the determinants and impact of land market access for smallholders. The research program will generate new insights on how to improve access to key markets for agricultural producers. We expect the findings of the study will generate high interest among academics, development practitioners, and policymakers.

1 499 913 €

Start date: 2021-01-01, End date: 2025-12-31

Real-world optimization problems pose major challenges to algorithmic research. For instance, (i) many important problems are believed to be intractable (i.e. NP-hard) and (ii) with the growth of data size, modern applications often require a decision making under {\em incomplete and dynamically changing input data}. After several decades of research, central problems in these domains have remained poorly understood (e.g. Is there an asymptotically most efficient binary search trees?) Existing algorithmic techniques either reach their limitation or are inherently tailored to special cases. This project attempts to untangle this gap in the state of the art and seeks new interplay across multiple areas of algorithms, such as approximation algorithms, online algorithms, fixed-parameter tractable (FPT) algorithms, exponential time algorithms, and data structures. We propose new directions from the {\em structural perspectives} that connect the aforementioned algorithmic problems to basic questions in combinatorics. Our approaches fall into one of the three broad schemes: (i) new structural theory, (ii) intermediate problems, and (iii) transfer of techniques. These directions partially build on the PI's successes in resolving more than ten classical problems in this context. Resolving the proposed problems will likely revolutionize our understanding about algorithms and data structures and potentially unify techniques in multiple algorithmic regimes. Any progress is, in fact, already a significant contribution to the algorithms community. We suggest concrete intermediate goals that are of independent interest and have lower risks, so they are suitable for Ph.D students.

1 411 258 €

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

The hippocampus is critical for the storage of episodic memories and has been extensively studied on its role in spatial memory. The hippocampus is also a central model for in vitro studies on the molecular, cellular and microcircuit basis for learning and memory. I propose to use a new technology that I developed to record and manipulate the membrane potential of multiple neurons, simultaneously, in behaving animals to reveal the mechanisms by which hippocampal circuits process spatial information. This research will bridge the gap between the in vitro mechanistic studies and the in vivo efforts to describe the spatial representations. I first propose to employ the voltage imaging technology for detailed mechanistic studies of the function and plasticity of hippocampal microcircuits during place cell formation (Objective 1). To this end, we will combine voltage imaging with Optogenetics in head-fixed mice performing virtual navigation in familiar and novel environments. To expand to a ‘systems’ view on hippocampal plasticity, we will next establish a method for optical selection of single neurons based on their functional profile (Objective 2). We will use this technology to trace the long-range projections and the pre- and postsynaptic landscape of photo-selected CA1 neurons. In the last objective, we will combine both technologies to dissect the contribution of different entorhinal cell types (i.e. grid cells, border cells, and speed cells) to place cell formation in CA1 (objective 3). To this end, we will image the entorhinal cortex and photo-select cells based on their functional profiles. We will then image CA1 while manipulating the activity of the selected entorhinal cells. Our work will provide new discoveries on the mechanistic basis for spatial memory and will comprise a first step towards broader understanding of how the brain stores and retrieves episodic memories.

1 486 797 €

Start date: 2020-12-01, End date: 2025-11-30

Today, much interest in several fields of physics is devoted to the study of small, open quantum systems, whose properties are profoundly affected by the environment; i.e., the continuum of decay channels. In nuclear physics, these problems were originally studied in the context of nuclear reactions but their importance has been reestablished with the advent of radioactive-beam physics and the resulting interest in exotic nuclei. In particular, strong theory initiatives in this area of research will be instrumental for the success of the experimental program at the Facility for Antiproton and Ion Research (FAIR) in Germany. In addition, many of the aspects of open quantum systems are also being explored in the rapidly evolving research on ultracold atomic gases, quantum dots, and other nanodevices. A first-principles description of open quantum systems presents a substantial theoretical and computational challenge. However, the current availability of enormous computing power has allowed theorists to make spectacular progress on problems that were previously thought intractable. The importance of computational methods to study quantum many-body systems is stressed in this proposal. Our approach is based on the ab initio no-core shell model (NCSM), which is a well-established theoretical framework aimed originally at an exact description of nuclear structure starting from realistic inter-nucleon forces. A successful completion of this project requires extensions of the NCSM mathematical framework and the development of highly advanced computer codes. The '++' in the project title indicates the interdisciplinary aspects of the present research proposal and the ambition to make a significant impact on connected fields of many-body physics.

1 304 800 €

Start date: 2009-12-01, End date: 2014-11-30

The evolutionary pressures exerted by viruses on their host cells constitute a major force that drives the evolution of cellular antiviral mechanisms. The proposed research is motivated by our interest in the roles of protein-RNA interactions in both prokaryotic and eukaryotic antiviral pathways and will proceed in two directions. The first project stems from our current work on the CRISPR pathway, a recently discovered RNA-guided adaptive defense mechanism in bacteria and archaea that silences mobile genetic elements such as viruses (bacteriophages) and plasmids. CRISPR systems rely on short RNAs (crRNAs) that associate with CRISPR-associated (Cas) proteins and function as sequence-specific guides in the detection and destruction of invading nucleic acids. To obtain molecular insights into the mechanisms of crRNA-guided interference, we will pursue structural and functional studies of DNA-targeting ribonuceoprotein complexes from type II and III CRISPR systems. Our work will shed light on the function of these systems in microbial pathogenesis and provide a framework for the informed engineering of RNA-guided gene targeting technologies. The second proposed research direction centres on RNA-targeting antiviral strategies employed by the human innate immune system. Here, our work will focus on structural studies of major interferon-induced effector proteins, initially examining the allosteric activation mechanism of RNase L and subsequently focusing on other antiviral nucleases and RNA helicases, as well as mechanisms by which RNA viruses evade the innate immune response of the host. In our investigations, we plan to approach these questions using an integrated strategy combining structural biology, biochemistry and biophysics with cell-based functional studies. Together, our studies will provide fundamental molecular insights into RNA-centred antiviral mechanisms and their impact on human health and disease.

1 467 180 €

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

Main goal. We aim to understand the puzzling coexistence of antibiotic-resistant and antibiotic-sensitive species in natural soil environments, using novel quantitative experimental techniques and mathematical analysis. The ecological insights gained will be translated into novel treatment strategies for combating antibiotic resistance. Background. Microbial soil ecosystems comprise communities of species interacting through copious secretion of antibiotics and other chemicals. Defence mechanisms, i.e. resistance to antibiotics, are ubiquitous in these wild communities. However, in sharp contrast to clinical settings, resistance does not take over the population. Our hypothesis is that the ecological setting provides natural mechanisms that keep antibiotic resistance in check. We are motivated by our recent finding that specific antibiotic combinations can generate selection against resistance and that soil microbial strains produce compounds that directly target antibiotic resistant mechanisms. Approaches. We will: (1) Isolate natural bacterial species from individual grains of soil, characterize their ability to produce and resist antibiotics and identify the spatial scale for correlations between resistance and production. (2) Systematically measure interactions between species and identify interaction patterns enriched in co-existing communities derived from the same grain of soil. (3) Introducing fluorescently-labelled resistant and sensitive strains into natural soil, we will measure the fitness cost and benefit of antibiotic resistance in situ and identify natural compounds that select against resistance. (4) Test whether such “selection-inverting” compounds can slow evolution of resistance to antibiotics in continuous culture experiments. Conclusions. These findings will provide insights into the ecological processes that keep antibiotic resistance in check, and will suggest novel antimicrobial treatment strategies.

