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Project acronym 2MoveMate4Melanoma
Project A treatment for BRAF inhibitor resistant melanoma
Researcher (PI) René BERNARDS
Host Institution (HI) STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Call Details Proof of Concept (PoC), PC1, ERC-2015-PoC
Summary Some 50% of human melanoma tumors have activating mutations in the BRAF gene. BRAF inhibitor drugs given either alone or in combination with MEK inhibitors have improved progression-free and overall survival in patients with BRAF mutant metastatic melanoma. However, drug resistance invariably limits the duration of clinical benefit of such treatments and is almost always associated with re-activation of signaling through the MAP kinase pathway in the presence of drug due to secondary mutations in the pathway. This highlights the urgent need to develop strategies to treat melanomas that have developed resistance to BRAF and/or MEK inhibitors. As part of an ERC advanced grant, my laboratory has shown that BRAF inhibitor withdrawal in melanomas that have developed resistance to BRAF inhibitors leads to a transient growth arrest that is the consequence of temporary hyperactivation of signaling through the MAP kinase pathway, explaining the so called "drug holiday effect". We have also found that subsequent treatment of such BRAF inhibitor resistant melanomas with Histone DeACetylase inhibitor drugs (HDACi) leads to persistent hyperactivation of MAP kinase signaling, causing both chronic proliferation arrest and cell death, ultimately leading to complete regression of BRAF-inhibitor resistant melanomas in mice. We propose here to perform a proof of concept study in at least 10 evaluable melanoma patients that, after proven initial tumor response, have developed resistance to BRAF inhibitors to validate that subsequent treatment of such patients with an HDACi drug will result in durable responses. Translational studies on tumor biopsies taken before, during and after HDACi treatment will be performed to study the cellular effects of HDACi treatment. Our goal is to provide initial proof of concept in patients for use of this sequential BRAFi-HDACi therapy as the treatment of choice for the some 40,000 BRAF mutant melanomas that are diagnosed in the EU annually.
Some 50% of human melanoma tumors have activating mutations in the BRAF gene. BRAF inhibitor drugs given either alone or in combination with MEK inhibitors have improved progression-free and overall survival in patients with BRAF mutant metastatic melanoma. However, drug resistance invariably limits the duration of clinical benefit of such treatments and is almost always associated with re-activation of signaling through the MAP kinase pathway in the presence of drug due to secondary mutations in the pathway. This highlights the urgent need to develop strategies to treat melanomas that have developed resistance to BRAF and/or MEK inhibitors. As part of an ERC advanced grant, my laboratory has shown that BRAF inhibitor withdrawal in melanomas that have developed resistance to BRAF inhibitors leads to a transient growth arrest that is the consequence of temporary hyperactivation of signaling through the MAP kinase pathway, explaining the so called "drug holiday effect". We have also found that subsequent treatment of such BRAF inhibitor resistant melanomas with Histone DeACetylase inhibitor drugs (HDACi) leads to persistent hyperactivation of MAP kinase signaling, causing both chronic proliferation arrest and cell death, ultimately leading to complete regression of BRAF-inhibitor resistant melanomas in mice. We propose here to perform a proof of concept study in at least 10 evaluable melanoma patients that, after proven initial tumor response, have developed resistance to BRAF inhibitors to validate that subsequent treatment of such patients with an HDACi drug will result in durable responses. Translational studies on tumor biopsies taken before, during and after HDACi treatment will be performed to study the cellular effects of HDACi treatment. Our goal is to provide initial proof of concept in patients for use of this sequential BRAFi-HDACi therapy as the treatment of choice for the some 40,000 BRAF mutant melanomas that are diagnosed in the EU annually.
Project acronym AD-HOC
Project Artificial Dielectrics for High-frequency On-Chip antennas
Researcher (PI) Andrea Neto
Host Institution (HI) TECHNISCHE UNIVERSITEIT DELFT
Summary High-speed wireless communication and automotive radars are two applications with huge social and market potentials that can be revolutionized by the development of high-frequency (sub-terahertz) technology. Despite the recent advances in low-cost integrated circuits, the poor performance of on-chip antennas is nowadays the major bottleneck in converting the electrical signals (on-chip) into radiated ones (off-chip). For decades the problem of "surface waves" has prevented the efficient use of radiators on chip. The AD-HOC project aims at exploiting the breakthrough technology of Artificial Dielectric (AD) layers as the solution to the surface-wave problem of High-frequency On-Chip antennas. The processes necessary to micro-fabricate AD layers will be optimized with the goal of achieving reliable manufacturing, while offering design flexibility at low costs. This will allow the wide exploitation of the AD layers, as they can be used by industrial technology providers as add-on components to at least double the efficiency of their integrated circuit front ends. By overcoming the fundamental limitation of integrated antennas, AD layers have high potential to become a "standard" component in all future car-safety and wireless-communication devices. The AD-HOC project will bring this innovative technology to a pre-demonstration stage to strengthen commercialization and scaling-up opportunities.
