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Project acronym AlterMateria
Project Designer Quantum Materials Out of Equilibrium
Researcher (PI) Andrea Caviglia
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Call Details Starting Grant (StG), PE3, ERC-2015-STG
Summary Recently, 'designer' quantum materials, synthesised layer by layer, have been realised, sparking ground-breaking new scientific insights. These artificial materials, such as oxide heterostructures, are interesting building blocks for a new generation of technologies, provided that one is able to access, study and ultimately control their quantum phases in practical conditions such as at room temperature and high speeds. On the other hand, an independent research area is emerging that uses ultra-short bursts of light to stimulate changes in the macroscopic electronic properties of solids at unprecedented speeds. Here I propose to bridge the gap between material design and ultrafast control of solids. This new synergy will allow us to explore fundamental research questions on the non-equilibrium dynamics of quantum materials with competing ground states. Specifically, I will utilize intense THz and mid-infrared electromagnetic fields to manipulate the electronic properties of artificial quantum materials on pico- to femto-second time scales. Beyond the development of novel techniques to generate THz electric fields of unprecedented intensity, I will investigate metal-insulator and magnetic transitions in oxide heterostructures as they unfold in time. This research programme takes oxide electronics in a new direction and establishes a new methodology for the control of quantum phases at high temperature and high speed.
Recently, 'designer' quantum materials, synthesised layer by layer, have been realised, sparking ground-breaking new scientific insights. These artificial materials, such as oxide heterostructures, are interesting building blocks for a new generation of technologies, provided that one is able to access, study and ultimately control their quantum phases in practical conditions such as at room temperature and high speeds. On the other hand, an independent research area is emerging that uses ultra-short bursts of light to stimulate changes in the macroscopic electronic properties of solids at unprecedented speeds. Here I propose to bridge the gap between material design and ultrafast control of solids. This new synergy will allow us to explore fundamental research questions on the non-equilibrium dynamics of quantum materials with competing ground states. Specifically, I will utilize intense THz and mid-infrared electromagnetic fields to manipulate the electronic properties of artificial quantum materials on pico- to femto-second time scales. Beyond the development of novel techniques to generate THz electric fields of unprecedented intensity, I will investigate metal-insulator and magnetic transitions in oxide heterostructures as they unfold in time. This research programme takes oxide electronics in a new direction and establishes a new methodology for the control of quantum phases at high temperature and high speed.
Project acronym ATUNE
Project Attenuation Tomography Using Novel observations of Earth's free oscillations
Researcher (PI) Arwen Fedora Deuss
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Consolidator Grant (CoG), PE10, ERC-2015-CoG
Summary Tectonic phenomena at the Earth's surface, like volcanic eruptions and earthquakes,are driven by convection deep in the mantle. Seismic tomography has been very successful in elucidating the Earth's internal velocity structure. However, seismic velocity is insufficient to obtain robust estimates of temperature and composition, and make direct links with mantle convection. Thus, fundamental questions remain unanswered: Do subducting slabs bring water into the lower mantle? Are the large low-shear velocity provinces under the Pacific and Africa mainly thermal or compositional? Is there any partial melt or water near the mantle transition zone or core mantle boundary? Seismic attenuation, or loss of energy, is key to mapping melt, water and temperature variations, and answering these questions. Unfortunately, attenuation has only been imaged using short- and intermediate-period seismic data, showing little similarity even for the upper mantle and no reliable lower mantle models exist. The aim of ATUNE is to develop novel full-spectrum techniques and apply them to Earth's long period free oscillations to observe global-scale regional variations in seismic attenuation from the lithosphere to the core mantle boundary. Scattering and focussing - problematic for shorter period techniques - are easily included using cross-coupling (or resonance) between free oscillations not requiring approximations. The recent occurrence of large earthquakes, increase in computer power and my world-leading expertise in free oscillations now make it possible to increase the frequency dependence of attenuation to a much wider frequency band, allowing us to distinguish between scattering (redistribution of energy) versus intrinsic attenuation. ATUNE will deliver the first ever full-waveform global tomographic model of 3D attenuation variations in the lower mantle, providing essential constraints on melt, water and temperature for understanding the complex dynamics of our planet.
Tectonic phenomena at the Earth's surface, like volcanic eruptions and earthquakes,are driven by convection deep in the mantle. Seismic tomography has been very successful in elucidating the Earth's internal velocity structure. However, seismic velocity is insufficient to obtain robust estimates of temperature and composition, and make direct links with mantle convection. Thus, fundamental questions remain unanswered: Do subducting slabs bring water into the lower mantle? Are the large low-shear velocity provinces under the Pacific and Africa mainly thermal or compositional? Is there any partial melt or water near the mantle transition zone or core mantle boundary? Seismic attenuation, or loss of energy, is key to mapping melt, water and temperature variations, and answering these questions. Unfortunately, attenuation has only been imaged using short- and intermediate-period seismic data, showing little similarity even for the upper mantle and no reliable lower mantle models exist. The aim of ATUNE is to develop novel full-spectrum techniques and apply them to Earth's long period free oscillations to observe global-scale regional variations in seismic attenuation from the lithosphere to the core mantle boundary. Scattering and focussing - problematic for shorter period techniques - are easily included using cross-coupling (or resonance) between free oscillations not requiring approximations. The recent occurrence of large earthquakes, increase in computer power and my world-leading expertise in free oscillations now make it possible to increase the frequency dependence of attenuation to a much wider frequency band, allowing us to distinguish between scattering (redistribution of energy) versus intrinsic attenuation. ATUNE will deliver the first ever full-waveform global tomographic model of 3D attenuation variations in the lower mantle, providing essential constraints on melt, water and temperature for understanding the complex dynamics of our planet.
Project acronym BROKERS
Project Participatory Urban Governance between Democracy and Clientelism: Brokers and (In)formal Politics
Researcher (PI) Martijn Koster
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Summary The emergence of participatory governance has resulted in the delegation of governmental responsibilities to citizens. Individuals position themselves as voluntary mediators, or brokers, between the government and their fellow citizens. This research asks: what are the roles of such brokers in participatory urban governance, and how do they influence democratic governance? This study will investigate ethnographically how brokers position themselves in administrative schemes, and examine the formal and informal dimensions of their performance. It will analyse the practices, discourses and networks, both in and out of officially sanctioned channels and government institutions. The research approaches brokers as 'assemblers', connective agents who actively bring together different governmental and citizen actors, institutions and resources. The scholarly debate on brokerage within participatory governance is divided into two different arguments: first, an argument about neoliberal deregulation located in the Global North, which encourages the practices of active citizen-mediators, and second, a modernization argument in the Global South, which sees brokers as remnants of a clientelist political system. This research will combine these arguments to study settings in both the North and the South. It employs a comparative urbanism design to study four cities that are recognized as pioneers in democratic participatory governance, two in the North and two in the South: Rotterdam (NL), Manchester (UK), Cochabamba (Bolivia) and Recife (Brazil). This research builds upon theories from political anthropology, urban studies, citizenship studies and public administration to develop a new framework for analysing brokerage in participatory urban governance. Understanding how the formal and informal dimensions of participatory governance are entwined will contribute to our ability to theorize the conditions under which this type of governance can give rise to more democratic cities.
The emergence of participatory governance has resulted in the delegation of governmental responsibilities to citizens. Individuals position themselves as voluntary mediators, or brokers, between the government and their fellow citizens. This research asks: what are the roles of such brokers in participatory urban governance, and how do they influence democratic governance? This study will investigate ethnographically how brokers position themselves in administrative schemes, and examine the formal and informal dimensions of their performance. It will analyse the practices, discourses and networks, both in and out of officially sanctioned channels and government institutions. The research approaches brokers as 'assemblers', connective agents who actively bring together different governmental and citizen actors, institutions and resources. The scholarly debate on brokerage within participatory governance is divided into two different arguments: first, an argument about neoliberal deregulation located in the Global North, which encourages the practices of active citizen-mediators, and second, a modernization argument in the Global South, which sees brokers as remnants of a clientelist political system. This research will combine these arguments to study settings in both the North and the South. It employs a comparative urbanism design to study four cities that are recognized as pioneers in democratic participatory governance, two in the North and two in the South: Rotterdam (NL), Manchester (UK), Cochabamba (Bolivia) and Recife (Brazil). This research builds upon theories from political anthropology, urban studies, citizenship studies and public administration to develop a new framework for analysing brokerage in participatory urban governance. Understanding how the formal and informal dimensions of participatory governance are entwined will contribute to our ability to theorize the conditions under which this type of governance can give rise to more democratic cities.
Project acronym BUILDUP
Project Galaxy Buildup in the Young Universe: from the First Billion Years through the Peak Activity Epoch
Researcher (PI) Karina Caputi
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Summary Deep galaxy surveys are the most valuable asset to understand the history of our Universe. They are key to test galaxy formation models which, based on the Cold Dark Matter framework, are successful at reproducing general aspects of galaxy evolution with cosmic time. However, important discrepancies still exist between models and observations, most notably at high redshifts. This Project will reconstruct the history of galaxy buildup from the first billion years of cosmic time through the peak activity epoch of the Universe, which occurred 10 billion years ago, providing a fundamental constraint for galaxy formation models. I am leading the largest ultra-deep galaxy survey that will ever be conducted with the Spitzer Space Telescope. In this Project, I will exploit my new Spitzer program to do a groundbreaking study of galaxy buildup in the young Universe, paving the way for further galaxy evolution studies with the forthcoming James Webb Space Telescope (JWST). My main objectives are: 1) quantifying galaxy stellar mass assembly beyond the peak activity epoch, through the study of the galaxy stellar mass function up to z~7; 2) measuring, for the first time, galaxy clustering with stellar mass information up to such high redshifts; 3) linking galaxy growth to dust-obscured star formation using Spitzer and new APEX/AMKID sub-millimetre data; 4) unveiling the first steps of galaxy buildup at z>7 with JWST; 5) optimizing the official JWST Mid Infrared Instrument (MIRI) data reduction pipeline for the analysis of deep galaxy surveys. The delivery of an optimized MIRI pipeline is an important added value to the scientific outcome of this Project, which will benefit the general Astronomical community. This is the right time for this Project to make a maximum impact. We are now in a turning point for IR Astronomy, and this opportunity should not be missed. This Project will have a long-lasting legacy, bridging current and next generations of IR galaxy surveys.
Deep galaxy surveys are the most valuable asset to understand the history of our Universe. They are key to test galaxy formation models which, based on the Cold Dark Matter framework, are successful at reproducing general aspects of galaxy evolution with cosmic time. However, important discrepancies still exist between models and observations, most notably at high redshifts. This Project will reconstruct the history of galaxy buildup from the first billion years of cosmic time through the peak activity epoch of the Universe, which occurred 10 billion years ago, providing a fundamental constraint for galaxy formation models. I am leading the largest ultra-deep galaxy survey that will ever be conducted with the Spitzer Space Telescope. In this Project, I will exploit my new Spitzer program to do a groundbreaking study of galaxy buildup in the young Universe, paving the way for further galaxy evolution studies with the forthcoming James Webb Space Telescope (JWST). My main objectives are: 1) quantifying galaxy stellar mass assembly beyond the peak activity epoch, through the study of the galaxy stellar mass function up to z~7; 2) measuring, for the first time, galaxy clustering with stellar mass information up to such high redshifts; 3) linking galaxy growth to dust-obscured star formation using Spitzer and new APEX/AMKID sub-millimetre data; 4) unveiling the first steps of galaxy buildup at z>7 with JWST; 5) optimizing the official JWST Mid Infrared Instrument (MIRI) data reduction pipeline for the analysis of deep galaxy surveys. The delivery of an optimized MIRI pipeline is an important added value to the scientific outcome of this Project, which will benefit the general Astronomical community. This is the right time for this Project to make a maximum impact. We are now in a turning point for IR Astronomy, and this opportunity should not be missed. This Project will have a long-lasting legacy, bridging current and next generations of IR galaxy surveys.