1 900 000 €

Start date: 2012-09-01, End date: 2018-08-31

Since the invention of the spinning frame, automation has been one of the drivers of economic growth. Yet, workers, economist or the general public have been concerned that automation may destroy jobs or create inequality. This concern is particularly prevalent today with the sustained rise in economic inequality and fast technological progress in IT, robotics or self-driving cars. The empirical literature has showed the impact of automation on income distribution. Yet, the level of wages itself should also affect the incentives to undertake automation innovations. Understanding this feedback is key to assess the long-term effect of policies. My project aims to provide the first quantitative account of the two-way relationship between automation and the income distribution. It is articulated around three parts. First, I will use patent data to study empirically the causal effect of wages on automation innovations. To do so, I will build firm-level variation in the wages of the customers of innovating firms by exploiting variations in firms’ exposure to international markets. Second, I will study empirically the causal effect of automation innovations on wages. There, I will focus on local labour market and use the patent data to build exogenous variations in local knowledge. Third, I will calibrate an endogenous growth model with firm dynamics and automation using Danish firm-level data. The model will replicate stylized facts on the labour share distribution across firms. It will be used to compute the contribution of automation to economic growth or the decline of the labour share. Moreover, as a whole, the project will use two different methods (regression analysis and calibrated model) and two different types of data, to answer questions of crucial policy importance such as: Taking into account the response of automation, what are the long-term effects on wages of an increase in the minimum wage, a reduction in labour costs, or a robot tax?

1 295 890 €

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

Pseudoscalar QCD axions and axion-like Particles (ALPs) are an excellent candidate for Dark Matter or can act as a mediator particle for Dark Matter. Since the discovery of the Higgs boson, we know that fundamental scalars exist and it is timely to explore the Axion/ALP parameter space more intensively. A look at the allowed axion/ALP parameter space makes it clear that these might exist at low mass (below few eV), as (part of) Dark Matter. Alternatively they might exist at higher mass, above roughly the MeV scale, potentially as a Dark Matter mediator particle. AxScale explores parts of these different mass regions, with complementary techniques but with one research team. Firstly, with RADES, it develops a novel concept for a filter-like cavity for the search of QCD axion Dark matter at a few tens of a micro-eV. Dark Matter Axions can be discovered by their resonant conversion in that cavity embedded in a strong magnetic field. The `classical axion window' has recently received much interest from cosmological model-building and I will implement a novel cavity concept that will allow to explore this Dark Matter parameter region. Secondly, AxScale searches for axions and ALPs using the NA62 detector at CERN's SPS. Especially the mass region above a few MeV can be efficiently searched by the use of a proton fixed-target facility. During nominal data taking NA62 investigates a Kaon beam. NA62 can also run in a mode in which its primary proton beam is fully dumped. With the resulting high interaction rate, the existence of weakly coupled particles can be efficiently probed. Thus, searches for ALPs from Kaon decays as well as from production in dumped protons with NA62 are foreseen in AxScale. More generally, NA62 can look for a plethora of `Dark Sector' particles with recorded and future data. With the AxScale program I aim at maximizing the reach of NA62 for these new physics models.

1 134 375 €

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

When triggered by nutrient limitation, the Gram-positive bacterium Bacillus subtilis and its relatives enter a pathway of cellular differentiation culminating in the formation of a dormant cell type called a spore, the most resilient cell type known. Bacterial spores can survive for long periods of time and are able to endure extremes of heat, radiation and chemical assault. Remarkably, dormant spores can rapidly convert back to actively growing cells by a process called germination. Consequently, spore forming bacteria, including dangerous pathogens, (such as C. botulinum and B. anthracis) are highly resistant to antibacterial treatments and difficult to eradicate. Despite significant advances in our understanding of the process of spore formation, little is known about the nature of the mature spore. It is unrevealed how dormancy is maintained within the spore and how it is ceased, as the organization and the dynamics of the spore macromolecules remain obscure. The unusual biochemical and biophysical characteristics of the dormant spore make it a challenging biological system to investigate using conventional methods, and thus set the need to develop innovative approaches to study spore biology. We propose to explore the nature of spores by using B. subtilis as a primary experimental system. We intend to: (1) define the architecture of the spore chromosome, (2) track the complexity and fate of mRNA and protein molecules during sporulation, dormancy and germination, (3) revisit the basic notion of the spore dormancy (is it metabolically inert?), (4) compare the characteristics of bacilli spores from diverse ecophysiological groups, (5) investigate the features of spores belonging to distant bacterial genera, (6) generate an integrative database that categorizes the molecular features of spores. Our study will provide original insights and introduce novel concepts to the field of spore biology and may help devise innovative ways to combat spore forming pathogens.

1 630 000 €

Start date: 2008-10-01, End date: 2013-09-30

Non-Alcoholic Fatty Liver Disease (NAFLD), a disease characterized by accumulation of lipid droplets in the liver, is the major precursor for liver failure and liver cancer, and constitutes a global health challenge. An estimated 25% of the adult population suffers from NAFLD, but no FDA approved drugs are available to treat this condition. Obesity is a major NAFLD risk factor and weight-loss improves disease severity in obese patients. Bariatric surgeries are an effective treatment for obesity when lifestyle modifications fail and often lead to improvement in NAFLD and type 2 diabetes. The overreaching objective of this proposal is to combine bariatric surgery in mice and humans with advanced molecular and computational analyses to discover novel, weight-loss independent mechanisms that lead to NAFLD alleviation, and harness them to treat NAFLD. In preliminary studies, I discovered that bariatric surgery clears lipid droplets from the livers of obese db/db mice without inducing weight-loss. Using metabolic and computational analysis, I found that bariatric surgery shifts hepatic gene expression and blood metabolome of post-bariatric patients to a new trajectory, distinct from lean or sick patients. Data analysis revealed the transcription factor Egr1 and one-carbon and choline metabolism to be key drivers of weight-loss independent effects of bariatric surgery. I will use two NAFLD mouse models that do not lose weight after bariatric surgery to characterize livers of mice post-surgery. Human patients do lose weight following surgery, therefore I will use computational methods to elucidate weight-independent pathways induced by surgery, by comparing livers of lean patients to those of NAFLD patients before and shortly after bariatric surgery. Candidate pathways will be studied by metabolic flux analysis and manipulated genetically, with the ultimate goal of reaching systems-levels understanding of NAFLD and identifying surgery-mimetic therapies for this disease.