High-speed wireless communication and automotive radars are two applications with huge social and market potentials that can be revolutionized by the development of high-frequency (sub-terahertz) technology. Despite the recent advances in low-cost integrated circuits, the poor performance of on-chip antennas is nowadays the major bottleneck in converting the electrical signals (on-chip) into radiated ones (off-chip). For decades the problem of "surface waves" has prevented the efficient use of radiators on chip. The AD-HOC project aims at exploiting the breakthrough technology of Artificial Dielectric (AD) layers as the solution to the surface-wave problem of High-frequency On-Chip antennas. The processes necessary to micro-fabricate AD layers will be optimized with the goal of achieving reliable manufacturing, while offering design flexibility at low costs. This will allow the wide exploitation of the AD layers, as they can be used by industrial technology providers as add-on components to at least double the efficiency of their integrated circuit front ends. By overcoming the fundamental limitation of integrated antennas, AD layers have high potential to become a "standard" component in all future car-safety and wireless-communication devices. The AD-HOC project will bring this innovative technology to a pre-demonstration stage to strengthen commercialization and scaling-up opportunities.
Project acronym AFFORDS-HIGHER
Project Skilled Intentionality for 'Higher' Embodied Cognition: Joining forces with a field of affordances in flux
Researcher (PI) Dirk Willem Rietveld
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Summary In many situations experts act adequately, yet without deliberation. Architects e.g, immediately sense opportunities offered by the site of a new project. One could label these manifestations of expert intuition as 'higher-level' cognition, but still these experts act unreflectively. The aim of my project is to develop the Skilled Intentionality Framework (SIF), a new conceptual framework for the field of embodied/enactive cognitive science (Chemero, 2009; Thompson, 2007). I argue that affordances - possibilities for action provided by our surroundings - are highly significant in cases of unreflective and reflective 'higher' cognition. Skilled Intentionality is skilled coordination with multiple affordances simultaneously. The two central ideas behind this proposal are (a) that episodes of skilled 'higher' cognition can be understood as responsiveness to affordances for 'higher' cognition and (b) that our surroundings are highly resourceful and contribute to skillful action and cognition in a far more fundamental way than is generally acknowledged. I use embedded philosophical research in a particular practice of architecture to shed new light on the ways in which affordances for 'higher' cognition support creative imagination, anticipation, explicit planning and self-reflection. The Skilled Intentionality Framework is groundbreaking in relating findings established at several complementary levels of analysis: philosophy/phenomenology, ecological psychology, affective science and neurodynamics. Empirical findings thought to be exclusively valid for everyday unreflective action can now be used to explain skilled 'higher' cognition as well. Moreover, SIF brings both the context and the social back into cognitive science. I will show SIF's relevance for Friston's work on the anticipating brain, and apply it in the domain of architecture and public health. SIF will radically widen the scope of the increasingly influential field of embodied cognitive science.
In many situations experts act adequately, yet without deliberation. Architects e.g, immediately sense opportunities offered by the site of a new project. One could label these manifestations of expert intuition as 'higher-level' cognition, but still these experts act unreflectively. The aim of my project is to develop the Skilled Intentionality Framework (SIF), a new conceptual framework for the field of embodied/enactive cognitive science (Chemero, 2009; Thompson, 2007). I argue that affordances - possibilities for action provided by our surroundings - are highly significant in cases of unreflective and reflective 'higher' cognition. Skilled Intentionality is skilled coordination with multiple affordances simultaneously. The two central ideas behind this proposal are (a) that episodes of skilled 'higher' cognition can be understood as responsiveness to affordances for 'higher' cognition and (b) that our surroundings are highly resourceful and contribute to skillful action and cognition in a far more fundamental way than is generally acknowledged. I use embedded philosophical research in a particular practice of architecture to shed new light on the ways in which affordances for 'higher' cognition support creative imagination, anticipation, explicit planning and self-reflection. The Skilled Intentionality Framework is groundbreaking in relating findings established at several complementary levels of analysis: philosophy/phenomenology, ecological psychology, affective science and neurodynamics. Empirical findings thought to be exclusively valid for everyday unreflective action can now be used to explain skilled 'higher' cognition as well. Moreover, SIF brings both the context and the social back into cognitive science. I will show SIF's relevance for Friston's work on the anticipating brain, and apply it in the domain of architecture and public health. SIF will radically widen the scope of the increasingly influential field of embodied cognitive science.