Project acronym CAPTURE
Project CApturing Paradata for documenTing data creation and Use for the REsearch of the future
Researcher (PI) Isto HUVILA
Host Institution (HI) UPPSALA UNIVERSITET
Summary "Considerable investments have been made in Europe and worldwide in research data infrastructures. Instead of a general lack of data about data, it has become apparent that the pivotal factor that drastically constrains the use of data is the absence of contextual knowledge about how data was created and how it has been used. This applies especially to many branches of SSH research where data is highly heterogeneous, both by its kind (e.g. being qualitative, quantitative, naturalistic, purposefully created) and origins (e.g. being historical/contemporary, from different contexts and geographical places). The problem is that there may be enough metadata (data about data) but there is too little paradata (data on the processes of its creation and use). In contrast to the rather straightforward problem of describing the data, the high-risk/high-gain problem no-one has managed to solve, is the lack of comprehensive understanding of what information about the creation and use of research data is needed and how to capture enough of that information to make the data reusable and to avoid the risk that currently collected vast amounts of research data become useless in the future. The wickedness of the problem lies in the practical impossibility to document and keep everything and the difficulty to determine optimal procedures for capturing just enough. With an empirical focus on archaeological and cultural heritage data, which stands out by its extreme heterogeneity and rapid accumulation due to the scale of ongoing development-led archaeological fieldwork, CAPTURE develops an in-depth understanding of how paradata is #1 created and #2 used at the moment, #3 elicits methods for capturing paradata on the basis of the findings of #1-2, #4 tests the new methods in field trials, and #5 synthesises the findings in a reference model to inform the capturing of paradata and enabling data-intensive research using heterogeneous research data stemming from diverse origins. "
"Considerable investments have been made in Europe and worldwide in research data infrastructures. Instead of a general lack of data about data, it has become apparent that the pivotal factor that drastically constrains the use of data is the absence of contextual knowledge about how data was created and how it has been used. This applies especially to many branches of SSH research where data is highly heterogeneous, both by its kind (e.g. being qualitative, quantitative, naturalistic, purposefully created) and origins (e.g. being historical/contemporary, from different contexts and geographical places). The problem is that there may be enough metadata (data about data) but there is too little paradata (data on the processes of its creation and use). In contrast to the rather straightforward problem of describing the data, the high-risk/high-gain problem no-one has managed to solve, is the lack of comprehensive understanding of what information about the creation and use of research data is needed and how to capture enough of that information to make the data reusable and to avoid the risk that currently collected vast amounts of research data become useless in the future. The wickedness of the problem lies in the practical impossibility to document and keep everything and the difficulty to determine optimal procedures for capturing just enough. With an empirical focus on archaeological and cultural heritage data, which stands out by its extreme heterogeneity and rapid accumulation due to the scale of ongoing development-led archaeological fieldwork, CAPTURE develops an in-depth understanding of how paradata is #1 created and #2 used at the moment, #3 elicits methods for capturing paradata on the basis of the findings of #1-2, #4 tests the new methods in field trials, and #5 synthesises the findings in a reference model to inform the capturing of paradata and enabling data-intensive research using heterogeneous research data stemming from diverse origins. "
Project acronym CODECHECK
Project CRACKING THE CODE BEHIND MITOTIC FIDELITY: the roles of tubulin post-translational modifications and a chromosome separation checkpoint
Researcher (PI) Helder Jose Martins Maiato
Host Institution (HI) INSTITUTO DE BIOLOGIA MOLECULAR E CELULAR-IBMC
Summary During the human lifetime 10000 trillion cell divisions take place to ensure tissue homeostasis and several vital functions in the organism. Mitosis is the process that ensures that dividing cells preserve the chromosome number of their progenitors, while deviation from this, a condition known as aneuploidy, represents the most common feature in human cancers. Here we will test two original concepts with strong implications for chromosome segregation fidelity. The first concept is based on the "tubulin code" hypothesis, which predicts that molecular motors "read" tubulin post-translational modifications on spindle microtubules. Our proof-of-concept experiments demonstrate that tubulin detyrosination works as a navigation system that guides chromosomes towards the cell equator. Thus, in addition to regulating the motors required for chromosome motion, the cell might regulate the tracks in which they move on. We will combine proteomic, super-resolution and live-cell microscopy, with in vitro reconstitutions, to perform a comprehensive survey of the tubulin code and the respective implications for motors involved in chromosome motion, mitotic spindle assembly and correction of kinetochore-microtubule attachments. The second concept is centered on the recently uncovered chromosome separation checkpoint mediated by a midzone-associated Aurora B gradient, which delays nuclear envelope reformation in response to incompletely separated chromosomes. We aim to identify Aurora B targets involved in the spatiotemporal regulation of the anaphase-telophase transition. We will establish powerful live-cell microscopy assays and a novel mammalian model system to dissect how this checkpoint allows the detection and correction of lagging/long chromosomes and DNA bridges that would otherwise contribute to genomic instability. Overall, this work will establish a paradigm shift in our understanding of how spatial information is conveyed to faithfully segregate chromosomes during mitosis.
During the human lifetime 10000 trillion cell divisions take place to ensure tissue homeostasis and several vital functions in the organism. Mitosis is the process that ensures that dividing cells preserve the chromosome number of their progenitors, while deviation from this, a condition known as aneuploidy, represents the most common feature in human cancers. Here we will test two original concepts with strong implications for chromosome segregation fidelity. The first concept is based on the "tubulin code" hypothesis, which predicts that molecular motors "read" tubulin post-translational modifications on spindle microtubules. Our proof-of-concept experiments demonstrate that tubulin detyrosination works as a navigation system that guides chromosomes towards the cell equator. Thus, in addition to regulating the motors required for chromosome motion, the cell might regulate the tracks in which they move on. We will combine proteomic, super-resolution and live-cell microscopy, with in vitro reconstitutions, to perform a comprehensive survey of the tubulin code and the respective implications for motors involved in chromosome motion, mitotic spindle assembly and correction of kinetochore-microtubule attachments. The second concept is centered on the recently uncovered chromosome separation checkpoint mediated by a midzone-associated Aurora B gradient, which delays nuclear envelope reformation in response to incompletely separated chromosomes. We aim to identify Aurora B targets involved in the spatiotemporal regulation of the anaphase-telophase transition. We will establish powerful live-cell microscopy assays and a novel mammalian model system to dissect how this checkpoint allows the detection and correction of lagging/long chromosomes and DNA bridges that would otherwise contribute to genomic instability. Overall, this work will establish a paradigm shift in our understanding of how spatial information is conveyed to faithfully segregate chromosomes during mitosis.
Project acronym CONPOL
Project Contexts, networks and participation: The social logic of political engagement
Researcher (PI) Sven Aron Oskarsson
Summary The statement that individuals' immediate social circumstances influence how they think and act in the political sphere is a truism. However, both theoretical and empirical considerations have often prevented political scientists from incorporating this logic into analyses of political behavior. In the CONPOL project we argue that it is necessary to return to the idea that politics follows a social logic in order to push the theoretical and empirical boundaries in explaining political behavior. That is, people do not act as isolated individuals when confronting complex political tasks such as deciding whether to vote and which party or candidate to vote for. Instead politics should be seen as a social experience in which individuals arrive at their decisions within particular social settings: the family, the peer group, the workplace, the neighborhood. In what way do parents and other family members influence an individual's political choices? What is the role of workmates and neighbors when individuals arrive at political decisions? Do friends and friends' friends affect how you think and act in the political sphere? To answer such questions the standard approach to gather empirical evidence on political behavior based on national sample surveys needs to be complemented by the use of population wide register data. The empirical core of the CONPOL project is unique Swedish register data. Via the population registers provided by Statistics Sweden it is possible to identify several relevant social settings such as parent-child relations and the location of individuals within workplaces and neighborhoods. The registers also allow us to identify certain network links between individuals. Furthermore, Statistics Sweden holds information on several variables measuring important political traits. A major aim for CONPOL is to complement this information by scanning in and digitalizing election rolls with individual-level information on turnout across several elections.
The statement that individuals' immediate social circumstances influence how they think and act in the political sphere is a truism. However, both theoretical and empirical considerations have often prevented political scientists from incorporating this logic into analyses of political behavior. In the CONPOL project we argue that it is necessary to return to the idea that politics follows a social logic in order to push the theoretical and empirical boundaries in explaining political behavior. That is, people do not act as isolated individuals when confronting complex political tasks such as deciding whether to vote and which party or candidate to vote for. Instead politics should be seen as a social experience in which individuals arrive at their decisions within particular social settings: the family, the peer group, the workplace, the neighborhood. In what way do parents and other family members influence an individual's political choices? What is the role of workmates and neighbors when individuals arrive at political decisions? Do friends and friends' friends affect how you think and act in the political sphere? To answer such questions the standard approach to gather empirical evidence on political behavior based on national sample surveys needs to be complemented by the use of population wide register data. The empirical core of the CONPOL project is unique Swedish register data. Via the population registers provided by Statistics Sweden it is possible to identify several relevant social settings such as parent-child relations and the location of individuals within workplaces and neighborhoods. The registers also allow us to identify certain network links between individuals. Furthermore, Statistics Sweden holds information on several variables measuring important political traits. A major aim for CONPOL is to complement this information by scanning in and digitalizing election rolls with individual-level information on turnout across several elections.
Project acronym DNACom
Project Compartmentalized DNA Computers for In-Vitro Diagnostic Applications
Researcher (PI) Tom DE GREEF
Host Institution (HI) TECHNISCHE UNIVERSITEIT EINDHOVEN
Call Details Proof of Concept (PoC), ERC-2018-PoC
Summary Changes in human microRNA (miRNA) levels are associated with several important human diseases. Monitoring changes in miRNA levels would enable clinicians to perform diagnosis and evaluate therapeutic efficacy of drugs. In principle, changes in a miRNA signature could be detected by existing methods such as quantitative reverse transcription PCR (RT-qPCR). However, the experimental complexity and computational analysis of the data prevents the measurements of miRNA signatures in a clinical setting. DNA-based molecular computers combine multiplex detection of DNA and RNA strands with molecular computation and are thus able to process and classify miRNA signatures into easy interpretable answers. In my ERC starting grant BioCircuit, we have made a technological breakthrough by compartmentalizing DNA-based molecular computers inside semipermeable micrometer-sized compartments made from a Bovine serum albumin (BSA) polymer conjugate. We have shown that compartmentalization of DNA circuits improves their speed by an order of magnitude and decreases their overall leakiness. Importantly, our work has revealed that this platform is capable of distributed sensing and processing of DNA and RNA strands. In 'DNACom' we will 1) establish the technical proof of concept of compartmentalized DNA computers for in-vitro molecular diagnostics (IVDs) and 2) validate the commercial application of compartmentalized DNA circuits as low-cost, portable point-of-care devices for detection and classification of microRNA signatures.
Changes in human microRNA (miRNA) levels are associated with several important human diseases. Monitoring changes in miRNA levels would enable clinicians to perform diagnosis and evaluate therapeutic efficacy of drugs. In principle, changes in a miRNA signature could be detected by existing methods such as quantitative reverse transcription PCR (RT-qPCR). However, the experimental complexity and computational analysis of the data prevents the measurements of miRNA signatures in a clinical setting. DNA-based molecular computers combine multiplex detection of DNA and RNA strands with molecular computation and are thus able to process and classify miRNA signatures into easy interpretable answers. In my ERC starting grant BioCircuit, we have made a technological breakthrough by compartmentalizing DNA-based molecular computers inside semipermeable micrometer-sized compartments made from a Bovine serum albumin (BSA) polymer conjugate. We have shown that compartmentalization of DNA circuits improves their speed by an order of magnitude and decreases their overall leakiness. Importantly, our work has revealed that this platform is capable of distributed sensing and processing of DNA and RNA strands. In 'DNACom' we will 1) establish the technical proof of concept of compartmentalized DNA computers for in-vitro molecular diagnostics (IVDs) and 2) validate the commercial application of compartmentalized DNA circuits as low-cost, portable point-of-care devices for detection and classification of microRNA signatures.