1 499 354 €

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

The ectoparasitic mite, Varroa destructor, vectors lethal honeybee viruses, in particular Deformed wing virus (DWV) and is unarguably the leading cause of honeybee (Apis mellifera) colony mortality world-wide causing critical economic and ecological consequences for pollination-dependent crop production and wild plant biodiversity, respectively. Since the introduction of the mite in the 1970s and 1980s, wild honeybees in Europe and North America have been nearly completely eradicated and managed honeybees only survive through mite control treatment, or otherwise die within 1-2 years. These treatments remove the selective pressure necessary to establish a stable host-parasite relationship, which hampers the evolution of resistance and obstructs fundamental research on natural selection host‒parasite coevolution in this new host‒parasite system, which is now only possible in a few small honeybee populations surviving long-term (>20 years) without varroa control in Sweden, France and Norway. These rare and valuable naturally selected populations offer unique insight into the natural adaptive capacity of honeybees, yet little is understood about their mechanisms of resistance or tolerance to varroa mites and the viruses they vector. Having exclusive access to these populations, the BEE NATURAL project sets out to comprehensively describe their host resistant and tolerant phenotypes towards both mites and viruses, using a variety of innovative experimental designs, in order to deeper our fundamental understanding of host-parasite interactions. Genomic regions or target genes associated with resistant and tolerant traits will be identified using Next Generation Sequencing (NGS) technologies such as RNA-seq and whole genome sequencing (WGS), providing valuable information that can be applied towards developing marker-assisted selection: a powerful new approach for disease resistant breeding that can facilitate major advances in genetic stock improvement.

1 499 703 €

Start date: 2021-03-01, End date: 2026-02-28

There are large differences in earnings between men and women. Recent work highlights the importance of parenthood for the existence of gender inequality in the labour market. Estimates of the long-run ‘child penalty’, i.e. the impact of having children on women’s relative to men’s earnings, are large and vary substantially across countries. Neither the existence of child penalties nor the striking cross-country variation in child penalties is well understood. BELIEFS will collect a representative dataset of 80,000 individuals in the 28 EU Member States to study the role of several factors in explaining the cross-country differences in child penalties. It will examine the role of (i) beliefs about the benefits/costs to fertility and labour supply decisions, (ii) preferences for having children and for work/leisure, (iii) constraints, and (iv) social norms. BELIEFS will explore different dimensions of heterogeneity and study the individual-level (gender, age etc.) and country-level (labour regulations, family policies etc.) determinants of these factors. It will study whether there are misperceptions of norms and identify whether informing individuals of prevalent social norms shifts their beliefs about the benefits/costs to men/women working and their support for public policies. BELIEFS examines educational, fertility and labour supply decisions in a dynamic life-cycle framework and explores the role of beliefs, preferences, constraints and norms in those decisions. The dynamic framework will also be used to study the role of perceived child penalties in explaining fertility and educational choices. The project is highly ambitious in its scope and it is highly innovative in its combination of research methods. Ultimately, this research agenda will shed light on what drives gender gaps in labour market outcomes as well as which policies may be effective in narrowing these gaps.

1 496 957 €

Start date: 2021-01-01, End date: 2025-12-31

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

The goal of this proposal is to fundamentally change the way we build and reason about software. We aim to develop new kinds of statistical programming systems that provide probabilistically likely solutions to tasks that are difficult or impossible to solve with traditional approaches. These statistical programming systems will be based on probabilistic models of massive codebases (also known as ``Big Code'') built via a combination of advanced programming languages and powerful machine learning and natural language processing techniques. To solve a particular challenge, a statistical programming system will query a probabilistic model, compute the most likely predictions, and present those to the developer. Based on probabilistic models of ``Big Code'', we propose to investigate new statistical techniques in the context of three fundamental research directions: i) statistical program synthesis where we develop techniques that automatically synthesize and predict new programs, ii) statistical prediction of program properties where we develop new techniques that can predict important facts (e.g., types) about programs, and iii) statistical translation of programs where we investigate new techniques for statistical translation of programs (e.g., from one programming language to another, or to a natural language). We believe the research direction outlined in this interdisciplinary proposal opens a new and exciting area of computer science. This area will combine sophisticated statistical learning and advanced programming language techniques for building the next-generation statistical programming systems. We expect the results of this proposal to have an immediate impact upon millions of developers worldwide, triggering a paradigm shift in the way tomorrow's software is built, as well as a long-lasting impact on scientific fields such as machine learning, natural language processing, programming languages and software engineering.

1 500 000 €

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

In mammals, transcriptional control of many genes relies on cis-regulatory elements such as enhancers, which are often located tens to hundreds of kilobases away from their cognate promoters. Functional interactions between distal regulatory elements and target promoters require mutual physical proximity, which is linked to the three-dimensional structure of the chromatin fiber. Chromosome conformation capture studies revealed that chromosomes are partitioned into Topologically Associating Domains (TADs), sub-megabase domains of preferential physical interactions of the chromatin fiber. Genetic evidence showed that TAD boundaries restrict the genomic range of enhancer-promoter communication, and that interactions between regulatory sequences within TADs are further fine-tuned by smaller-scale structures. However, the mechanistic details of how physical interactions translate into transcriptional outputs are totally unknown. Here we propose to explore the biophysical mechanisms that link chromosome conformation and long-range transcriptional regulation using molecular biology, genetic engineering, single-cell experiments and physical modeling. We will measure chromosomal interactions in single cells and in time using a novel method that relies on an enzymatic process in vivo. Genetic engineering will be used to establish a cell system that allows quantitative measurement of how enhancer-promoter interactions relate to transcription at the population and single-cell levels, and to test the effects of perturbations without confounding effects. Finally, we will develop physical models of promoter operation in the presence of distal enhancers, which will be used to interpret the experimental data and formulate new testable predictions. With this integrated approach we aim at providing an entirely new layer of description of the general principles underlying transcriptional control, which could establish new paradigms for research in epigenetics and gene regulation.

1 500 000 €

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

Almost ten years into the highly successful program both in ATLAS and CMS, our understanding of the Standard Model (SM) of particle physics has deepened. Nonetheless, what lies beyond the SM remains one of the most urgent questions of physics in the 21st century. To move forward, one must think outside of the box and leap into uncharted waters. Searches today are aiming at the high-energy frontier, while low-mass resonances are mostly overlooked by the Large Hadron Collider (LHC). Consequently, far-reaching hints of new physics may silentlyhide in the data. Motivated by numerous New Physics (NP) scenarios that often predict light states, such as extended Higgs sectors, axion physics, or dark sector models, among others, the PI will develop new techniques to search for low-mass resonances decaying into two collimated low-pT hadronic τ leptons. τs, being the heaviest, third-generation leptons, provide a unique experimental opportunity to search for low-lying states that would otherwise go undetected. In particular, novel methods to identify boosted hadronic τ+τ− pairs will be established. These techniques will then be used to pave a new path towards discovery of low-mass resonances produced through various production modes. As part of this proposal, the PI will also develop new trigger-level capabilities to further extend the reach of this program at Run-3. As a former leader of the ATLAS Beyond the Standard Model physics group, and current leader of low-mass resonance searches, the PI is ideally positioned to establish a strong research team and take this project to completion, laying the groundwork for the discovery of new physics beyond the SM.