Project acronym AlterMateria
Project Designer Quantum Materials Out of Equilibrium
Researcher (PI) Andrea Caviglia
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 APOLOGY
Project Political Apologies across Cultures
Researcher (PI) Juliëtte Schaafsma
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT BRABANT
Summary In the past decades, there has been a considerable rise in the number of apologies offered by states for injustices and human rights violations. Among transitional justice scholars, there is significant debate about how useful such apologies are. Whereas some have applauded these gestures as an important step in peacemaking processes, others have argued that they may not fit in all cultures and may even be a risky tool for peacemaking. Unfortunately, theorizing and research in the field of transitional justice is still in its infancy and has not systematically addressed questions of cross-cultural variability yet. So, at present, we do not know whether political apologies are a universally viable way to restore justice and harmony. My project addresses this challenge. Using an innovative, interdisciplinary, and multi-method approach with in-depth interviews, (experimental) surveys, and content analyses of apologies, I analyze whether there are universals in how political apologies are valued, expressed, and interpreted or whether this varies as a function of cross-cultural differences in key values (collectivism and individualism) and norms (face and honor). Based on these findings, I build a theoretical framework that will fundamentally advance our understanding of the potential value and role of apologies in transitional justice processes. This project breaks new ground because it is the first to take the difficult step to collect cross-cultural data to examine whether key assumptions regarding political apologies hold across cultures. It is also the first in this area to use a multi-method approach, which makes it possible to take into account the complex reality of political apologies. Combining insights from transitional justice, cross-cultural psychology and anthropology, this project places theorizing on transitional justice on a much firmer footing and paves the way to more cross-culturally valid models to restore justice and promote reconciliation.
In the past decades, there has been a considerable rise in the number of apologies offered by states for injustices and human rights violations. Among transitional justice scholars, there is significant debate about how useful such apologies are. Whereas some have applauded these gestures as an important step in peacemaking processes, others have argued that they may not fit in all cultures and may even be a risky tool for peacemaking. Unfortunately, theorizing and research in the field of transitional justice is still in its infancy and has not systematically addressed questions of cross-cultural variability yet. So, at present, we do not know whether political apologies are a universally viable way to restore justice and harmony. My project addresses this challenge. Using an innovative, interdisciplinary, and multi-method approach with in-depth interviews, (experimental) surveys, and content analyses of apologies, I analyze whether there are universals in how political apologies are valued, expressed, and interpreted or whether this varies as a function of cross-cultural differences in key values (collectivism and individualism) and norms (face and honor). Based on these findings, I build a theoretical framework that will fundamentally advance our understanding of the potential value and role of apologies in transitional justice processes. This project breaks new ground because it is the first to take the difficult step to collect cross-cultural data to examine whether key assumptions regarding political apologies hold across cultures. It is also the first in this area to use a multi-method approach, which makes it possible to take into account the complex reality of political apologies. Combining insights from transitional justice, cross-cultural psychology and anthropology, this project places theorizing on transitional justice on a much firmer footing and paves the way to more cross-culturally valid models to restore justice and promote reconciliation.
Project acronym ART
Project Development of an Anger Regulation Tool for Hand-Held Devices
Researcher (PI) Sander Leon KOOLE
Host Institution (HI) STICHTING VU
Summary Our research team at the Amsterdam Emotion regulation Lab (emotionregulationlab.com) has recently established that avoidance movements can lower anger and aggression among individuals with chronic anger management problems. Building on and extending these findings, we propose to develop, test, and market an interactive application that runs on mobile devices such as smart phones and tablets. This Anger Reduction Tool (ART) will consist of a 'serious game' that trains people to make avoidance movements to angry faces. The ART will be commercialized through a freemium model, such that it will be made freely available, while users can purchase additional functionalities using bio- and neuro-feedback modules. The ART will be marketed to mental health professionals with clients who are not willing or able to respond to traditional cognitive interventions, such as high school children or lower-educated violent offenders. By harnessing the possibilities of smart technology, the ART allows people to become co-managers of their (mental) health and well-being.