Project acronym EpiID
Project Single-cell epigenomics: quantifying epigenetic changes in individual cells using DamID
Researcher (PI) jop Kind
Host Institution (HI) KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Summary Phenotypic variation arises from the heritable acquisition of cell-type specific gene-expression programs. Key in understanding cellular specification is to elucidate the epigenetic mechanism that underlies transcriptional heterogeneity. Thus a central question in biology is how cell-to-cell variability in the epigenome contributes to the emergence of phenotypic differences. However, current techniques to profile the epigenome require populations of cells and consequently present ensemble averages of the underlying biology. Therefore, to grasp the molecular concept behind the cellular acquisition of heritable traits it is essential to develop techniques to profile the epigenome at the single-cell level. The advent of single-cell genomics enabled profiling of few epigenetic features and transcriptomics in single cells; however, this toolbox is still very restricted and moreover, to directly correlate the variability in the epigenome to changes in gene-expression activity it is pivotal to device methods to obtain both measurements from the same cell. Therefore, to bridge these shortcomings in the epigenetic toolbox, we plan to develop and apply novel techniques to profile the epigenome in single cells. With this proposal we aim to (1) develop a method to map histone modifications in single cells (2) develop a method to map chromatin organization in single cells (3) develop a method to obtain combined measurements of the epigenome and the transcriptome of the same cell (4) apply these and previously developed single-cell methods, to different biological systems to study how the epigenome contributes to lineage specification. Collectively, the goal of this proposal is to develop a comprehensive single-cell toolbox to take the field to the next (epigenomic) level and to work towards elucidating the molecular mechanism behind cellular specification.
Phenotypic variation arises from the heritable acquisition of cell-type specific gene-expression programs. Key in understanding cellular specification is to elucidate the epigenetic mechanism that underlies transcriptional heterogeneity. Thus a central question in biology is how cell-to-cell variability in the epigenome contributes to the emergence of phenotypic differences. However, current techniques to profile the epigenome require populations of cells and consequently present ensemble averages of the underlying biology. Therefore, to grasp the molecular concept behind the cellular acquisition of heritable traits it is essential to develop techniques to profile the epigenome at the single-cell level. The advent of single-cell genomics enabled profiling of few epigenetic features and transcriptomics in single cells; however, this toolbox is still very restricted and moreover, to directly correlate the variability in the epigenome to changes in gene-expression activity it is pivotal to device methods to obtain both measurements from the same cell. Therefore, to bridge these shortcomings in the epigenetic toolbox, we plan to develop and apply novel techniques to profile the epigenome in single cells. With this proposal we aim to (1) develop a method to map histone modifications in single cells (2) develop a method to map chromatin organization in single cells (3) develop a method to obtain combined measurements of the epigenome and the transcriptome of the same cell (4) apply these and previously developed single-cell methods, to different biological systems to study how the epigenome contributes to lineage specification. Collectively, the goal of this proposal is to develop a comprehensive single-cell toolbox to take the field to the next (epigenomic) level and to work towards elucidating the molecular mechanism behind cellular specification.
Project acronym EPIScOPE
Project Reversing the epigenetic state of oligodendrocyte precursors cells in multiple sclerosis
Researcher (PI) Gonçalo DE SÁ E SOUSA DE CASTELO BRANCO
Host Institution (HI) KAROLINSKA INSTITUTET
Summary Oligodendrocytes (OL) are glial cells that mediate myelination of neurons, a process that is defective in multiple sclerosis (MS). Although OL precursor cells (OPCs) can initially promote remyelination in MS, this regenerative mechanism eventually fails in progressive MS. OPCs go through several epigenetic states that ultimately define their potential to differentiate and myelinate. OPCs in progressive MS stall in a distinct epigenetic state, incompatible with differentiation and remyelination. We hypothesize that these OPCs regress to an epigenetic state reminiscent of the state of embryonic OPCs, which remain undifferentiated. In this proposal, we aim to uncover the causes behind the remyelination failure upon disease progression in MS. We will determine the epigenetic/transcriptional states of OPCs during development and in MS, using single cell and bulk RNA sequencing and quantitative proteomics. We will further investigate how the interplay between transcription factors (TFs), chromatin modifiers (ChMs) and non-coding RNAs (ncRNAs) contributes to the transition between epigenetic states of OPCs. The results will allow the identification of ChMs and ncRNAs that can modulate these states and thereby control OPC differentiation and myelination. We will use this knowledge to investigate whether we can reverse the epigenetic state of OPCs in MS, in order to promote their differentiation and remyelination. The unique combination of leading-edge techniques such as SILAC coupled with immunoprecipitation and mass-spectrometry, single-cell RNA sequencing, ChIP-Sequencing, among others, will allow us to provide insights into novel epigenetic mechanisms that might be underlying the effects of environmental and lifestyle risk factors for MS. Moreover, this project has the potential to lead to the discovery of new targets for epigenetic-based therapies for MS, which could provide major opportunities for improved clinical outcome of MS patients in the near future.
Oligodendrocytes (OL) are glial cells that mediate myelination of neurons, a process that is defective in multiple sclerosis (MS). Although OL precursor cells (OPCs) can initially promote remyelination in MS, this regenerative mechanism eventually fails in progressive MS. OPCs go through several epigenetic states that ultimately define their potential to differentiate and myelinate. OPCs in progressive MS stall in a distinct epigenetic state, incompatible with differentiation and remyelination. We hypothesize that these OPCs regress to an epigenetic state reminiscent of the state of embryonic OPCs, which remain undifferentiated. In this proposal, we aim to uncover the causes behind the remyelination failure upon disease progression in MS. We will determine the epigenetic/transcriptional states of OPCs during development and in MS, using single cell and bulk RNA sequencing and quantitative proteomics. We will further investigate how the interplay between transcription factors (TFs), chromatin modifiers (ChMs) and non-coding RNAs (ncRNAs) contributes to the transition between epigenetic states of OPCs. The results will allow the identification of ChMs and ncRNAs that can modulate these states and thereby control OPC differentiation and myelination. We will use this knowledge to investigate whether we can reverse the epigenetic state of OPCs in MS, in order to promote their differentiation and remyelination. The unique combination of leading-edge techniques such as SILAC coupled with immunoprecipitation and mass-spectrometry, single-cell RNA sequencing, ChIP-Sequencing, among others, will allow us to provide insights into novel epigenetic mechanisms that might be underlying the effects of environmental and lifestyle risk factors for MS. Moreover, this project has the potential to lead to the discovery of new targets for epigenetic-based therapies for MS, which could provide major opportunities for improved clinical outcome of MS patients in the near future.
Project acronym EQEC
Project Engineering Quantum Error Correction
Researcher (PI) Barbara Terhal
Summary This proposal will advance the theory of quantum error correction towards its application in real physical devices, in particular superconducting transmon qubit systems. The research will result in proposals for experiments: how to use physical qubits to redundantly represent logical quantum information and how error information can be obtained and classically processed. The research will consider novel ways of using transmon qubits to achieve a universal fault-tolerant surface code architecture. The research will produce a design of a universal fault-tolerant architecture in which qubits are encoded in the electromagnetic field of a (microwave) cavity. Research will also focus on mathematical and numerical studies in quantum error correction which are technology-independent, but shed light on coding overhead, decoding efficiency and logical universality.
This proposal will advance the theory of quantum error correction towards its application in real physical devices, in particular superconducting transmon qubit systems. The research will result in proposals for experiments: how to use physical qubits to redundantly represent logical quantum information and how error information can be obtained and classically processed. The research will consider novel ways of using transmon qubits to achieve a universal fault-tolerant surface code architecture. The research will produce a design of a universal fault-tolerant architecture in which qubits are encoded in the electromagnetic field of a (microwave) cavity. Research will also focus on mathematical and numerical studies in quantum error correction which are technology-independent, but shed light on coding overhead, decoding efficiency and logical universality.
Project acronym GWAS2FUNC
Project From GWAS to functional studies: Tackling the complex nature of brain disorders
Researcher (PI) Danielle POSTHUMA
Host Institution (HI) STICHTING VU
Call Details Advanced Grant (AdG), LS5, ERC-2018-ADG
Summary Genome-wide association studies (GWAS) of unprecedented sample size have recently provided robust insight into the polygenic architecture of many different brain disorders. Despite this exciting potential, GWAS results have rarely translated into mechanistic disease insight. This is because the detected genetic effects are small and numerous, and hardly ever directly actionable for functional follow-up. In addition, the polygenic nature of brain disorders comes with large genetic heterogeneity, where different patients with the same disorder may carry completely different combinations of genetic risk variants, possibly corresponding to different etiological mechanisms, requiring different treatment regimens. To benefit from GWAS, extensive biological interpretation and insight into genetic heterogeneity is needed. In this ERC I will develop much needed tools for (i) extensive biological interpretation at cellular resolution and (ii) assessing genetic heterogeneity, both aimed at formulating hypotheses that take into account the polygenic nature of brain disorders and can be tested in functional experiments. I will apply the developed tools to a wide range of brain-related traits, providing ample starting points for functional follow-up. As a proof-of-concept I will test the viability of two neuroscientific approaches (iPSC and DREADDs) for functional follow-up of GWAS results. First, I will conduct scRNA sequencing and electrophysiological assessments on iPSC derived neurons and astrocytes from genetically selected (schizophrenia) patients and controls. Second, I will use in vivo chemogenetic manipulation to target specific cell types that have been implicated by GWAS (for insomnia). The primary goal of this proposal is to bridge the gap between GWAS and function. The results will facilitate the translation of GWAS findings for brain disorders into functional mechanisms that are biologically important in disease pathogenesis and, ultimately, treatment design.
Genome-wide association studies (GWAS) of unprecedented sample size have recently provided robust insight into the polygenic architecture of many different brain disorders. Despite this exciting potential, GWAS results have rarely translated into mechanistic disease insight. This is because the detected genetic effects are small and numerous, and hardly ever directly actionable for functional follow-up. In addition, the polygenic nature of brain disorders comes with large genetic heterogeneity, where different patients with the same disorder may carry completely different combinations of genetic risk variants, possibly corresponding to different etiological mechanisms, requiring different treatment regimens. To benefit from GWAS, extensive biological interpretation and insight into genetic heterogeneity is needed. In this ERC I will develop much needed tools for (i) extensive biological interpretation at cellular resolution and (ii) assessing genetic heterogeneity, both aimed at formulating hypotheses that take into account the polygenic nature of brain disorders and can be tested in functional experiments. I will apply the developed tools to a wide range of brain-related traits, providing ample starting points for functional follow-up. As a proof-of-concept I will test the viability of two neuroscientific approaches (iPSC and DREADDs) for functional follow-up of GWAS results. First, I will conduct scRNA sequencing and electrophysiological assessments on iPSC derived neurons and astrocytes from genetically selected (schizophrenia) patients and controls. Second, I will use in vivo chemogenetic manipulation to target specific cell types that have been implicated by GWAS (for insomnia). The primary goal of this proposal is to bridge the gap between GWAS and function. The results will facilitate the translation of GWAS findings for brain disorders into functional mechanisms that are biologically important in disease pathogenesis and, ultimately, treatment design.
Project acronym HARVEST
Project Plant foods in human evolution: Factors affecting the harvest of nutrients from the floral environment
Researcher (PI) Amanda Georganna Henry
Host Institution (HI) UNIVERSITEIT LEIDEN
Summary Plant foods comprise the majority of most human diets, yet the potential importance of these foods in human evolution is often overlooked. Using a behavioral ecology framework, the HARVEST project explores fundamental questions: Why did hominins choose to eat certain plants? What were their foraging goals? We will focus on two objectives: 1) Reconstructing the diets of fossil hominins and 2) Exploring the costs and benefits of plant foods. To understand the factors driving food choice by ancient hominins, we must know what they ate. Analyses of plant remains, proteins, DNA and other residues preserved in dental calculus are cutting-edge methods for reconstructing diets, and provide information about food, processing techniques, and oral microbiota. With a sequential sampling approach, we will combine these analyses to identify foods consumed by hominin groups for which plants are thought to be of great importance. The decision to consume a particular plant depends on its inherent properties (nutrients and antifeedants) and on the biological and technological abilities of the consumer, so that each potential food has a different cost and benefit. We will study the variation in plant properties among microhabitats in African environments similar to those used by hominins, to better model their food choices. Separately, our study of the food choices among living African foraging and farming groups will reveal if plants are chosen for calories, micronutrients or cultural preferences, while analysis of their gut microbiota and studies of their food processing behaviors will indicate how they acquire nutrients from these foods. Finally, we will assess how the costs of fire might influence food processing choices. Results from these studies will help fill important lacunae in our understanding of hominin diets, broaden our knowledge of hominin behaviors in a variety of environments, and help generate hypotheses about the relationships between diet and human evolution.