1 420 000 €

Start date: 2021-01-01, End date: 2025-12-31

Embryogenesis is the temporal unfolding of cellular processes: proliferation, migration, differentiation, morphogenesis, apoptosis and functional specialization. These processes are well understood in specific tissues, and for specific cell types. Nevertheless, our systematic knowledge of the types of cells present in the developing and adult animal, and about their functional and lineage relationships, is limited. For example, there is no consensus on the number of cell types, and many important stem cells and progenitors remain to be discovered. Similarly, the lineage relationships between specific cell types are often poorly characterized. This is particularly true for the mammalian nervous system. We have developed (1) a reliable high-throghput method for sequencing all transcripts in 96 single cells at a time; and (2) a system for high-throughput phylogenetic lineage reconstruction. We now propose to characterize embryogenesis using a shotgun approach borrowed from genomics. Tissues will be dissected from multiple stages and dissociated to single cells. A total of 10,000 cells will be analyzed by RNA sequencing, revealing their functional cell type, their lineage relationships, and their current state (e.g. cell cycle phase). The novel approach proposed here will bring the powerful strategies pioneered in genomics into the field of developmental biology, including automation, digitization, and the random shotgun method. The data thus obtained will bring clarity to the concept of ‘cell type’; will provide a first catalog of mouse brain cell types with deep functional annotation; will provide markers for every cell type, including stem cells; and will serve as a basis for future comparative work, especially with human embryos.

1 496 032 €

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

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

1 500 000 €

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

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

1 499 900 €

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

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

1 498 729 €

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

The Smart Building Networks (BuildNet) program will develop optimizing controllers capable of coordinating the flow of power to and from large networks of smart buildings in order to offer critical services to the power grid. The network will make use of the thermal storage of the structures and on-site micro generation capabilities of next-generation buildings, as well as the electrical capacity of attached electric vehicles in order to intelligently control the interaction between the network of buildings and the grid. The wide range of electric utility applications, such as wind capacity firming or congestion relief, that will be possible as a result of this coordinated control will in turn allow a significant increase in the percentage of European power generated from destabilizing renewable sources. Technologically, BuildNet will be built around optimization-based or model predictive control (MPC), a paradigm that is ideally suited to the task of incorporating the current network state and forward-looking information into an optimal decision-making process. The project team will develop novel distributed MPC controllers that utilize the flexibility in the consumption, storage and generation of a distributed network of buildings by exploiting the extensive experience of the PI in optimization-based control and MPC for energy efficient buildings. Because of its theoretically grounded optimization-based control approach, holistic view of building systems and connected networks, as well as a future-looking technological scope, BuildNet's outputs will deliver impact and be relevant to researchers and practitioners alike.

1 460 232 €

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

My objective is to understand the physiologic and medical importance of the posttranslational processing of CAAX proteins (e.g., K-RAS and prelamin A) and to define the suitability of the CAAX protein processing enzymes as therapeutic targets for the treatment of cancer and progeria. CAAX proteins undergo three posttranslational processing steps at a carboxyl-terminal CAAX motif. These processing steps, which are mediated by four different enzymes (FTase, GGTase-I, RCE1, and ICMT), increase the hydrophobicity of the carboxyl terminus of the protein and thereby facilitate interactions with membrane surfaces. Somatic mutations in K-RAS deregulate cell growth and are etiologically involved in the pathogenesis of many forms of cancer. A mutation in prelamin A causes Hutchinson-Gilford progeria syndrome—a pediatric progeroid syndrome associated with misshaped cell nuclei and a host of aging-like disease phenotypes. One strategy to render the mutant K-RAS and prelamin A less harmful is to interfere with their ability to bind to membrane surfaces (e.g., the plasma membrane and the nuclear envelope). This could be accomplished by inhibiting the enzymes that modify the CAAX motif. My Specific Aims are: (1) To define the suitability of the CAAX processing enzymes as therapeutic targets in the treatment of K-RAS-induced lung cancer and leukemia; and (2) To test the hypothesis that inactivation of FTase or ICMT will ameliorate disease phenotypes of progeria. I have developed genetic strategies to produce lung cancer or leukemia in mice by activating an oncogenic K-RAS and simultaneously inactivating different CAAX processing enzymes. I will also inactivate several CAAX processing enzymes in mice with progeria—both before the emergence of phenotypes and after the development of advanced disease phenotypes. These experiments should reveal whether the absence of the different CAAX processing enzymes affects the onset, progression, or regression of cancer and progeria.

1 689 600 €

Start date: 2008-06-01, End date: 2013-05-31

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

Clinical experience with globally-acting cannabinoid-1 receptor (CB1R) antagonists revealed the benefits of blocking CB1Rs for the treatment of obesity and diabetes. However, their use is hampered by increased CNS-mediated side effects. Recently, I have demonstrated that peripherally-restricted CB1R antagonists have the potential to treat the metabolic syndrome without eliciting these adverse effects. While these results are promising and are currently being developed into the clinic, our ability to rationally design CB1R blockers that would target a diseased organ is limited. The current proposal aims to develop and test cell- and organelle-specific CB1R antagonists. To establish this paradigm, I will focus our interest on the kidney, since chronic kidney disease (CKD) is the leading cause of increased morbidity and mortality of patients with diabetes. Our first goal will be to characterize the obligatory role of the renal proximal tubular CB1R in the pathogenesis of diabetic renal complications. Next, we will attempt to link renal proximal CB1R with diabetic mitochondrial dysfunction. Finally, we will develop proximal tubular (cell-specific) and mitochondrial (organelle-specific) CB1R blockers and test their effectiveness in treating CKD. To that end, we will encapsulate CB1R blockers into biocompatible polymeric nanoparticles that will serve as targeted drug delivery systems, via their conjugation to targeting ligands. The implications of this work are far reaching as they will (i) point to renal proximal tubule CB1R as a novel target for CKD; (ii) identify mitochondrial CB1R as a new player in the regulation of proximal tubular cell function, and (iii) eventually become the drug-of-choice in treating diabetic CKD and its comorbidities. Moreover, this work will lead to the development of a novel organ-specific drug delivery system for CB1R blockers, which could be then exploited in other tissues affected by obesity, diabetes and the metabolic syndrome.