Our research team at the Amsterdam Emotion regulation Lab (emotionregulationlab.com) has recently established that avoidance movements can lower anger and aggression among individuals with chronic anger management problems. Building on and extending these findings, we propose to develop, test, and market an interactive application that runs on mobile devices such as smart phones and tablets. This Anger Reduction Tool (ART) will consist of a 'serious game' that trains people to make avoidance movements to angry faces. The ART will be commercialized through a freemium model, such that it will be made freely available, while users can purchase additional functionalities using bio- and neuro-feedback modules. The ART will be marketed to mental health professionals with clients who are not willing or able to respond to traditional cognitive interventions, such as high school children or lower-educated violent offenders. By harnessing the possibilities of smart technology, the ART allows people to become co-managers of their (mental) health and well-being.
Project acronym ARTISYM
Project Artificial endosymbiosis
Researcher (PI) Jan Van hest
Host Institution (HI) TECHNISCHE UNIVERSITEIT EINDHOVEN
Summary Living organisms have acquired new functionalities by uptake and integration of species to create symbiotic life-forms. This process of endosymbiosis has intrigued scientists over the years, albeit mostly from an evolution biology perspective. With the advance of chemical and synthetic biology, our ability to create molecular-life-like systems has increased tremendously, which enables us to build cell and organelle-like structures. However, these advances have not been taken to a level to study comprehensively if endosymbiosis can be applied to non-living systems or to integrate living with non-living matter. The aim of the research described in the ARTISYM proposal is to establish the field of artificial endosymbiosis. Two lines of research will be followed. First, we will incorporate artificial organelles in living cells to design hybrid cells with acquired functionality. This investigation is scientifically of great interest, as it will show us how to introduce novel compartmentalized pathways into living organisms. It also serves an important societal goal, as with these compartments dysfunctional cellular processes can be corrected. We will follow both a transient and a permanent approach. With the transient route biodegradable nanoreactors are introduced to supply living cells temporarily with novel function. Functionality is permanently introduced using genetic engineering to express protein-based nanoreactors in living cells, or via organelle transplantation of healthy mitochondria in diseased living cells. Secondly I aim to create artificial cells with the ability to perform endosymbiosis; the uptake and presence of artificial organelles in synthetic vesicles allows them to dynamically respond to their environment. Responses that are envisaged are shape changes, motility, and growth and division. Furthermore, the incorporation of natural organelles in liposomes provides biocatalytic cascades with the necessary cofactors to function in an artificial cell
Living organisms have acquired new functionalities by uptake and integration of species to create symbiotic life-forms. This process of endosymbiosis has intrigued scientists over the years, albeit mostly from an evolution biology perspective. With the advance of chemical and synthetic biology, our ability to create molecular-life-like systems has increased tremendously, which enables us to build cell and organelle-like structures. However, these advances have not been taken to a level to study comprehensively if endosymbiosis can be applied to non-living systems or to integrate living with non-living matter. The aim of the research described in the ARTISYM proposal is to establish the field of artificial endosymbiosis. Two lines of research will be followed. First, we will incorporate artificial organelles in living cells to design hybrid cells with acquired functionality. This investigation is scientifically of great interest, as it will show us how to introduce novel compartmentalized pathways into living organisms. It also serves an important societal goal, as with these compartments dysfunctional cellular processes can be corrected. We will follow both a transient and a permanent approach. With the transient route biodegradable nanoreactors are introduced to supply living cells temporarily with novel function. Functionality is permanently introduced using genetic engineering to express protein-based nanoreactors in living cells, or via organelle transplantation of healthy mitochondria in diseased living cells. Secondly I aim to create artificial cells with the ability to perform endosymbiosis; the uptake and presence of artificial organelles in synthetic vesicles allows them to dynamically respond to their environment. Responses that are envisaged are shape changes, motility, and growth and division. Furthermore, the incorporation of natural organelles in liposomes provides biocatalytic cascades with the necessary cofactors to function in an artificial cell
Project acronym AstroMetrix
Project Precision tracking with tools from Astrophysics
Researcher (PI) Heino Falcke
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Summary In our ERC-funded project we have used interferometric techniques from radio astronomy to precisely localize bunches of cosmic ray particles rushing through our Earth atmosphere at light speed. Here we want to use this technique to provide precise and robust tracking of tracking of vehicles, such as robotic lawnmowers, ships and planes. Localizing vehicles as precisely as possible has become an ever more important aspect of modern day life, as is evident from the success of GPS. However, under certain circumstances GPS will not work well, either because the vehicle is indoors or the accuracy of GPS-systems is not sufficient. To achieve the feat of catching particles at light speed in our ERC project, we combined the knowledge from radio astronomy, particle physics and modern digital data processing. We developed solar-powered smart receivers linked over large areas into a single interferometer and developed software tools that allow us to do radio interferometric measurements in the presence of distorting signals. In the past, radio astronomical techniques were too compute- and power-intensive for commercial applications; however, the game changers are now powerful mobile phone processors developed for the consumer market. As a result we can in principle robustly localize radio sources to within a fraction of a wavelength – i.e., anywhere from millimetres to metres depending on the radio frequency. The concept is scalable, can be used to measure accurate locations over distances from metres to thousands of kilometres, and can be employed on earth or from space. The earth-based applications has a potential economic and social impact for instance via the tracking of objects (parcels or people) indoors, while the space-based application will allow for continuous tracking of ships and planes. The main goal of this proposal is to prepare for the launch of a start-up country that can commercialize this knowledge.