Plant foods comprise the majority of most human diets, yet the potential importance of these foods in human evolution is often overlooked. Using a behavioral ecology framework, the HARVEST project explores fundamental questions: Why did hominins choose to eat certain plants? What were their foraging goals? We will focus on two objectives: 1) Reconstructing the diets of fossil hominins and 2) Exploring the costs and benefits of plant foods. To understand the factors driving food choice by ancient hominins, we must know what they ate. Analyses of plant remains, proteins, DNA and other residues preserved in dental calculus are cutting-edge methods for reconstructing diets, and provide information about food, processing techniques, and oral microbiota. With a sequential sampling approach, we will combine these analyses to identify foods consumed by hominin groups for which plants are thought to be of great importance. The decision to consume a particular plant depends on its inherent properties (nutrients and antifeedants) and on the biological and technological abilities of the consumer, so that each potential food has a different cost and benefit. We will study the variation in plant properties among microhabitats in African environments similar to those used by hominins, to better model their food choices. Separately, our study of the food choices among living African foraging and farming groups will reveal if plants are chosen for calories, micronutrients or cultural preferences, while analysis of their gut microbiota and studies of their food processing behaviors will indicate how they acquire nutrients from these foods. Finally, we will assess how the costs of fire might influence food processing choices. Results from these studies will help fill important lacunae in our understanding of hominin diets, broaden our knowledge of hominin behaviors in a variety of environments, and help generate hypotheses about the relationships between diet and human evolution.
Project acronym MEDIATE
Project Middlebrow Enlightenment: Disseminating Ideas, Authors, and Texts in 18th-century Europe
Researcher (PI) Alicia Montoya
Summary Intellectual history has long focused on a small number of authors and conceptual frameworks in studying societal change during the Enlightenment. Historians of the book have similarly restricted their vision, tending to privilege radical, subversive or forbidden texts. Yet ever since Daniel Mornet launched the history of the book approach a century ago, historians have recognized that it was authors who were not radical or subversive who produced the best-selling texts of the 18th century. This project will push Enlightenment studies in a new direction by moving beyond the present, narrow corpus of texts and models that dominate the field, and propose a new conceptual framework that takes as its starting-point the heuristic concept of middlebrow culture. Developing a state-of-the-art database, it will, firstly, identify not the 'high' Enlightenment texts studied by the history of ideas, and not the 'low', forbidden texts of book history, but the real best-sellers of the 18th century. These were the texts that, to readers on the ground, represented the most visible face of the Enlightenment, but have hitherto never really been studied. Secondly, it will elaborate a typology of this corpus describing its generic traits, intended readers, relation to major political-religious debates, and how readers in different parts of Europe appropriated these texts through translations, reworkings and other uses. Finally, it examines how historiography came to define the Enlightenment as the work of an intellectual elite, downplaying the impact of middlebrow texts and readers. The project thus brings an ambitious, bottom-up approach to intellectual history, using book history data and innovative digital tools to argue that the Enlightenment was fashioned not only by the progressive intellectuals we know today, but just as importantly, also by a large mass of forgotten, middlebrow best-sellers that need to be adequately studied if we are to truly understand how we 'became modern'
Intellectual history has long focused on a small number of authors and conceptual frameworks in studying societal change during the Enlightenment. Historians of the book have similarly restricted their vision, tending to privilege radical, subversive or forbidden texts. Yet ever since Daniel Mornet launched the history of the book approach a century ago, historians have recognized that it was authors who were not radical or subversive who produced the best-selling texts of the 18th century. This project will push Enlightenment studies in a new direction by moving beyond the present, narrow corpus of texts and models that dominate the field, and propose a new conceptual framework that takes as its starting-point the heuristic concept of middlebrow culture. Developing a state-of-the-art database, it will, firstly, identify not the 'high' Enlightenment texts studied by the history of ideas, and not the 'low', forbidden texts of book history, but the real best-sellers of the 18th century. These were the texts that, to readers on the ground, represented the most visible face of the Enlightenment, but have hitherto never really been studied. Secondly, it will elaborate a typology of this corpus describing its generic traits, intended readers, relation to major political-religious debates, and how readers in different parts of Europe appropriated these texts through translations, reworkings and other uses. Finally, it examines how historiography came to define the Enlightenment as the work of an intellectual elite, downplaying the impact of middlebrow texts and readers. The project thus brings an ambitious, bottom-up approach to intellectual history, using book history data and innovative digital tools to argue that the Enlightenment was fashioned not only by the progressive intellectuals we know today, but just as importantly, also by a large mass of forgotten, middlebrow best-sellers that need to be adequately studied if we are to truly understand how we 'became modern'
Project acronym MegaALS
Project Unravelling the Interplay between Metabolism, Gut Microbiome and Adaptive Immunity in Amyotrophic Lateral Sclerosis
Researcher (PI) Fang FANG
Summary Amyotrophic lateral sclerosis (ALS) is a rare but devastating neurodegenerative disorder that in lack of effective treatments leads to death within a few years of diagnosis. ALS is increasingly being recognized as a systemic disease affecting not only the central nervous system but also other physiological aspects. We hypothesize that there is a disease-specific interplay between metabolism, gut microbiome and adaptive immunity, which substantially contributes to the etiopathogenesis of ALS. The overarching aim of this project is therefore to explore such interplay, and to assess the effectiveness of a treatment regimen that specifically targets it. Using a population-based case-control study of ALS in Stockholm, I will first characterize the complex interactions between metabolism, microbiome, and immunity in ALS, through comprehensive proteomic, metagenomic and immune-response profiling. The specificity of these interactions will be tested in contrast to healthy individuals at high risk for ALS (siblings), individuals with similar environmental and lifestyle factors (spouses), and unrelated population-controls. I will then use an established ALS mouse model (SOD1G93A) to understand the usefulness of combining a high-caloric diet with a fecal microbiota transplant from healthy human donors in disease prevention and treatment. To better understand the underlying mechanisms, I will compare microbiome and immune-response profiles before and after the intervention. The proposed research is unique as it 1) combines innovative molecular platforms with a high-quality epidemiological study design, 2) uses a novel strategy of investigating multiple aspects of human physiology, and 3) offers a possibility to directly translate findings between human observational and animal experimental studies. The ultimate goal is to significantly advance our knowledge about ALS as a disease, and more importantly to identify novel and highly warranted preventive and therapeutic targets.
Amyotrophic lateral sclerosis (ALS) is a rare but devastating neurodegenerative disorder that in lack of effective treatments leads to death within a few years of diagnosis. ALS is increasingly being recognized as a systemic disease affecting not only the central nervous system but also other physiological aspects. We hypothesize that there is a disease-specific interplay between metabolism, gut microbiome and adaptive immunity, which substantially contributes to the etiopathogenesis of ALS. The overarching aim of this project is therefore to explore such interplay, and to assess the effectiveness of a treatment regimen that specifically targets it. Using a population-based case-control study of ALS in Stockholm, I will first characterize the complex interactions between metabolism, microbiome, and immunity in ALS, through comprehensive proteomic, metagenomic and immune-response profiling. The specificity of these interactions will be tested in contrast to healthy individuals at high risk for ALS (siblings), individuals with similar environmental and lifestyle factors (spouses), and unrelated population-controls. I will then use an established ALS mouse model (SOD1G93A) to understand the usefulness of combining a high-caloric diet with a fecal microbiota transplant from healthy human donors in disease prevention and treatment. To better understand the underlying mechanisms, I will compare microbiome and immune-response profiles before and after the intervention. The proposed research is unique as it 1) combines innovative molecular platforms with a high-quality epidemiological study design, 2) uses a novel strategy of investigating multiple aspects of human physiology, and 3) offers a possibility to directly translate findings between human observational and animal experimental studies. The ultimate goal is to significantly advance our knowledge about ALS as a disease, and more importantly to identify novel and highly warranted preventive and therapeutic targets.
Project acronym MESOTAS-SIEVE
Project Sieving neuronal network communication
Researcher (PI) Regina LUTTGE
Call Details Proof of Concept (PoC), PC1, ERC-2015-PoC
Summary This project will demonstrate the technical and commercial viability of the MESOTAS-SIEVE bioreactor, a novel 3D brain-on-chip microculture system. This allows the culturing and in vitro functional analysis of neuronal networks that mimic the human brain in a physiologically much more relevant way than conventional cell culture systems or animal models. Therefore, the MESOTAS-SIEVE system has great potential towards the realisation of tissue models of the brain for drug efficacy and toxicity assays. This project is based on exciting discoveries done in the ERC Starting Grant project MESOTAS (2011-2016). In MESOTAS, a bioreactor on a microelectrode array (MEA) has been developed to study the 'natural' behaviour of 3D neuronal networks. For this bioreactor, a neuronal cell line has been identified that uniquely survives >30 days and forms neuronal networks. To further improve function and network formation capacity, this project will integrate a micro-sieve at the bottom of the MESOTAS bioreactor to improve cell shape, function and optimal connection to the MEA electrodes for single-cell readout of activity. PoC of this MESOTAS-SIEVE bioreactor provides the basis for further development towards a commercial brain-on-a-chip platform. The first steps towards commercialization of MESOTAS-SIEVE will be performed as part of this project and initial industry contact are already in place. During the project we will establish a solid business model, including intellectual property (IP) protection, a market/competitor analysis, and an exploitation plan. Towards the end of this project the "data package" will be used to attract further financing towards commercialization.
This project will demonstrate the technical and commercial viability of the MESOTAS-SIEVE bioreactor, a novel 3D brain-on-chip microculture system. This allows the culturing and in vitro functional analysis of neuronal networks that mimic the human brain in a physiologically much more relevant way than conventional cell culture systems or animal models. Therefore, the MESOTAS-SIEVE system has great potential towards the realisation of tissue models of the brain for drug efficacy and toxicity assays. This project is based on exciting discoveries done in the ERC Starting Grant project MESOTAS (2011-2016). In MESOTAS, a bioreactor on a microelectrode array (MEA) has been developed to study the 'natural' behaviour of 3D neuronal networks. For this bioreactor, a neuronal cell line has been identified that uniquely survives >30 days and forms neuronal networks. To further improve function and network formation capacity, this project will integrate a micro-sieve at the bottom of the MESOTAS bioreactor to improve cell shape, function and optimal connection to the MEA electrodes for single-cell readout of activity. PoC of this MESOTAS-SIEVE bioreactor provides the basis for further development towards a commercial brain-on-a-chip platform. The first steps towards commercialization of MESOTAS-SIEVE will be performed as part of this project and initial industry contact are already in place. During the project we will establish a solid business model, including intellectual property (IP) protection, a market/competitor analysis, and an exploitation plan. Towards the end of this project the "data package" will be used to attract further financing towards commercialization.
Project acronym Metacontrol
Project Cognitive control in context: Neural, functional, and social mechanisms of metacontrol
Researcher (PI) Bernhard Hommel
Summary Human behavior is commonly understood as emerging from a struggle between will and habit, i.e., between "intentional" processes driven by the current goal and "automatic" processes driven by available stimuli. This scenario suggests that it is mainly the goal-related processes that render behavior adaptive. Based on a novel theoretical framework (the Metacontrol State Model, combined with the Theory of Event Coding) that is motivated by recent behavioral and neuroscientific observations, I suggest an alternative view and argue that people can control the relative contributions of goal-driven and stimulus-driven processes to decision-making and action selection. In particular, people regulate the interaction between these processes by determining the ratio between (goal) persistence and flexi-bility, depending on task, situation, and personal experience—a process that I refer to as "metacontrol". The project aims to identify and trace individual "metacontrol policies" (biases towards persistence or flexibility) and task- and condition-specific changes therein by means of behavioral, computational, and neuroscientific techniques, and by using virtual-reality methods. I shall study, account for, and try predicting individual differences in the choice and implementation of such policies, identify and explain the cognitive and social consequences of adopting a particular policy, and investigate whether and how people can adopt meta¬control policies from others—either intentionally or automati-cally. I shall also study whether and to what degree people use situational cues to automatize the implementation of suitable policies, and whether often-used, highly practiced policies can become chron-ified and turn into a trait-like processing style, as suggested by cultural studies.