1 500 000 €

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

Recent advances have shown that therapeutic manipulations of key cell-cell interactions can have dramatic clinical outcomes. Most notable are several early successes in cancer immunotherapy that target the tumor-T cell interface. However, these successes were only partial. This is likely because the few known interactions are just a few pieces of a much larger puzzle, involving additional signaling molecules and cell types. Dendritic cells (DCs), play critical roles in the induction/suppression of T cells. At early cancer stages, DCs capture tumor antigens and present them to T cells. However, in advanced cancers, the tumor microenvironment (TME) disrupts the crosstalk between DCs and T cells. We will take a multi-step approach to explore how the TME imposes a suppressive effect on DCs and how to reverse this hazardous effect. First, we will use single cell RNA-seq to search for genes in aggressive human and mouse ovarian tumors that are highly expressed in advanced tumors compared to early tumors and that encode molecules that suppress DC activity. Second, we will design a set of CRISPR screens to find genes that are expressed in DCs and regulate the transfer of the suppressive signals. The screens will be performed in the presence of suppressive molecules to mimic the TME and are expected to uncover many key genes in DCs biology. We will develop a new strategy to find synergistic combinations of genes to target (named Perturb-comb), thereby reversing the effect of local tumor immunosuppressive signals. Lastly, we will examine the effect of modified DCs on T cell activation and proliferation in-vivo, and on tumor growth. We expect to find: (1) Signaling molecules in the TME that affect the immune system. (2) New cytokines and cell surface receptors that are expressed in DCs and signal to T cells. (3) New key regulators in DC biology and their mechanisms. (4) Combinations of genes to target in DCs that reverse the TME’s hazardous effects.

1 500 000 €

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

Cancer genomics has revolutionized cancer research by systematic mapping of oncogenic genetic alterations of genes, yet oncogenic epigenetic alterations of regulatory elements away from genes remain elusive. I recently demonstrated that aberrant DNA methylation of CTCF binding sites perturbs chromosomal topology in IDH-mutant glioma and SDH-deficient gastrointestinal stromal tumors (GISTs). Loss of CTCF binding at the boundary between two topologically associating domains disrupts their insulation, leading to oncogene activation. This groundbreaking model links metabolic, epigenetic and topological alterations and demonstrates that they can drive oncogenesis. Aberrant DNA methylation is common in many tumors and therefore epigenetic CTCF disruption may play a role in other cancers, but this has not been studied to date. Prompted by my findings, recent advances in genome-wide characterization methods and newly available large-scale data, I now propose to systematically uncover the rules of regulation of DNA methylation at CTCF binding sites, and how its disruption in cancer leads to epigenetic heterogeneity and drives oncogenesis. To achieve that, we will develop new statistical models to systematically uncover the rules of regulation of DNA methylation at CTCF binding sites and its impact on topology (Aim 1); uncover mechanisms of epigenetic topological alterations and their role in cancer (Aim 2); and develop computational tools to study intratumor epigenetic heterogeneity to investigate the interplay between different subclones (Aim 3). Taken together, this research program will facilitate a systematic understanding of epigenetic topological alterations and their role in cancer. These are critical goals for the field in order to understand the events that drive cancer, to discover new biomarkers, dependencies and therapeutic strategies, and to inform epigenetic and other personalized therapies.

1 500 000 €

Start date: 2021-02-01, End date: 2026-01-31

Plant chemical defences play a central role in mediating interactions between plants and their enemies. Phytochemical diversity may be advantageous to reduce herbivore pressure, and plants commonly produce vast numbers of chemicals. However, the diversity of functional classes of defensive chemicals is often more limited and subject to strong phylogenetic constraints. Such functional conservatism may accelerate the evolution of tolerance in specialized herbivores, resulting in plant-herbivore systems dominated by specialists resistant to host plant defences. This presents major challenges for the study of phytochemically-mediated coevolution, as most systems lack the early stages of coevolutionary interactions that are crucially important to predict evolutionary trajectories. Occasionally however, the gain of functionally novel traits allows plants to escape their coevolved herbivores. The genus Erysimum (Brassicaceae) has gained functionally novel cardenolides in addition to ancestral glucosinolate defences, allowing it to escape several glucosinolate-adapted specialists. Making use of the unique natural and emerging molecular resources in this system, CARDEVOL will comprehensively evaluate the ecological, physiological, and evolutionary consequences of novel defences for the plant and its herbivores. CARDEVOL has four main objectives: 1) to characterize the full extent of natural variation in defence of a widespread Erysimum species and to identify environmental drivers; 2) to manipulate both defences and evaluate their contributions to plant fitness in the field; 3) to evaluate tolerance and resistance mechanisms of a community of non-adapted specialist herbivores towards the new defence; and 4), to evolve herbivores under artificial selection for increased resistance. CARDEVOL thus aims at pushing the boundaries of chemical ecology and transforming the field by elucidating the causes and consequences of phytochemical diversification involving gains of function.

1 500 000 €

Start date: 2021-02-01, End date: 2026-01-31

Computer systems today are power limited. As a result, efficiency gains can be translated into performance. Over the past decade we have been so effective at making computation more efficient that we are now at the point where we spend as much energy moving data (from memory to cache to processor) as we do computing the results. And this trend is only becoming worse as we demand more bandwidth for more powerful processors. To improve performance we need to revisit the way we design memory systems from an energy-first perspective, both at the hardware level and by coordinating data movement between hardware and software. CC-MEM will address memory system efficiency by redesigning low-level hardware and high-level hardware/software integration for energy efficiency. The key novelty is in developing a framework for creating efficient memory systems. This framework will enable researchers and designers to compose solutions to different memory system problems (through a shared exchange of metadata) and coordinate them towards high-level system efficiency goals (through a shared policy framework). Central to this framework is a bilateral exchange of metadata and policy between hardware and software components. This novel communication will open new challenges and opportunities for fine-grained optimizations, system-level efficiency metrics, and more effective divisions of responsibility between hardware and software components. CC-MEM will change how researchers and designers approach memory system design from today’s ad hoc development of local solutions to one wherein disparate components can be integrated (composed) and driven (coordinated) by system-level metrics. As a result, we will be able to more intelligently manage data, leading to dramatically lower memory system energy and increased performance, and open new possibilities for hardware and software optimizations.

1 610 000 €

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

The newly emerging discipline of Synthetic Biology holds the promise of radically changing the way we probe, control and augment living matter from single cells to entire organisms, and revolutionize basic biological research, biotechnology, and medicine. However, practical work toward these important goals is still in its infancy, in part because concrete approaches to achieve rational control of cell physiology are currently lacking. In order to advance this vision, here we propose a detailed strategy toward engineered regulatory circuits that read out complex cellular states based on multiple biological signals, and convert this information into a desired action based on pre-programmed signal integration. If successful, our strategy will enable unprecedented level of rational intervention with the cell. Specifically, we suggest to read out cellular information as relayed by expression and activity of cell’s transcription factors, proteins that control gene expression and serve as major regulators of cell fate and cell response to transient stimuli. The readout will be accomplished with the help of specially-designed sensor promoters that will in turn drive the expression of engineered microRNA molecules. Those molecules in turn will converge on a small number of response elements in engineered downstream transcripts, implementing highly-flexible and programmable logic integration of the original transcription factor signals (Rinaudo et al, Nature Biotechnology, 2007 and Leisner et al, Nature Nanotechnology, 2010). We propose a stepwise bottom-up construction strategy whereby we first design, test and optimize sensor promoters for individual TFs, next we integrate them into large networks, and finally we show how to utilize these networks as prototype selective anti-cancer therapies. To validate our approaches, we will use human cancer cell lines as a model system.