In our ERC-funded project we have used interferometric techniques from radio astronomy to precisely localize bunches of cosmic ray particles rushing through our Earth atmosphere at light speed. Here we want to use this technique to provide precise and robust tracking of tracking of vehicles, such as robotic lawnmowers, ships and planes. Localizing vehicles as precisely as possible has become an ever more important aspect of modern day life, as is evident from the success of GPS. However, under certain circumstances GPS will not work well, either because the vehicle is indoors or the accuracy of GPS-systems is not sufficient. To achieve the feat of catching particles at light speed in our ERC project, we combined the knowledge from radio astronomy, particle physics and modern digital data processing. We developed solar-powered smart receivers linked over large areas into a single interferometer and developed software tools that allow us to do radio interferometric measurements in the presence of distorting signals. In the past, radio astronomical techniques were too compute- and power-intensive for commercial applications; however, the game changers are now powerful mobile phone processors developed for the consumer market. As a result we can in principle robustly localize radio sources to within a fraction of a wavelength – i.e., anywhere from millimetres to metres depending on the radio frequency. The concept is scalable, can be used to measure accurate locations over distances from metres to thousands of kilometres, and can be employed on earth or from space. The earth-based applications has a potential economic and social impact for instance via the tracking of objects (parcels or people) indoors, while the space-based application will allow for continuous tracking of ships and planes. The main goal of this proposal is to prepare for the launch of a start-up country that can commercialize this knowledge.
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 BIO-ORIGAMI
Project Meta-biomaterials: 3D printing meets Origami
Researcher (PI) Amir Abbas Zadpoor
Summary Meta-materials, best known for their extraordinary properties (e.g. negative stiffness), are halfway from both materials and structures: their unusual properties are direct results of their complex 3D structures. This project introduces a new class of meta-materials called meta-biomaterials. Meta-biomaterials go beyond meta-materials by adding an extra dimension to the complex 3D structure, i.e. complex and precisely controlled surface nano-patterns. The 3D structure gives rise to unprecedented or rare combination of mechanical (e.g. stiffness), mass transport (e.g. permeability, diffusivity), and biological (e.g. tissue regeneration rate) properties. Those properties optimize the distribution of mechanical loads and the transport of nutrients and oxygen while providing geometrical shapes preferable for tissue regeneration (e.g. higher curvatures). Surface nano-patterns communicate with (stem) cells, control their differentiation behavior, and enhance tissue regeneration. There is one important problem: meta-biomaterials cannot be manufactured with current technology. 3D printing can create complex shapes while nanolithography creates complex surface nano-patterns down to a few nanometers but only on flat surfaces. There is, however, no way of combining complex shapes with complex surface nano-patterns. The groundbreaking nature of this project is in solving that deadlock using the Origami concept (the ancient Japanese art of paper folding). In this approach, I first decorate flat 3D-printed sheets with nano-patterns. Then, I apply Origami techniques to fold the decorated flat sheet and create complex 3D shapes. The sheet knows how to self-fold to the desired structure when subjected to compression, owing to pre-designed joints, crease patterns, and thickness/material distributions that control its mechanical instability. I will demonstrate the added value of meta-biomaterials in improving bone tissue regeneration using in vitro cell culture assays and animal models
Meta-materials, best known for their extraordinary properties (e.g. negative stiffness), are halfway from both materials and structures: their unusual properties are direct results of their complex 3D structures. This project introduces a new class of meta-materials called meta-biomaterials. Meta-biomaterials go beyond meta-materials by adding an extra dimension to the complex 3D structure, i.e. complex and precisely controlled surface nano-patterns. The 3D structure gives rise to unprecedented or rare combination of mechanical (e.g. stiffness), mass transport (e.g. permeability, diffusivity), and biological (e.g. tissue regeneration rate) properties. Those properties optimize the distribution of mechanical loads and the transport of nutrients and oxygen while providing geometrical shapes preferable for tissue regeneration (e.g. higher curvatures). Surface nano-patterns communicate with (stem) cells, control their differentiation behavior, and enhance tissue regeneration. There is one important problem: meta-biomaterials cannot be manufactured with current technology. 