Human behavior is commonly understood as emerging from a struggle between will and habit, i.e., between "intentional" processes driven by the current goal and "automatic" processes driven by available stimuli. This scenario suggests that it is mainly the goal-related processes that render behavior adaptive. Based on a novel theoretical framework (the Metacontrol State Model, combined with the Theory of Event Coding) that is motivated by recent behavioral and neuroscientific observations, I suggest an alternative view and argue that people can control the relative contributions of goal-driven and stimulus-driven processes to decision-making and action selection. In particular, people regulate the interaction between these processes by determining the ratio between (goal) persistence and flexi-bility, depending on task, situation, and personal experience—a process that I refer to as "metacontrol". The project aims to identify and trace individual "metacontrol policies" (biases towards persistence or flexibility) and task- and condition-specific changes therein by means of behavioral, computational, and neuroscientific techniques, and by using virtual-reality methods. I shall study, account for, and try predicting individual differences in the choice and implementation of such policies, identify and explain the cognitive and social consequences of adopting a particular policy, and investigate whether and how people can adopt meta¬control policies from others—either intentionally or automati-cally. I shall also study whether and to what degree people use situational cues to automatize the implementation of suitable policies, and whether often-used, highly practiced policies can become chron-ified and turn into a trait-like processing style, as suggested by cultural studies.
Project acronym MIMICS
Project MicroRNA Isoforms for Molecular Interception of Cervical cancer using Self-samples
Researcher (PI) Christophorus Joannes Lambertus Maria Meijer
Host Institution (HI) STICHTING VUMC
Summary With 13,000 deaths each year in the EU, cervical cancer (CC) is one of the deadliest cancers worldwide. This is unnecessary, since CC is well detectable and treatable at early stages. For this reason, most EU countries have screening programs in place. These screening programs have had (varying) success in reducing CC incidence, however, this reduction has reached a plateau and new strategies are needed to improve screening success. An important reason for the stagnating decline in CC incidence is the relative high rate of non-compliance to screening because the gynaecological procedure to collect a sample is seen as highly uncomfortable and very invasive. Offering self-sampling options increases the participation rate in non-responder women by 30%. However, self-sampling is not compatible with the current cytology-based screening method (e.g. Pap test). There is thus a great need for the development of new, molecular screening assays for CC that can be used on self-samples. In the ERC-AdG MASS-CARE, we investigate the value of two classes of molecular markers, DNA methylation and miRNA for the detection of cervical disease in self-samples. In our analyses, we frequently observed variations at the 3' end of the miRNA markers. Such variations (isomiRs) have great impact on their detectability by standard assays and thus specific assay development for these isomiRs constitutes a great improvement compared to using the canonical miRNA sequence. In MIMICS, we aim to select the isomiRs with the strongest association with CC which therefore have added value as disease biomarker compared to the canonical miRNAs. The identified isomiRs, which improve CC detection compared to the canonical miRNAs will be added to the panel of DNA methylation and canonical miRNAs as identified in the ERC-AdG. This assay will constitute the first full molecular, non-morphology-based, objective screening assay for cervical cancer fully compatible with self-sampling.
With 13,000 deaths each year in the EU, cervical cancer (CC) is one of the deadliest cancers worldwide. This is unnecessary, since CC is well detectable and treatable at early stages. For this reason, most EU countries have screening programs in place. These screening programs have had (varying) success in reducing CC incidence, however, this reduction has reached a plateau and new strategies are needed to improve screening success. An important reason for the stagnating decline in CC incidence is the relative high rate of non-compliance to screening because the gynaecological procedure to collect a sample is seen as highly uncomfortable and very invasive. Offering self-sampling options increases the participation rate in non-responder women by 30%. However, self-sampling is not compatible with the current cytology-based screening method (e.g. Pap test). There is thus a great need for the development of new, molecular screening assays for CC that can be used on self-samples. In the ERC-AdG MASS-CARE, we investigate the value of two classes of molecular markers, DNA methylation and miRNA for the detection of cervical disease in self-samples. In our analyses, we frequently observed variations at the 3' end of the miRNA markers. Such variations (isomiRs) have great impact on their detectability by standard assays and thus specific assay development for these isomiRs constitutes a great improvement compared to using the canonical miRNA sequence. In MIMICS, we aim to select the isomiRs with the strongest association with CC which therefore have added value as disease biomarker compared to the canonical miRNAs. The identified isomiRs, which improve CC detection compared to the canonical miRNAs will be added to the panel of DNA methylation and canonical miRNAs as identified in the ERC-AdG. This assay will constitute the first full molecular, non-morphology-based, objective screening assay for cervical cancer fully compatible with self-sampling.
Project acronym MMDYNASYS
Project Molecular Motors, powering dynamic functional molecular systems
Researcher (PI) Benard Lucas FERINGA
Summary In this proposal the unique properties of unidirectional light driven molecular rotary motors will be built upon to achieve dynamic control of function and develop responsive systems with a particular focus on systems in water. Light-driven molecular rotary motors are distinct from the majority of molecular switches, as they allow sequential access to multiple functional states in a responsive system through non-invasive stimulation. Importantly, continuous irradiation induces continuous rotary motion which provides a unique opportunity to design dynamic systems and responsive materials that can be driven out-of-equilibrium. The research program is divided in four work-packages: a) chemical and redox driven unidirectional motors; here we will develop processive unidirectional motors that can use (electro)chemical energy in a continuous manner, b) amplification of motion; here rotary motors operate in assemblies to amplify mechanical function over a wide range of length scales. Specifically we will use liquid crystal-water interfaces as a unique platform to control motion and organization. c) dissipative self-assembly: molecular motors offer fantastic opportunities to control self-assembly and drive such systems out-of-equilibrium. We aim at metastable aggregate formation (hydrogels) and the design of amphiphilic motors for responsive self-assembled nanostructures; d)triggering biomolecular function; the goal is to use rotary motors to regulate DNA transcription and ultimately as genuine powering device to control cardiac cell function. In the emerging field of photopharmacology, we take advantage of non-invasive high spatio-temporal control that switching with light provides. The proposed research program is highly challenging but provides the comprehensive effort required to achieve control of complex nanomechanical systems and will opening a bright future for applications ranging from stimuli responsive materials to spatio-temporal control of biomolecular systems
In this proposal the unique properties of unidirectional light driven molecular rotary motors will be built upon to achieve dynamic control of function and develop responsive systems with a particular focus on systems in water. Light-driven molecular rotary motors are distinct from the majority of molecular switches, as they allow sequential access to multiple functional states in a responsive system through non-invasive stimulation. Importantly, continuous irradiation induces continuous rotary motion which provides a unique opportunity to design dynamic systems and responsive materials that can be driven out-of-equilibrium. The research program is divided in four work-packages: a) chemical and redox driven unidirectional motors; here we will develop processive unidirectional motors that can use (electro)chemical energy in a continuous manner, b) amplification of motion; here rotary motors operate in assemblies to amplify mechanical function over a wide range of length scales. Specifically we will use liquid crystal-water interfaces as a unique platform to control motion and organization. c) dissipative self-assembly: molecular motors offer fantastic opportunities to control self-assembly and drive such systems out-of-equilibrium. We aim at metastable aggregate formation (hydrogels) and the design of amphiphilic motors for responsive self-assembled nanostructures; d)triggering biomolecular function; the goal is to use rotary motors to regulate DNA transcription and ultimately as genuine powering device to control cardiac cell function. In the emerging field of photopharmacology, we take advantage of non-invasive high spatio-temporal control that switching with light provides. The proposed research program is highly challenging but provides the comprehensive effort required to achieve control of complex nanomechanical systems and will opening a bright future for applications ranging from stimuli responsive materials to spatio-temporal control of biomolecular systems
Project acronym MYMOVE
Project Migrant youth mobility in Europe: patterns, processes and consequences
Researcher (PI) Helga DE VALK
Summary Although many immigrant children are more likely to move within the country of settlement than native born youth, little is known on the potential effects of this so called internal mobility. When does childhood internal mobility have negative consequences on an individual's life? Are there differences in processes and consequences for those of immigrant and non-immigrant background? Do the number of moves or the reason for moving make a difference? Is the age at which moving takes place decisive and is distance relevant? Despite the fact that moving is a major stress-inducing life event, so far little is known on the potential consequences of childhood internal mobility for people of diverse immigrant origins. Given Europe's diverse population and immigration being the key factor in population change, it is crucial to understand if, how and for whom childhood internal mobility matters. The main objective of the MYMOVE project is to advance knowledge on the relationship between childhood internal mobility and adult life chances as defined by demographic family life choices, health and well-being for those with and without immigrant background. The project makes five innovative contributions to the so far scattered literature. It will 1) comprehensively map childhood internal mobility patterns; 2) study its mid- and long-term consequences for diverse immigrant groups and the native-born; 3) cover two key outcomes that are crucial in the individual life path (demographic family behaviour and health and well-being); 4) simultaneously study different dimensions of internal mobility (number, reason, timing, distance), and 5), distinguish three levels of influence that may moderate the effect of internal mobility (the neighbourhood of origin and destination, family background, and individual characteristics). The MYMOVE project will break new ground by using unique and new longitudinal (full-) population register and survey panel data from across Europe.
Although many immigrant children are more likely to move within the country of settlement than native born youth, little is known on the potential effects of this so called internal mobility. When does childhood internal mobility have negative consequences on an individual's life? Are there differences in processes and consequences for those of immigrant and non-immigrant background? Do the number of moves or the reason for moving make a difference? Is the age at which moving takes place decisive and is distance relevant? Despite the fact that moving is a major stress-inducing life event, so far little is known on the potential consequences of childhood internal mobility for people of diverse immigrant origins. Given Europe's diverse population and immigration being the key factor in population change, it is crucial to understand if, how and for whom childhood internal mobility matters. The main objective of the MYMOVE project is to advance knowledge on the relationship between childhood internal mobility and adult life chances as defined by demographic family life choices, health and well-being for those with and without immigrant background. The project makes five innovative contributions to the so far scattered literature. It will 1) comprehensively map childhood internal mobility patterns; 2) study its mid- and long-term consequences for diverse immigrant groups and the native-born; 3) cover two key outcomes that are crucial in the individual life path (demographic family behaviour and health and well-being); 4) simultaneously study different dimensions of internal mobility (number, reason, timing, distance), and 5), distinguish three levels of influence that may moderate the effect of internal mobility (the neighbourhood of origin and destination, family background, and individual characteristics). The MYMOVE project will break new ground by using unique and new longitudinal (full-) population register and survey panel data from across Europe.
Project acronym NANO-INSITU
Project Nanoscale Chemical Reactions Studied with In-Situ Transmission Electron Microscopy
Researcher (PI) Marijn Arnout Van Huis
Summary Great successes have been achieved in nanoscience where the development of functional properties and the assembly of nanostructures into nanomaterials have become increasingly important. In general, both the tuning of the chemical and physical properties and the self-assembly of nanocrystals into 2D or 3D superstructures take place in a liquid environment. When analysing the structural properties of nanocrystals using Transmission Electron Microscopy (TEM), this liquid environment is contained between membranes to keep it in the high vacuum. At present, the thickness of the liquid is not controlled, which renders standard imaging at atomic resolution impossible. Here I propose to integrate micro-electromechanical actuator functionalities in the Liquid Cell chips to overcome this problem so that real-time atomic resolution imaging and chemical analysis on nanoparticles in solution becomes a reality. This new in-situ technology will elucidate what really happens during chemical reactions, and will thereby enable the development of new nanomaterials for optoelectronics, lighting, and catalysis. Oriented attachment processes and self-assembly of nanoparticles, which are key to the large-scale production of 2D and 3D nanomaterials, can also be followed in the Liquid Cell. Furthermore, the hydration of nanoscale model systems of earth materials such as magnesia, alumina, and calcium oxide is of major importance in the geosciences. In the field of enhanced oil recovery, for example, the huge volumetric expansion that comes with the hydration of these minerals could facilitate access to reservoirs. My research group has extensive experience in in-situ TEM and recently has achieved significant successes in Liquid Cell studies. We are in an ideal position to develop this new technology and open up these new research areas, which will have a major impact on science, industry, and society.