1 479 009 €

Start date: 2011-10-01, End date: 2017-09-30

The mammalian brain is assembled from thousands of neuronal cell types that are organized into distinct circuits to perform behaviourally relevant computations. To gain mechanistic insights about brain function and to treat specific diseases of the nervous system it is crucial to understand what these local circuits are computing and how they achieve these computations. By examining the structure and function of a few genetically identified and experimentally accessible neural circuits we plan to address fundamental questions about the functional architecture of neural circuits. First, are cell types assigned to a unique functional circuit with a well-defined function or do they participate in multiple circuits (“multitasking cell types”), adjusting their role depending on the state of these circuits? Second, does a neural circuit perform “a single computation” or depending on the information content of its inputs can it carry out radically different functions? Third, how, among the large number of other cell types, do the cells belonging to the same functional circuit connect together during development? We use the mouse retina as a model system to address these questions. Finally, we will study the structure and function of a specialised neural circuit in the human fovea that enables humans to read. We predict that our insights into the mechanism of multitasking, network switches and the development of selective connectivity will be instructive to study similar phenomena in other brain circuits. Knowledge of the structure and function of the human fovea will open up new opportunities to correlate human retinal function with human visual behaviour and our genetic technologies to study human foveal function will allow us and others to design better strategies for restoring vision for the blind.

1 499 000 €

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

The interest on autophagy, an evolutionarily conserved process in eukaryotes, has enormously increased in the last years, since autophagy is involved in many diseases such as cancer and neurodegenerative disorders. Autophagosome formation is the key process in autophagy. Despite extensive work, the model of autophagosome formation is not yet well established. Some important questions on autophagosome biogenesis remain to be elusive, such as where the bona fide marker protein of autophagosome, LC3, is lipidated, how lipidated LC3 functions in autophagosome formation, and how the proteins for LC3 lipidation and delipidation are involved in autophagosome formation. Although genetic approaches have been useful to identify genes involved in autophagy, they are chronic and thereby the dynamics of phenotypic change cannot be followed, making them not suited for study highly dynamic process such as autophagosome formation. Herein, I propose to develop and use novel chemical probes to address these issues. First, I plan to prepare semi-synthetic caged LC3 proteins and apply them to monitor dynamics of autophagosome formation in the cell in order to address those questions on autophagosome formation. The semi-synthetic LC3 proteins are expected to confer a temporal control and to realize manipulation of protein structure, which renders such studies possible. Second, I intend to develop a versatile approach targeting specific endogenous proteins using a reversible chemically induced dimerization (CID) system, termed as “knock on and off” strategy. I plan to use this approach to elucidate the function of two distinct PI3K complexes in autophagosome formation. On one hand, the establishment of novel approaches will open up a new avenue for studying biological processes. On the other hand, the use of the tool will reveal the mechanism of autophagy.

1 500 000 €

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

The mammalian circadian clock plays a fundamental role in the liver by regulating fatty acid, glucose and xenobiotic metabolism. Impairment of this rhythm has been show to lead to diverse pathologies including metabolic syndrome. At present, it is supposed that the circadian clock regulates metabolism mostly by regulating the expression of liver enzymes at the transcriptional level. We have now collected evidence that post-transcriptional regulations play also an important role in this regulation. Particularly, recent results from our laboratory show that the circadian clock can synchronize mRNA translation in mouse liver through rhythmic activation of the Target Of Rapamycin Complex 1 (TORC1) with a 12-hours period. Based on this unexpected observation, we plan to identify the genes rhythmically translated in the mouse liver as well as the mechanisms involved in this translation. Indeed, our initial observations suggest a cap-independent translation during the day and a cap-dependent translation during the night. Identification of the different complexes involved in translation at this two different times and their correlation with the sequence, structure, and/or function of the translated genes will provide new insight into the action of the circadian clock on animal metabolism. In parallel, we will identify the signalling pathways involved in the rhythmic activation of TORC1 in mouse liver. Finally, we will study the consequences of a deregulated rhythmic translation in circadian clock-deficient mice on the metabolism and the longevity of these animals. Perturbations of the circadian clock have been linked to numerous pathologies, including obesity, type 2 diabetes and cancer. Our project on the importance of circadian clock-coordinated translation will likely reveal new findings in the field of regulation of animal metabolism by the circadian clock.

1 475 831 €

Start date: 2011-03-01, End date: 2016-02-29

The quest to restore damaged organs is one of the major challenges in medicine. Recent studies in both animals and in humans suggest that the heart has a limited capacity to replenish its own cardiomyocytes (CMs) throughout life, albeit inadequate to compensate for major injuries such as acute myocardial infarction (MI). Most therapeutic research in regenerative cardiogenesis is geared toward stem cell therapy as a means to replace lost CMs associated with ischemic heart disease. Clinical data evaluating the efficacy of cell-based therapy for heart disease are relatively disappointing. This proposal encompasses multidisciplinary and novel approaches to study the molecular and cellular mechanisms that govern the proliferation, differentiation and dedifferentiation of endogenous CMs, combining developmental-, systems- and cell-biology methodologies in vitro and in vivo, in chick, rodent, and human tissue samples. First, we will perform combinatorial perturbations of signaling pathways in chick embryos, focusing primarily on the FGF-ERK pathway, to investigate the molecular switch between cardiac progenitors and CMs (Aim 1). Because adult CMs have limited proliferative capacity, mainly due to mechanical constraints, in Aim 2, we will apply state-of-the-art techniques in cell biology, to determine whether specific mechno-transduction stimuli can prime the proliferation of differentiated CMs. In order to gain deeper insights into the capacity of adult CMs to renew themselves under normal and pathological conditions, in Aim 3, we will employ a novel cell lineage methodology in mouse and human tissue, based on information encoded in genome. Using this methodology, we hope to shed light on the maintenance, renewal and regenerative capacities of adult CMs in vivo. The expected outcome will be a significantly greater understanding of the bidirectional transition from proliferating cardiac progenitors into differentiated CMs, in embryonic and adult hearts.