3D printing can create complex shapes while nanolithography creates complex surface nano-patterns down to a few nanometers but only on flat surfaces. There is, however, no way of combining complex shapes with complex surface nano-patterns. The groundbreaking nature of this project is in solving that deadlock using the Origami concept (the ancient Japanese art of paper folding). In this approach, I first decorate flat 3D-printed sheets with nano-patterns. Then, I apply Origami techniques to fold the decorated flat sheet and create complex 3D shapes. The sheet knows how to self-fold to the desired structure when subjected to compression, owing to pre-designed joints, crease patterns, and thickness/material distributions that control its mechanical instability. I will demonstrate the added value of meta-biomaterials in improving bone tissue regeneration using in vitro cell culture assays and animal models
Project acronym BioCircuit
Project Programmable BioMolecular Circuits: Emulating Regulatory Functions in Living Cells Using a Bottom-Up Approach
Researcher (PI) Tom Antonius Franciscus De greef
Summary Programmable biomolecular circuits have received increasing attention in recent years as the scope of chemistry expands from the synthesis of individual molecules to the construction of chemical networks that can perform sophisticated functions such as logic operations and feedback control. Rationally engineered biomolecular circuits that robustly execute higher-order spatiotemporal behaviours typically associated with intracellular regulatory functions present a unique and uncharted platform to systematically explore the molecular logic and physical design principles of the cell. The experience gained by in-vitro construction of artificial cells displaying advanced system-level functions deepens our understanding of regulatory networks in living cells and allows theoretical assumptions and models to be refined in a controlled setting. This proposal combines elements from systems chemistry, in-vitro synthetic biology and micro-engineering and explores generic strategies to investigate the molecular logic of biology's regulatory circuits by applying a physical chemistry-driven bottom-up approach. Progress in this field requires 1) proof-of-principle systems where in-vitro biomolecular circuits are designed to emulate characteristic system-level functions of regulatory circuits in living cells and 2) novel experimental tools to operate biochemical networks under out-of-equilibrium conditions. Here, a comprehensive research program is proposed that addresses these challenges by engineering three biochemical model systems that display elementary signal transduction and information processing capabilities. In addition, an open microfluidic droplet reactor is developed that will allow, for the first time, high-throughput analysis of biomolecular circuits encapsulated in water-in-oil droplets. An integral part of the research program is to combine the computational design of in-vitro circuits with novel biochemistry and innovative micro-engineering tools.
Programmable biomolecular circuits have received increasing attention in recent years as the scope of chemistry expands from the synthesis of individual molecules to the construction of chemical networks that can perform sophisticated functions such as logic operations and feedback control. Rationally engineered biomolecular circuits that robustly execute higher-order spatiotemporal behaviours typically associated with intracellular regulatory functions present a unique and uncharted platform to systematically explore the molecular logic and physical design principles of the cell. The experience gained by in-vitro construction of artificial cells displaying advanced system-level functions deepens our understanding of regulatory networks in living cells and allows theoretical assumptions and models to be refined in a controlled setting. This proposal combines elements from systems chemistry, in-vitro synthetic biology and micro-engineering and explores generic strategies to investigate the molecular logic of biology's regulatory circuits by applying a physical chemistry-driven bottom-up approach. Progress in this field requires 1) proof-of-principle systems where in-vitro biomolecular circuits are designed to emulate characteristic system-level functions of regulatory circuits in living cells and 2) novel experimental tools to operate biochemical networks under out-of-equilibrium conditions. Here, a comprehensive research program is proposed that addresses these challenges by engineering three biochemical model systems that display elementary signal transduction and information processing capabilities. In addition, an open microfluidic droplet reactor is developed that will allow, for the first time, high-throughput analysis of biomolecular circuits encapsulated in water-in-oil droplets. An integral part of the research program is to combine the computational design of in-vitro circuits with novel biochemistry and innovative micro-engineering tools.