Great successes have been achieved in nanoscience where the development of functional properties and the assembly of nanostructures into nanomaterials have become increasingly important. In general, both the tuning of the chemical and physical properties and the self-assembly of nanocrystals into 2D or 3D superstructures take place in a liquid environment. When analysing the structural properties of nanocrystals using Transmission Electron Microscopy (TEM), this liquid environment is contained between membranes to keep it in the high vacuum. At present, the thickness of the liquid is not controlled, which renders standard imaging at atomic resolution impossible. Here I propose to integrate micro-electromechanical actuator functionalities in the Liquid Cell chips to overcome this problem so that real-time atomic resolution imaging and chemical analysis on nanoparticles in solution becomes a reality. This new in-situ technology will elucidate what really happens during chemical reactions, and will thereby enable the development of new nanomaterials for optoelectronics, lighting, and catalysis. Oriented attachment processes and self-assembly of nanoparticles, which are key to the large-scale production of 2D and 3D nanomaterials, can also be followed in the Liquid Cell. Furthermore, the hydration of nanoscale model systems of earth materials such as magnesia, alumina, and calcium oxide is of major importance in the geosciences. In the field of enhanced oil recovery, for example, the huge volumetric expansion that comes with the hydration of these minerals could facilitate access to reservoirs. My research group has extensive experience in in-situ TEM and recently has achieved significant successes in Liquid Cell studies. We are in an ideal position to develop this new technology and open up these new research areas, which will have a major impact on science, industry, and society.
Project acronym NaviFlu
Project Navigating the evolutionary routes of influenza viruses
Researcher (PI) Colin Russell
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Summary Seasonal influenza viruses re-infect us repeatedly, escaping antibody recognition, due to the evolution of the virus itself. Being able to predict when and how the virus will evolve would be transformative for influenza virus control. Problematically, we have only observed one of the likely many possible routes of virus evolution. We do not know how many viable routes may have existed or about the repeatability of the observed evolution. These knowledge gaps limit the predictability of influenza virus evolution. NaviFlu will fill these gaps by rigorously assessing the repeatability of influenza virus evolution and the diversity of routes the virus can explore. Recent work has shown that prolonged influenza virus infections can result in substantial virus evolution and occasionally portend virus mutational patterns on a global scale. However, observing large numbers of such infections is challenging. We will use an innovative ex-vivo human airway epithelium culture system to artificially create and study prolonged human infections. Together with cutting-edge next generation sequencing and new analysis tools, we will quantify the evolutionary landscape of seasonal influenza viruses. The project has three objectives, each building in complexity: 1–Quantify the evolutionary dynamics of seasonal influenza viruses in the absence of antibody-mediated selection. 2–Determine how the antibody complexity of immune sera shape the evolutionary trajectories of virus antigenic evolution. 3–Quantify the impact of differences in selection pressures by site of infection and underlying host variation on virus evolution. Through these objectives we will "play evolution forwards", revealing the relative roles of different factors governing the mode and tempo of influenza virus evolution and quantify the predictability of virus evolution. This will improve the design of influenza vaccines, enhance prospects for influenza control, and lay new groundwork for exploring virus evolution.
Seasonal influenza viruses re-infect us repeatedly, escaping antibody recognition, due to the evolution of the virus itself. Being able to predict when and how the virus will evolve would be transformative for influenza virus control. Problematically, we have only observed one of the likely many possible routes of virus evolution. We do not know how many viable routes may have existed or about the repeatability of the observed evolution. These knowledge gaps limit the predictability of influenza virus evolution. NaviFlu will fill these gaps by rigorously assessing the repeatability of influenza virus evolution and the diversity of routes the virus can explore. Recent work has shown that prolonged influenza virus infections can result in substantial virus evolution and occasionally portend virus mutational patterns on a global scale. However, observing large numbers of such infections is challenging. We will use an innovative ex-vivo human airway epithelium culture system to artificially create and study prolonged human infections. Together with cutting-edge next generation sequencing and new analysis tools, we will quantify the evolutionary landscape of seasonal influenza viruses. The project has three objectives, each building in complexity: 1–Quantify the evolutionary dynamics of seasonal influenza viruses in the absence of antibody-mediated selection. 2–Determine how the antibody complexity of immune sera shape the evolutionary trajectories of virus antigenic evolution. 3–Quantify the impact of differences in selection pressures by site of infection and underlying host variation on virus evolution. Through these objectives we will "play evolution forwards", revealing the relative roles of different factors governing the mode and tempo of influenza virus evolution and quantify the predictability of virus evolution. This will improve the design of influenza vaccines, enhance prospects for influenza control, and lay new groundwork for exploring virus evolution.
Project acronym QINTERNET
Project Quantum communication networks
Researcher (PI) Stephanie Wehner
Summary My goal is to overcome the two-most pressing theoretical challenges necessary to build large-scale quantum communication networks: routing and designing protocols that use them to solve useful tasks. In two interconnected projects, I will devise entirely new concepts, models and mathematical methods that take into account the intricacies of real world quantum devices that can operate on only very few quantum bits at a time. (1) Security: I will prove the security of quantum cryptographic protocols under realistic conditions, and implement them in collaboration with experimentalists. I will develop a general theory and practical tests for the security of multi-party cryptographic primitives using untrusted quantum devices. This is mathematically challenging due to the possibility of entanglement between the devices. (2) Routing: I will initiate the systematic study of effective routing in a quantum communication network. This is necessary for quantum networks to grow in scale. Quantum entanglement offers very different means of routing messages than is possible in classical networks, and poses genuinely new challenges to computer science. I will design routing protocols in a multi-node quantum network of potentially different physical implementations, i.e., hybrid networks, that will establish a new line of research in my field. Quantum networks are still in their infancy, even though quantum communication offers unparalleled advantages that are provably impossible using classical communication. Building a quantum network is an interdisciplinary effort bringing together computer science, physics, and engineering. I am in a unique position in computer science, since I have recently joined QuTech where I have direct access to small quantum devices - bringing me tantalizingly close to seeing such networks realized. As with early classical networks, it is difficult to predict where our journey will end, but my research will join theory and experiment to move forward.
My goal is to overcome the two-most pressing theoretical challenges necessary to build large-scale quantum communication networks: routing and designing protocols that use them to solve useful tasks. In two interconnected projects, I will devise entirely new concepts, models and mathematical methods that take into account the intricacies of real world quantum devices that can operate on only very few quantum bits at a time. (1) Security: I will prove the security of quantum cryptographic protocols under realistic conditions, and implement them in collaboration with experimentalists. I will develop a general theory and practical tests for the security of multi-party cryptographic primitives using untrusted quantum devices. This is mathematically challenging due to the possibility of entanglement between the devices. (2) Routing: I will initiate the systematic study of effective routing in a quantum communication network. This is necessary for quantum networks to grow in scale. Quantum entanglement offers very different means of routing messages than is possible in classical networks, and poses genuinely new challenges to computer science. I will design routing protocols in a multi-node quantum network of potentially different physical implementations, i.e., hybrid networks, that will establish a new line of research in my field. Quantum networks are still in their infancy, even though quantum communication offers unparalleled advantages that are provably impossible using classical communication. Building a quantum network is an interdisciplinary effort bringing together computer science, physics, and engineering. I am in a unique position in computer science, since I have recently joined QuTech where I have direct access to small quantum devices - bringing me tantalizingly close to seeing such networks realized. As with early classical networks, it is difficult to predict where our journey will end, but my research will join theory and experiment to move forward.
Project acronym RNAREG
Project Single molecule observation and manipulation of gene expression dynamics to dissect mechanisms of cell cycle entry
Researcher (PI) Marvin Tanenbaum
Summary Gene expression is a highly dynamic and inherently variable process. Yet, it needs to be tightly regulated, especially during the cell cycle, when continuous large-scale changes occur to the proteome. Even small deviations in the expression levels of a single protein in individual cells can de-regulate cell cycle entry and promote tumorigenesis. Here, I will develop new technology to study gene expression dynamics in single cells to uncover how active regulation and stochastic variability shape the expression of key cell cycle genes and ensure reliable cell cycle-entry decisions. I recently developed a protein multimerization system, called SunTag, which allows very bright fluorescence imaging, as well as manipulation of transcription. To understand how accurate expression levels of a core set of cell cycle proteins are achieved, I will combine single-cell RNA sequencing with SunTag fluorescence imaging technology to visualize, with single molecule sensitivity, the rates of transcription, translation and mRNA degradation. These analyses will identify the contribution of each type of regulation to accurate gene expression, and will reveal how active regulation ensures correct cell cycle decisions in the presence of stochastic expression variability. Furthermore, I will develop new methodology to specifically perturb the different types of gene expression control during defined cell cycle stages. This will enable an unprecedented ability to interrogate the function of gene expression control for cell cycle entry, and will identify the genes for which tight control of expression is critical for correct cell cycle decisions. Together, this approach will: 1) Uncover how individual regulatory mechanisms (e.g. regulation of transcription, translation or mRNA degradation) contribute to accurate cell cycle entry through gene expression control of key cell cycle proteins 2) Examine how stochastic variability in gene expression influences the decision to enter the cell cycle
Gene expression is a highly dynamic and inherently variable process. Yet, it needs to be tightly regulated, especially during the cell cycle, when continuous large-scale changes occur to the proteome. Even small deviations in the expression levels of a single protein in individual cells can de-regulate cell cycle entry and promote tumorigenesis. Here, I will develop new technology to study gene expression dynamics in single cells to uncover how active regulation and stochastic variability shape the expression of key cell cycle genes and ensure reliable cell cycle-entry decisions. I recently developed a protein multimerization system, called SunTag, which allows very bright fluorescence imaging, as well as manipulation of transcription. To understand how accurate expression levels of a core set of cell cycle proteins are achieved, I will combine single-cell RNA sequencing with SunTag fluorescence imaging technology to visualize, with single molecule sensitivity, the rates of transcription, translation and mRNA degradation. These analyses will identify the contribution of each type of regulation to accurate gene expression, and will reveal how active regulation ensures correct cell cycle decisions in the presence of stochastic expression variability. Furthermore, I will develop new methodology to specifically perturb the different types of gene expression control during defined cell cycle stages. This will enable an unprecedented ability to interrogate the function of gene expression control for cell cycle entry, and will identify the genes for which tight control of expression is critical for correct cell cycle decisions. Together, this approach will: 1) Uncover how individual regulatory mechanisms (e.g. regulation of transcription, translation or mRNA degradation) contribute to accurate cell cycle entry through gene expression control of key cell cycle proteins 2) Examine how stochastic variability in gene expression influences the decision to enter the cell cycle
Project acronym SOFTBREAK
Project From bond breaking to material failure in soft polymer networks
Researcher (PI) jasper Van der gucht
Host Institution (HI) WAGENINGEN UNIVERSITY
Summary The microscopic mechanisms that lead to mechanical failure of soft polymer materials are still poorly understood. The main reason for this is a lack of experimental tools to prepare well-controlled model systems and to observe the failure process in real time at the microscopic scale. Here, I propose to fill this gap by taking a multidisciplinary approach that combines innovative chemical tools with state-of-the art physical experiments and modelling. Previous work in my group has led to the development of polymer networks with extremely well-controlled architecture and bond strength, and of various tools to study their structure and mechanics. Here, I will take advantage of this expertise to systematically unravel the microscopic physics of failure of polymer networks. To visualize how the failure process proceeds, we will make use of recently developed mechanosensors, molecules that change colour in response to a force or that emit light when they break. These chemical tools will allow us to map in real time the spatial distribution of both strains and bond rupture events. Together with computer simulations carried out in parallel, this will give us unprecedented insight in the microscopic processes that occur during failure of the material, from the very first bonds that rupture, to the gradual accumulation of damage, all the way to macroscopic failure. We will use this to address the following unresolved questions about failure of polymer networks: 1. What is the microscopic mechanism that leads to delayed failure of polymer networks at subcritical loads? 2. How does the initiation of failure depend on the material's heterogeneity? 3. How does failure occur in a network with transient (viscoelastic) bonds? The project will not only provide detailed insight in the physics of failure of polymer networks, but it will also shed light on fracture physics in general. Finally, it will help material scientists to design new materials with superior properties.