1 500 000 €

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

Despite massive efforts in securing software, about 60 security bugs are publicly reported each month. Systems software is prone to low level bugs caused by undefined behavior (memory corruption, type confusion, or API confusion). Exploits abuse undefined behavior to execute attacker specified code, or to leak information. We propose code sanitization (CodeSan), a comprehensive approach to improve code quality. CodeSan will sanitize software by (i) automating bug discovery during development through software testing and (ii) protecting deployed software through reflective mitigations. CodeSan trades formal completeness for practical scalability in three steps: First, policy-based sanitization makes undefined behavior (through violations of memory safety, type safety, or API flow safety) explicit and detectable given concrete test inputs. Second, automatic test case generation increases testing coverage for large programs without the need for pre-existing test cases, enabling broader and automated use of policy-based sanitization. Third, for deployed software, reflective mitigations place runtime checks precisely where they are needed based on data-flow and control-flow coverage from our testing efforts. CodeSan complements formal approaches by protecting software that is currently out of reach due to its size, complexity, or low level nature. CodeSan is a compelling, comprehensive, and adaptive approach to thoroughly address undefined behavior for complex software. The three proposed thrusts complement each other naturally and will immediately guard large software systems such as Google Chromium, Mozilla Firefox, the Android system, or the Linux kernel, making them resilient against attacks. In line with PI Payer’s track record on open sourcing his group’s research artifacts on cast sanitization, transformative fuzzing, or control-flow hijacking mitigations, all prototypes produced during CodeSan will be released as open-source.

1 499 970 €

Start date: 2020-03-01, End date: 2025-02-28

Cognition is a collective term for complex but sophisticated mental processes such as attention, learning, social interaction, language production, decision making and other executive functions. For normal brain function, these higher-order functions need to be aptly regulated and controlled, and the physiology and cellular substrates for cognitive functions are under intense investigation. The loss of cognitive control is intricately related to pathological states such as schizophrenia, depression, attention deficit hyperactive disorder and addiction. Synchronized neural activity can be observed when the brain performs several important functions, including cognitive processes. As an example, gamma activity (30-80 Hz) predicts the allocation of attention and theta activity (4-12 Hz) is tightly linked to memory processes. A large body of work indicates that the integrity of local and global neural synchrony is mediated by interneuron networks and actuated by the balance of different neuromodulators. However, much knowledge is still needed on the functional role interneurons play in cognitive processes, i.e. how the interneurons contribute to local and global network processes subserving cognition, and ultimately play a role in behavior. In addition, we need to understand how neuro-modulators, such as dopamine, regulate interneuron function. The proposed project aims to functionally determine the specific role the parvalbumin interneurons and the neuromodulator dopamine in aspects of cognition, and in behavior. In addition, we ask the question if cognition can be enhanced. We are employing a true multidisciplinary approach where brain activity is recorded in conjunctions with optogenetic manipulations of parvalbumin interneurons in animals performing cognitive tasks. In one set of experiments knock-down of dopamine receptors specifically in parvalbumin interneurons is employed to probe how this neuromodulator regulate network functions.

1 400 000 €

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

Error correcting codes play a fundamental role in computer science. Good codes are codes with rate and distance that are asymptotically optimal. Some of the most successful good codes are constructed using expander graphs. In recent years a new notion of {\em robust} error correcting codes, known as locally testable codes (LTCs), has emerged. Locally testable codes are codes in which a proximity of a vector to an error correcting code can be achieved by probing the vector in {\em constant} many locations (independent of its length). LTCs are at the heart of Probabilistically Checkable Proofs (PCPs) and their construction has been sought since the discovery of the PCP theorem in the early 1990s. Despite 20 years of research, it is still widely open whether good locally testable codes exist. LTCs present completely new challenge to the field of error correcting codes. In the old paradigm a random code is a good code and the main focus was to construct explicit codes that imitate the random code. However, a random code is not an LTC. Thus, contrary to traditional codes, there are no natural candidates for LTCs. The known constructions of robust codes are ad hoc, and there is a lack of theory that explains their existence. The goal of the current research plan is to harness the emerging field of higher dimensional expanders and their topological properties for a systematic study of robust error correcting codes. Higher dimensional expanders are natural candidates for obtaining robust codes since they offer a strong form of redundancy that is essential for robustness. Such form of redundancy is lacking by their one dimensional analogue (i.e., expander graphs). Hence, the known expander codes are not robust. We expect that our study will draw new connections between error correcting codes, high dimensional expanders, topology and probability that will shed new light on these fields, and in particular, will advance the constructing of good and robust codes.

1 302 000 €

Start date: 2014-02-01, End date: 2020-01-31

The project focuses on the interface between computational and combinatorial geometry. Geometric problems emerge in a variety of computational fields that interact with the physical world. The performance of geometric algorithms is determined by the description complexity of their underlying combinatorial structures. Hence, most theoretical challenges faced by computational geometry are of a distinctly combinatorial nature. In the past two decades, computational geometry has been revolutionized by the powerful combination of random sampling techniques with the abstract machinery of geometric arrangements. These insights were used, in turn, to establish state-of-the-art results in combinatorial geometry. Nevertheless, a number of fundamental problems remained open and resisted numerous attempts to solve them. Motivated by the recent breakthrough results, in which the PI played a central role, we propose two exciting lines of study with the potential to change the landscape of this field. The first research direction concerns the complexity of Voronoi diagrams -- arguably the most common structures in computational geometry. The second direction concerns combinatorial and algorithmic aspects of geometric intersection structures, including some fundamental open problems in geometric transversal theory. Many of these questions are motivated by geometric variants of general covering and packing problems, and all efficient approximation schemes for them must rely on the intrinsic properties of geometric graphs and hypergraphs. Any progress in responding to these challenges will constitute a major breakthrough in both computational and combinatorial geometry.

1 303 750 €

Start date: 2016-09-01, End date: 2022-08-31

"Similarity is one of the most fundamental notions encountered in problems practically in every branch of science, and is especially crucial in image sciences such as computer vision and pattern recognition. The need to quantify similarity or dissimilarity of some data is central to broad categories of problems involving comparison, search, matching, alignment, or reconstruction. The most common way to model a similarity is using metrics (distances). Such constructions are well-studied in the field of metric geometry, and there exist numerous computational algorithms allowing, for example, to represent one metric using another by means of isometric embeddings. However, in many applications such a model appears to be too restrictive: many types of similarity are non-metric; it is not always possible to model the similarity precisely or completely e.g. due to missing data; some objects might be mutually incomparable e.g. if they are coming from different modalities. Such deficiencies of the metric similarity model are especially pronounced in large-scale computer vision, pattern recognition, and medical imaging applications. The ambitious goal of this project is to introduce a paradigm shift in the way we model and compute similarity. We will develop a unifying framework of computational similarity geometry that extends the theoretical metric model, and will allow developing efficient numerical and computational tools for the representation and computation of generic similarity models. The methods will be developed all the way from mathematical concepts to efficiently implemented code and will be applied to today’s most important and challenging problems in Internet-scale computer vision and pattern recognition, shape analysis, and medical imaging."