Project acronym BROKERS
Project Participatory Urban Governance between Democracy and Clientelism: Brokers and (In)formal Politics
Researcher (PI) Martijn Koster
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 BYPASSWITHOUTSURGERY
Project Reaching the effects of gastric bypass on diabetes and obesity without surgery
Researcher (PI) Jens Juul Holst
Summary Gastric bypass surgery results in massive weight loss and diabetes remission. The effect is superior to intensive medical treatment, showing that there are mechanisms within the body that can cure diabetes and obesity. Revealing the nature of these mechanisms could lead to new, cost-efficient, similarly effective, non-invasive treatments of these conditions. The hypothesis is that hyper-secretion of a number of gut hormones mediates the effect of surgery, as indicated by a series of our recent studies, demonstrating that hypersecretion of GLP-1, a hormone discovered in my laboratory and basis for the antidiabetic medication of millions of patients, is essential for the improved insulin secretion and glucose tolerance. But what are the mechanisms behind the up to 30-fold elevations in secretion of these hormones following surgery? Constantly with a translational scope, all elements involved in these responses will be addressed in this project, from detailed analysis of food items responsible for hormone secretion, to identification of the responsible regions of the gut, and to the molecular mechanisms leading to hypersecretion. Novel approaches for studies of human gut hormone secreting cells, including specific expression analysis, are combined with our advanced and unique isolated perfused gut preparations, the only tool that can provide physiologically relevant results with a translational potential regarding regulation of hormone secretion in the gut. This will lead to further groundbreaking experimental attempts to mimic and engage the identified mechanisms, creating similar hypersecretion and obtaining similar improvements as the operations in patients with obesity and diabetes. Based on our profound knowledge of gut hormone biology accumulated through decades of intensive and successful research and our successful elucidation of the antidiabetic actions of gastric bypass surgery, we are in a unique position to reach this ambitious goal.
Gastric bypass surgery results in massive weight loss and diabetes remission. The effect is superior to intensive medical treatment, showing that there are mechanisms within the body that can cure diabetes and obesity. Revealing the nature of these mechanisms could lead to new, cost-efficient, similarly effective, non-invasive treatments of these conditions. The hypothesis is that hyper-secretion of a number of gut hormones mediates the effect of surgery, as indicated by a series of our recent studies, demonstrating that hypersecretion of GLP-1, a hormone discovered in my laboratory and basis for the antidiabetic medication of millions of patients, is essential for the improved insulin secretion and glucose tolerance. But what are the mechanisms behind the up to 30-fold elevations in secretion of these hormones following surgery? Constantly with a translational scope, all elements involved in these responses will be addressed in this project, from detailed analysis of food items responsible for hormone secretion, to identification of the responsible regions of the gut, and to the molecular mechanisms leading to hypersecretion. Novel approaches for studies of human gut hormone secreting cells, including specific expression analysis, are combined with our advanced and unique isolated perfused gut preparations, the only tool that can provide physiologically relevant results with a translational potential regarding regulation of hormone secretion in the gut. This will lead to further groundbreaking experimental attempts to mimic and engage the identified mechanisms, creating similar hypersecretion and obtaining similar improvements as the operations in patients with obesity and diabetes. Based on our profound knowledge of gut hormone biology accumulated through decades of intensive and successful research and our successful elucidation of the antidiabetic actions of gastric bypass surgery, we are in a unique position to reach this ambitious goal.
Project acronym CAT
Project Climbing the Asian Water Tower
Researcher (PI) Wouter Willem Immerzeel
Call Details Starting Grant (StG), PE10, ERC-2015-STG
Summary The water cycle in the Himalaya is poorly understood because of its extreme topography that results in complex interactions between climate and water stored in snow and glaciers. Hydrological extremes in the greater Himalayas regularly cause great damage, e.g. the Pakistan floods in 2010, while the Himalayas also supply water to over 25% of the global population. So, the stakes are high and an accurate understanding of the Himalayan water cycle is imperative. The discovery of the monumental error on the future of the Himalayan glaciers in the fourth assessment report of the IPCC is exemplary for the scientific misconceptions which are associated to the Himalayan glaciers and its water supplying function. The underlying reason is the huge scale gap that exists between studies for individual glaciers that are not representative of the entire region and hydrological modelling studies that represent the variability in Himalayan climates. In CAT, I will bridge this knowledge gap and explain spatial differences in Himalayan glacio-hydrology at an unprecedented level of detail by combining high-altitude observations, the latest remote sensing technology and state-of-the-art atmospheric and hydrological models. I will generate a high-altitude meteorological observations and will employ drones to monitor glacier dynamics. The data will be used to parameterize key processes in hydro-meteorological models such as cloud resolving mechanisms, glacier dynamics and the ice and snow energy balance. The results will be integrated into atmospheric and glacio-hyrological models for two representative, but contrasting catchments using in combination with the systematic inclusion of the newly developed algorithms. CAT will unambiguously reveal spatial differences in Himalayan glacio-hydrology necessary to project future changes in water availability and extreme events. As such, CAT may provide the scientific base for climate change adaptation policies in this vulnerable region.