The microscopic mechanisms that lead to mechanical failure of soft polymer materials are still poorly understood. The main reason for this is a lack of experimental tools to prepare well-controlled model systems and to observe the failure process in real time at the microscopic scale. Here, I propose to fill this gap by taking a multidisciplinary approach that combines innovative chemical tools with state-of-the art physical experiments and modelling. Previous work in my group has led to the development of polymer networks with extremely well-controlled architecture and bond strength, and of various tools to study their structure and mechanics. Here, I will take advantage of this expertise to systematically unravel the microscopic physics of failure of polymer networks. To visualize how the failure process proceeds, we will make use of recently developed mechanosensors, molecules that change colour in response to a force or that emit light when they break. These chemical tools will allow us to map in real time the spatial distribution of both strains and bond rupture events. Together with computer simulations carried out in parallel, this will give us unprecedented insight in the microscopic processes that occur during failure of the material, from the very first bonds that rupture, to the gradual accumulation of damage, all the way to macroscopic failure. We will use this to address the following unresolved questions about failure of polymer networks: 1. What is the microscopic mechanism that leads to delayed failure of polymer networks at subcritical loads? 2. How does the initiation of failure depend on the material's heterogeneity? 3. How does failure occur in a network with transient (viscoelastic) bonds? The project will not only provide detailed insight in the physics of failure of polymer networks, but it will also shed light on fracture physics in general. Finally, it will help material scientists to design new materials with superior properties.
Project acronym Sphingolead
Project Development of a potent dual GCS/GBA2 inhibitor as a best in class Gaucher therapeutic
Researcher (PI) Hermen Steven OVERKLEEFT
Summary Gaucher disease (GD) is an autosomal recessive disorder caused by deficient activity of acid glucosylceramidase (GBA1). Most patients feature a non-neuronopathic (type 1) course of disease and are treated by either enzyme replacement therapy (ERT – administration of recombinant GBA1) or substrate reduction therapy (SRT – treatment with the iminosugar, Zavesca or the ceramide mimic, Eliglustat – inhibitors of glucosylceramide synthase (GCS)). These therapeutic agents do not prevent neurological symptoms in patients suffering from neuronopathic Gaucher forms (types 2/3) and there is thus an unmet medical need for these patients. Potent GCS inhibitors reduce glucosylceramide (GlcCer), the substrate of GBA and the storage material in Gaucher, and also higher glycosphingolipids including gangliosides and globosides, the causative storage materials in Tay-Sachs disease, GM1 gangliosidosis and Fabry disease. We have found a highly attractive lead, BiPheDNM 7 (Figure C below), which we plan to further develop towards a phase I/II clinical candidate. This proof of concept project will result in a packet comprising this lead molecule, accompanied by all the relevant data and tools to start phase I/II clinical development together with a pharmaceutical partner.
Gaucher disease (GD) is an autosomal recessive disorder caused by deficient activity of acid glucosylceramidase (GBA1). Most patients feature a non-neuronopathic (type 1) course of disease and are treated by either enzyme replacement therapy (ERT – administration of recombinant GBA1) or substrate reduction therapy (SRT – treatment with the iminosugar, Zavesca or the ceramide mimic, Eliglustat – inhibitors of glucosylceramide synthase (GCS)). These therapeutic agents do not prevent neurological symptoms in patients suffering from neuronopathic Gaucher forms (types 2/3) and there is thus an unmet medical need for these patients. Potent GCS inhibitors reduce glucosylceramide (GlcCer), the substrate of GBA and the storage material in Gaucher, and also higher glycosphingolipids including gangliosides and globosides, the causative storage materials in Tay-Sachs disease, GM1 gangliosidosis and Fabry disease. We have found a highly attractive lead, BiPheDNM 7 (Figure C below), which we plan to further develop towards a phase I/II clinical candidate. This proof of concept project will result in a packet comprising this lead molecule, accompanied by all the relevant data and tools to start phase I/II clinical development together with a pharmaceutical partner.
Project acronym SPINCAD
Project Spin correlations by atomic design
Researcher (PI) Alexander F. Otte
Summary Unexpected physical phenomena occurring in materials often result from the complex interplay between spins on the atomic scale. The field of quantum magnetism aims to capture the rich emergent physics that arises when multiple spins interact. While experimental techniques are available to probe the global quantum magnetic properties of materials, they fail to reveal the role of local features such as individual defects or phase boundaries. I propose to use custom-designed spin lattices created by low-temperature scanning tunnelling microscopy (STM) to probe spin correlations locally at the atomic scale, providing the ultimate tool to trace particle-like excitations (spinons) as they propagate. Since these excitations exist on timescales that are much too short to be accessed directly in real time, I will introduce 'spinon traps': atom-built detector bits that record the presence of a spinon and store this information immediately on the atomic scale, to be read out at a later time. This approach opens the possibility to study emergent material properties as a function of system size and test theories for quantum magnetism that were previously experimentally inaccessible. Based on preliminary experiments in my group that indicate the feasibility of SPINCAD, I will realize and demonstrate the spinon trapping technique by employing it to the study of attractive interactions between spinons, which may be forged independently through atom manipulation. In addition, I will observe the motion of spinons through two-dimensional frustrated spin lattices. Being the first technique to perform local injection and readout of excitations in custom-designed spin structures, SPINCAD will generate a long-lasting synergy between the fields of theoretical quantum magnetism and experimental surface science.
Unexpected physical phenomena occurring in materials often result from the complex interplay between spins on the atomic scale. The field of quantum magnetism aims to capture the rich emergent physics that arises when multiple spins interact. While experimental techniques are available to probe the global quantum magnetic properties of materials, they fail to reveal the role of local features such as individual defects or phase boundaries. I propose to use custom-designed spin lattices created by low-temperature scanning tunnelling microscopy (STM) to probe spin correlations locally at the atomic scale, providing the ultimate tool to trace particle-like excitations (spinons) as they propagate. Since these excitations exist on timescales that are much too short to be accessed directly in real time, I will introduce 'spinon traps': atom-built detector bits that record the presence of a spinon and store this information immediately on the atomic scale, to be read out at a later time. This approach opens the possibility to study emergent material properties as a function of system size and test theories for quantum magnetism that were previously experimentally inaccessible. Based on preliminary experiments in my group that indicate the feasibility of SPINCAD, I will realize and demonstrate the spinon trapping technique by employing it to the study of attractive interactions between spinons, which may be forged independently through atom manipulation. In addition, I will observe the motion of spinons through two-dimensional frustrated spin lattices. Being the first technique to perform local injection and readout of excitations in custom-designed spin structures, SPINCAD will generate a long-lasting synergy between the fields of theoretical quantum magnetism and experimental surface science.
Project acronym STAND4HERITAGE
Project New STANDards for seismic assessment of built cultural HERITAGE
Researcher (PI) Paulo B. LOURENCO
Host Institution (HI) UNIVERSIDADE DO MINHO
Summary STAND4HERITAGE ambitiously engages in introducing new standards for safeguarding built cultural heritage for the next generations, which is a major societal demand. Due to its large diversity, the accurate description of the structural behaviour of heritage buildings is still an open issue, particularly when subjected to earthquake ground motions. Among the most frequently observed seismic damage mechanisms in these buildings, the out-of-plane of masonry walls is acknowledged as the main cause for building loss and injuries to people. There are many unresolved challenges to effectively assess the out-of-plane seismic behaviour of masonry structures. First, it is necessary to understand less known phenomena in masonry dynamics, which largely influence the out-of-plane behaviour and capacity of heritage buildings. A recent blind exercise to predict the capacity of a benchmark masonry structure to resist a dynamic excitation demonstrated that, although advanced simulation tools are available, leading international researchers are still unable to consistently provide a collapse estimate. STAND4HERITAGE will address the aspects for successful development of approaches for seismic response prediction of masonry structures, integrating the necessary stages for out-of-plane assessment. It will generate novel: integrated stochastic-based models to consider the seismic signal in the dynamic response and capacity; datasets of the dynamic response evaluated after an extensive shake table testing program; numerical approaches for simulation of the out-of-plane seismic behaviour; an integrated analytical approach for out-of-plane seismic assessment of heritage buildings. STAND4HERITAGE objectives are in line with the UN 2030 agenda for sustainable cities and communities. The project will be founded on the experience of the PI in the topic, and on the interdisciplinary expertise of his team in facing the challenges to provide optimal intervention solutions for heritage buildings.
STAND4HERITAGE ambitiously engages in introducing new standards for safeguarding built cultural heritage for the next generations, which is a major societal demand. Due to its large diversity, the accurate description of the structural behaviour of heritage buildings is still an open issue, particularly when subjected to earthquake ground motions. Among the most frequently observed seismic damage mechanisms in these buildings, the out-of-plane of masonry walls is acknowledged as the main cause for building loss and injuries to people. There are many unresolved challenges to effectively assess the out-of-plane seismic behaviour of masonry structures. First, it is necessary to understand less known phenomena in masonry dynamics, which largely influence the out-of-plane behaviour and capacity of heritage buildings. A recent blind exercise to predict the capacity of a benchmark masonry structure to resist a dynamic excitation demonstrated that, although advanced simulation tools are available, leading international researchers are still unable to consistently provide a collapse estimate. STAND4HERITAGE will address the aspects for successful development of approaches for seismic response prediction of masonry structures, integrating the necessary stages for out-of-plane assessment. It will generate novel: integrated stochastic-based models to consider the seismic signal in the dynamic response and capacity; datasets of the dynamic response evaluated after an extensive shake table testing program; numerical approaches for simulation of the out-of-plane seismic behaviour; an integrated analytical approach for out-of-plane seismic assessment of heritage buildings. STAND4HERITAGE objectives are in line with the UN 2030 agenda for sustainable cities and communities. The project will be founded on the experience of the PI in the topic, and on the interdisciplinary expertise of his team in facing the challenges to provide optimal intervention solutions for heritage buildings.
Project acronym TiMaScan
Project Recirculated tissue macrophages (TiMa) in blood: Novel approach to early diagnosis and treatment monitoring in oncology
Researcher (PI) Jacques J.M. VAN DONGEN
Host Institution (HI) ACADEMISCH ZIEKENHUIS LEIDEN
Summary In the ageing European population, cancer has become the most common cause of death. Consequently, screening programs aim at early detection of cancer, while scanning/imaging technologies, serum assays and regular biopsies aim at monitoring of treatment effectiveness to improve cure rates and increase quality-of-life, thereby also attempting to reduce health care costs. However, in many cases the screening and monitoring methods do not provide sufficient sensitivity and specificity. Consequently novel diagnostic techniques are required. Completely Novel Concept: Sensitive intra-tissue total body scanning is continuously performed by our immune cells, particularly by monocytes and macrophages. Tissue macrophages (TiMas) continuously phagocytize and digest apoptotic cells and tissue debris. In cancer, many more TiMas are present to keep the involved tissue debris-free. When TiMas have fulfilled their local tissue-cleaning task, they can migrate via lymph vessels to lymph nodes and potentially recirculate to the blood stream, where they can be detected by flow cytometry and evaluated for the contents of their phagolysosomes. With State-of-the-Art technologies, this high-risk project aims to unravel phagocytosis of cancer cells, their digestion into tissue-specific and/or cancer-specific protein fragments, the migration/recirculation of TiMas to blood, and the detection of intra-phagosomal protein fragments in blood TiMas by antibodies. Building on this information, flowcytometric scanning of blood TiMas (TiMaScan) will be developed into a novel tool for early diagnosis and treatment monitoring in oncology, focusing on colon, lung, breast and prostate cancer. TiMaScan diagnostics will be minimally-invasive (~1ml of blood), rapid, accurate, broadly available and cost-effective, only requiring a flowcytometer. The TiMaScan Concept might also be applicable for early diagnosis and disease monitoring in other medical fields, such as neurodegenerative and infectious diseases.