1 495 020 €

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

The origin and evolution of sexual reproduction and sex differences represents one of the major unsolved problems in evolutionary biology, and although much progress had been made both via theory and empirical research, recent data suggest that sex chromosome evolution may be more complex than previously thought. The concept of sexual antagonism (when there is a positive intersexual genetic correlation in trait expression but opposite fitness effects of the trait(s) in males and females) has become essential to our understanding of sex chromosome evolution. The goal of this proposal is to understand how the interacting effects of sexual antagonism, sex-linked genetic variation, and sex-specific selection shape the genetic architecture of complex traits. I will test the hypotheses that: 1) individual sexually antagonistic loci are common in the genome, both in separate-sexed species and in hermaphrodites, and drive patterns of sexual antagonism often seen on the trait level. 2) That the response to sex-specific selection in sex-linked loci is usually due to standing sexually antagonistic genetic variation. 3) That sexually antagonistic variation is primarily non-additive in nature. To accomplish this, I will use a combination of approaches, including sex-limited experimental evolution of the X chromosome and reciprocal sex chromosome introgression among distantly related populations of Drosophila, quantitative genetic analysis and experimental evolution mimicking the creation of a novel sex chromosome in the hermaphroditic flatworm Macrostomum, and analytical and simulation modeling. This project will serve to confirm or refute the assumption that trait-level sexual antagonism reflects the contributions of many individual sexually antagonistic loci, increase our understanding of the contribution of coevolution of the sex chromosomes to population divergence, and help provide us with a better general understanding of how genotype maps to phenotype.

1 492 011 €

Start date: 2016-05-01, End date: 2022-04-30

PROBLEM: Despite extensive research on human-computer interaction (HCI), no method exists that guarantees the optimal or even a provably good user interface (UI) design. The prevailing approach relies on heuristics and iteration, which can be costly and even ineffective, because UI design often involves combinatorially hard problems with immense design spaces, multiple objectives and constraints, and complex user behavior. OBJECTIVES: COMPUTED establishes the foundations for optimizing UI designs. A design can be automatically optimized to given objectives and constraints by using combinatorial optimization methods that deploy predictive models of user behavior as objective functions. Although previous work has shown some improvements to usability, the scope has been restricted to keyboards and widgets. COMPUTED researches methods that can vastly expand the scope of optimizable problems. First, algorithmic support is developed for acquiring objective functions that cover the main human factors in a given HCI task. Second, formal analysis of decision problems in UI design allows combating a broader range of design tasks with efficient and appropriate optimization methods. Third, a novel interactive UI optimization paradigm for UI designers promotes fast convergence to good results even in the face of uncertainty and incomplete knowledge. IMPACT: Combinatorial UI optimization offers a strong complement to the prevailing design approaches. Because the structured search process has a high chance of finding good solutions, optimization could improve the quality of interfaces used in everyday life. Optimization can also increase cost-efficiency, because reference to optimality can eliminate fruitless iteration. Moreover, because no preknowledge of UI design is required, even novices will be able to design great UIs. Even in “messy,” less well-defined problems, it may support designers by allowing them to delegate the solving of well-known sub-problems.

1 499 790 €

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

Power relations are an integral part of economic organizations, as well as political and social institutions. People exercise power over others – or are exposed to the power of others – in government, in firms, and even in families. People care deeply about power and autonomy, and attitudes towards them have important economic and societal consequences. Examples include such diverse matters as the willingness to delegate power to government, empire building in public organizations, or sorting into more or less autonomous jobs. Despite their importance, we have remarkably little knowledge about preferences for power and autonomy. Clearly, power and autonomy are valued for being instrumental in achieving desirable outcomes, but it has also long been argued that they are valuable for their own sake. Existing value measures of power and autonomy, however, fail to distinguish between intrinsic and instrumental value components. Power distance and autonomy are even considered to be cultural values, but we don’t know whether differences in such measures are rooted in differences in the instrumental value or differences in preferences. We propose a novel revealed preference approach that allows us to address this shortcoming by separately measuring the intrinsic value of power and the intrinsic value of autonomy. We can then apply this method to properly assess heterogeneity in such values within and across cultures. By combining our measures with other data, we will be able to study the importance of such preferences in explaining individual differences, such as occupational choices or expressed political views, as well as economic outcomes across countries, such as the level of decentralization in economic organizations. Finally, we will study how behavioral reactions to power interact with such preferences and organizational structure, in order to better understand how institutions can be efficiently designed when behavioral reactions to power are accounted for.

1 492 785 €

Start date: 2019-03-01, End date: 2024-02-29

Reef corals are the foundation of ecosystems that host much of the ocean’s biodiversity, making them a significant component of economies and communities around the world. They are under severe threat from anthropogenic stressors, particularly global warming. Some parts of the world’s oceans have already lost the majority of their corals. Efforts to mitigate the damage are informed by research on understanding and transferring naturally-occurring resilient genotypes. This has a direct parallel in medicine; cell- or gene-therapy, which is founded on an ability to isolate and then transplant progenitor/stem cells. This technology does not exist for any coral species. In this research program we will develop robust tools for the isolation, characterization, and transplantation of coral progenitor cells. The tools will be species non-specific, and therefore widely applicable. We will develop generalized strategies for isolating cell-type enriched cell populations, especially progenitor cells, in four species of anemones and stony corals. We will develop cell transplantation techniques for engraftment in non-model species. We will then characterize the engraftment potentials of candidate progenitor cell populations in these species. This technology will have an impact on basic and applied research. Because of the broad applicability, it will become a valuable tool for researchers seeking a more complete cell biology in non-classical invertebrate species. Being able to isolate, manipulate, and replace progenitor cells in diverse species will assist in efforts to understand how the developmental programs that construct or regenerate an organism function and change during evolution. Being able to transfer progenitor cells from a stress-resilient coral to a sensitive one will assist in understanding the mechanisms governing stress tolerance. With this research, and using the tools developed here, it may become possible to confer resilience in the wild.

2 045 900 €

Start date: 2021-03-01, End date: 2026-02-28

The analysis and synthesis of complex 3D geometric data sets is of crucial importance in many scientific disciplines (e.g. bio-medicine, material science, mechanical engineering, physics) and industrial applications (e.g. drug design, entertainment, architecture). We are currently witnessing a tremendous increase in the size and complexity of geometric data, largely fueled by significant advances in 3D acquisition and digital production technology. However, existing computational tools are often not suited to handle this complexity. The goal of this project is to explore a fundamentally different way of processing 3D geometry. We will investigate a new generalized model of geometric symmetry as a unifying concept for studying spatial organization in geometric data. This model allows exposing the inherent redundancies in digital 3D data and will enable truly scalable algorithms for analysis, processing, and design of large-scale geometric data sets. The proposed research will address a number of fundamental questions: What is the information content of 3D geometric models? How can we represent, store, and transmit geometric data most efficiently? Can we we use symmetry to repair deficiencies and reduce noise in acquired data? What is the role of symmetry in the design process and how can it be used to reduce complexity? I will investigate these questions with an integrated approach that combines thorough theoretical studies with practical solutions for real-world applications. The proposed research has a strong interdisciplinary component and will consider the same fundamental questions from different perspectives, closely interacting with scientists of various disciplines, as well artists, architects, and designers.

1 160 302 €

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