In the ageing European population, cancer has become the most common cause of death. Consequently, screening programs aim at early detection of cancer, while scanning/imaging technologies, serum assays and regular biopsies aim at monitoring of treatment effectiveness to improve cure rates and increase quality-of-life, thereby also attempting to reduce health care costs. However, in many cases the screening and monitoring methods do not provide sufficient sensitivity and specificity. Consequently novel diagnostic techniques are required. Completely Novel Concept: Sensitive intra-tissue total body scanning is continuously performed by our immune cells, particularly by monocytes and macrophages. Tissue macrophages (TiMas) continuously phagocytize and digest apoptotic cells and tissue debris. In cancer, many more TiMas are present to keep the involved tissue debris-free. When TiMas have fulfilled their local tissue-cleaning task, they can migrate via lymph vessels to lymph nodes and potentially recirculate to the blood stream, where they can be detected by flow cytometry and evaluated for the contents of their phagolysosomes. With State-of-the-Art technologies, this high-risk project aims to unravel phagocytosis of cancer cells, their digestion into tissue-specific and/or cancer-specific protein fragments, the migration/recirculation of TiMas to blood, and the detection of intra-phagosomal protein fragments in blood TiMas by antibodies. Building on this information, flowcytometric scanning of blood TiMas (TiMaScan) will be developed into a novel tool for early diagnosis and treatment monitoring in oncology, focusing on colon, lung, breast and prostate cancer. TiMaScan diagnostics will be minimally-invasive (~1ml of blood), rapid, accurate, broadly available and cost-effective, only requiring a flowcytometer. The TiMaScan Concept might also be applicable for early diagnosis and disease monitoring in other medical fields, such as neurodegenerative and infectious diseases.
Project acronym TOPSPIN
Project Topotronic multi-dimensional spin Hall nano-oscillator networks
Researcher (PI) Johan Åkerman
Host Institution (HI) GOETEBORGS UNIVERSITET
Summary TOPSPIN will focus on spin Hall nano-oscillators (SHNOs), which are nano-sized, ultra-tunable, and CMOS compatible spin wave based microwave oscillators. TOPSPIN will push the boundaries of SHNO lithography, frequency, speed, and power consumption by combining topological insulators, having record high spin Hall efficiencies, with materials having ultra-high spin wave frequencies. TOPSPIN will reduce the required current densities 1-2 orders of magnitude compared to state-of-the-art, making SHNO operating currents approach 1 uA, and increase the SHNO operating frequencies an order of magnitude to as high as 300 GHz. TOPSPIN will use mutually synchronized SHNOs to achieve orders of magnitude higher signal coherence and achieve novel functionality such as pattern matching and neuromorphic computing. TOPSPIN will demonstrate mutual synchronization of up to 1,000 SHNOs in chains, and as many as 1,000,000 SHNOs in very large-scale two-dimensional arrays. Using dipolar coupling between SHNOs fabricated on top of each other, three-dimensional mutual synchronization will also be demonstrated. As the signal coherence increases linearly with the number of mutually synchronized SHNOs the oscillator quality factor will improve by many orders of magnitude. TOPSPIN will also develop such arrays using magnetic tunnel junction stacks thus combining ultra-high coherence with the highest possible microwave output power. TOPSPIN will demonstrate ultrafast pattern matching and neuromorphic computing using its SHNO networks. It will functionalize SHNOs to exhibit ultra-fast individual voltage controlled tuning and non-volatile tuning of both the SHNO frequency and the inter-SHNO coupling. TOPSPIN will characterize its SHNOs using novel methods and techniques such as multichannel electrical measurements, time- and phase-resolved Brillouin Light Scattering microscopy, time-resolved Scanning Transmission X-ray Microscopy, and ultrafast pump-probe Transmission Electron Microscopy.
TOPSPIN will focus on spin Hall nano-oscillators (SHNOs), which are nano-sized, ultra-tunable, and CMOS compatible spin wave based microwave oscillators. TOPSPIN will push the boundaries of SHNO lithography, frequency, speed, and power consumption by combining topological insulators, having record high spin Hall efficiencies, with materials having ultra-high spin wave frequencies. TOPSPIN will reduce the required current densities 1-2 orders of magnitude compared to state-of-the-art, making SHNO operating currents approach 1 uA, and increase the SHNO operating frequencies an order of magnitude to as high as 300 GHz. TOPSPIN will use mutually synchronized SHNOs to achieve orders of magnitude higher signal coherence and achieve novel functionality such as pattern matching and neuromorphic computing. TOPSPIN will demonstrate mutual synchronization of up to 1,000 SHNOs in chains, and as many as 1,000,000 SHNOs in very large-scale two-dimensional arrays. Using dipolar coupling between SHNOs fabricated on top of each other, three-dimensional mutual synchronization will also be demonstrated. As the signal coherence increases linearly with the number of mutually synchronized SHNOs the oscillator quality factor will improve by many orders of magnitude. TOPSPIN will also develop such arrays using magnetic tunnel junction stacks thus combining ultra-high coherence with the highest possible microwave output power. TOPSPIN will demonstrate ultrafast pattern matching and neuromorphic computing using its SHNO networks. It will functionalize SHNOs to exhibit ultra-fast individual voltage controlled tuning and non-volatile tuning of both the SHNO frequency and the inter-SHNO coupling. TOPSPIN will characterize its SHNOs using novel methods and techniques such as multichannel electrical measurements, time- and phase-resolved Brillouin Light Scattering microscopy, time-resolved Scanning Transmission X-ray Microscopy, and ultrafast pump-probe Transmission Electron Microscopy.
Project acronym VOLARE
Project Scentsitive nature: Green leaf volatile perception in plants and insects
Researcher (PI) Silke ALLMANN
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Summary Plant leaves can emit large amounts of volatiles into the air. When attacked by insects, the composition of these blends changes markedly. It is well known that these changes affect not only the behavior of insects interacting with the plant but also the metabolism of the plant itself as well as its nearby competitors. However, how plants perceive these volatiles and generate a functional response is not known. My research activities have been dedicated to a group of plant volatiles emitted the earliest upon herbivory, the so-called green leaf volatiles (GLVs). I discovered a class of enzymes, present in plants and insects, that profoundly affect ecological interactions by converting the highly abundant GLV Z-3-hexenal into E-2-hexenal (Science 2010, eLife 2013, Frontiers in Plant Science 2017). These two compounds, as well as their derivatives, among which Z-3- and E-2-hexenyl acetate, have distinct effects on the behavior of herbivorous and predacious insects as well as on the metabolism of plants. Here I propose to take my program to the next level by elucidating how plants and insects perceive E-2-hexenal and hexenyl acetates. First I will use a classical mutagenesis screen and a cutting-edge technique called chemical yeast 3-hybrid (Y3H) to identify plant proteins involved in signal processing and especially perception of volatiles. With the newly identified genes in hand I will create non-responsive mutant plants to investigate the role of these key volatiles in the plant's self-recognition and its interactions with herbivorous insects and pathogens. Simultaneously, I will use Y3H to also identify insect proteins that directly interact with either E-2-hexenal or E-2-hexenyl acetate and I will create non-responsive insects using CRISPR-Cas9 and assess how this affects their behavior. This interdisciplinary research project will uncover the perception mechanism of key plant volatile signals and the roles these play in the (eco)physiology of plants and insects.
Plant leaves can emit large amounts of volatiles into the air. When attacked by insects, the composition of these blends changes markedly. It is well known that these changes affect not only the behavior of insects interacting with the plant but also the metabolism of the plant itself as well as its nearby competitors. However, how plants perceive these volatiles and generate a functional response is not known. My research activities have been dedicated to a group of plant volatiles emitted the earliest upon herbivory, the so-called green leaf volatiles (GLVs). I discovered a class of enzymes, present in plants and insects, that profoundly affect ecological interactions by converting the highly abundant GLV Z-3-hexenal into E-2-hexenal (Science 2010, eLife 2013, Frontiers in Plant Science 2017). These two compounds, as well as their derivatives, among which Z-3- and E-2-hexenyl acetate, have distinct effects on the behavior of herbivorous and predacious insects as well as on the metabolism of plants. Here I propose to take my program to the next level by elucidating how plants and insects perceive E-2-hexenal and hexenyl acetates. First I will use a classical mutagenesis screen and a cutting-edge technique called chemical yeast 3-hybrid (Y3H) to identify plant proteins involved in signal processing and especially perception of volatiles. With the newly identified genes in hand I will create non-responsive mutant plants to investigate the role of these key volatiles in the plant's self-recognition and its interactions with herbivorous insects and pathogens. Simultaneously, I will use Y3H to also identify insect proteins that directly interact with either E-2-hexenal or E-2-hexenyl acetate and I will create non-responsive insects using CRISPR-Cas9 and assess how this affects their behavior. This interdisciplinary research project will uncover the perception mechanism of key plant volatile signals and the roles these play in the (eco)physiology of plants and insects.
Project acronym WEIRD WITNESSES
Project Beyond WEIRD Witnesses: Eyewitness Memory in Cross-Cultural Contexts
Researcher (PI) Annelies VREDEVELDT
Summary Our increasingly international society demands that eyewitnesses of serious crimes regularly provide testimony in cross-cultural settings, such as international criminal tribunals. This poses significant challenges for investigators and legal decision-makers. Errors in fact-finding may result in wrongful convictions and unjust acquittals. Yet, eyewitness memory research has predominantly focused on Western, Educated, Industrialized, Rich, and Democratic (WEIRD) witnesses. The project addresses two key objectives: (1) develop culturally modulated theory of eyewitness memory and (2) design and test evidence-based interview guidelines. In Subproject 1, I will examine what happens when police investigators interview eyewitnesses from a different cultural background. It will involve the systematic coding of culture-dependent variables in video-recorded police interviews with witnesses of serious crimes in South Africa, a society with many different subcultures. In Subproject 2, I will analyse the frequency, nature and legal consequences of culture-dependent variables in international criminal cases. It will involve an empirical document analysis of eyewitness evidence provided at the International Criminal Tribunal for Rwanda, and interviews with international legal scholars and practitioners. In Subproject 3, I will assess how different cultural groups encode, store and retrieve memories, and how memory reports are evaluated in immigration contexts. It will involve a series of experiments in which the objective and perceived characteristics of statements provided by asylum seekers originating from Sub-Saharan Africa are compared to a matched Western control group. The project integrates analyses of video, document and experimental data to provide insight into culture-dependent variables in eyewitness memory. The new theory will enable researchers and practitioners to steer away from the present WEIRD bias in legal psychology.
Our increasingly international society demands that eyewitnesses of serious crimes regularly provide testimony in cross-cultural settings, such as international criminal tribunals. This poses significant challenges for investigators and legal decision-makers. Errors in fact-finding may result in wrongful convictions and unjust acquittals. Yet, eyewitness memory research has predominantly focused on Western, Educated, Industrialized, Rich, and Democratic (WEIRD) witnesses. The project addresses two key objectives: (1) develop culturally modulated theory of eyewitness memory and (2) design and test evidence-based interview guidelines. In Subproject 1, I will examine what happens when police investigators interview eyewitnesses from a different cultural background. It will involve the systematic coding of culture-dependent variables in video-recorded police interviews with witnesses of serious crimes in South Africa, a society with many different subcultures. In Subproject 2, I will analyse the frequency, nature and legal consequences of culture-dependent variables in international criminal cases. It will involve an empirical document analysis of eyewitness evidence provided at the International Criminal Tribunal for Rwanda, and interviews with international legal scholars and practitioners. In Subproject 3, I will assess how different cultural groups encode, store and retrieve memories, and how memory reports are evaluated in immigration contexts. It will involve a series of experiments in which the objective and perceived characteristics of statements provided by asylum seekers originating from Sub-Saharan Africa are compared to a matched Western control group. The project integrates analyses of video, document and experimental data to provide insight into culture-dependent variables in eyewitness memory. The new theory will enable researchers and practitioners to steer away from the present WEIRD bias in legal psychology.

redpajama_set_name: RedPajamaCommonCrawl