The water cycle in the Himalaya is poorly understood because of its extreme topography that results in complex interactions between climate and water stored in snow and glaciers. Hydrological extremes in the greater Himalayas regularly cause great damage, e.g. the Pakistan floods in 2010, while the Himalayas also supply water to over 25% of the global population. So, the stakes are high and an accurate understanding of the Himalayan water cycle is imperative. The discovery of the monumental error on the future of the Himalayan glaciers in the fourth assessment report of the IPCC is exemplary for the scientific misconceptions which are associated to the Himalayan glaciers and its water supplying function. The underlying reason is the huge scale gap that exists between studies for individual glaciers that are not representative of the entire region and hydrological modelling studies that represent the variability in Himalayan climates. In CAT, I will bridge this knowledge gap and explain spatial differences in Himalayan glacio-hydrology at an unprecedented level of detail by combining high-altitude observations, the latest remote sensing technology and state-of-the-art atmospheric and hydrological models. I will generate a high-altitude meteorological observations and will employ drones to monitor glacier dynamics. The data will be used to parameterize key processes in hydro-meteorological models such as cloud resolving mechanisms, glacier dynamics and the ice and snow energy balance. The results will be integrated into atmospheric and glacio-hyrological models for two representative, but contrasting catchments using in combination with the systematic inclusion of the newly developed algorithms. CAT will unambiguously reveal spatial differences in Himalayan glacio-hydrology necessary to project future changes in water availability and extreme events. As such, CAT may provide the scientific base for climate change adaptation policies in this vulnerable region.
Project acronym CatASus
Project Cleave and couple: Fully sustainable catalytic conversion of renewable resources to amines
Researcher (PI) Katalin Barta Weissert
Summary Amines are crucially important classes of chemicals, widely present in pharmaceuticals, agrochemicals and surfactants. Yet, surprisingly, a systematic approach to obtaining this essential class of compounds from renewables has not been realized to date. The aim of this proposal is to enable chemical pathways for the production of amines through alcohols from renewable resources, preferably lignocellulose waste. Two key scientific challenges will be addressed: The development of efficient cleavage reactions of complex renewable resources by novel heterogeneous catalysts; and finding new homogeneous catalyst based on earth-abundant metals for the atom-economic coupling of the derived alcohol building blocks directly with ammonia as well as possible further functionalization reactions. The program is divided into 3 interrelated but not mutually dependent work packages, each research addressing a key challenge in their respective fields, these are: WP1: Lignin conversion to aromatics; WP2: Cellulose-derived platform chemicals to aromatic and aliphatic diols and solvents. WP3: New iron-based homogeneous catalysts for the direct, atom-economic C-O to C-N transformations. The approach taken will embrace the inherent complexity present in the renewable feedstock. A unique balance between cleavage and coupling pathways will allow to access chemical diversity in products that is necessary to achieve economic competitiveness with current fossil fuel-based pathways and will permit rapid conversion to higher value products such as functionalized amines that can enter the chemical supply chain at a much later stage than bulk chemicals derived from petroleum. The proposed high risk-high gain research will push the frontiers of sustainable and green chemistry and reach well beyond state of the art in this area. This universal, flexible and iterative approach is anticipated to give rise to a variety of similar systems targeting diverse product outcomes starting from renewables.
Amines are crucially important classes of chemicals, widely present in pharmaceuticals, agrochemicals and surfactants. Yet, surprisingly, a systematic approach to obtaining this essential class of compounds from renewables has not been realized to date. The aim of this proposal is to enable chemical pathways for the production of amines through alcohols from renewable resources, preferably lignocellulose waste. Two key scientific challenges will be addressed: The development of efficient cleavage reactions of complex renewable resources by novel heterogeneous catalysts; and finding new homogeneous catalyst based on earth-abundant metals for the atom-economic coupling of the derived alcohol building blocks directly with ammonia as well as possible further functionalization reactions. The program is divided into 3 interrelated but not mutually dependent work packages, each research addressing a key challenge in their respective fields, these are: WP1: Lignin conversion to aromatics; WP2: Cellulose-derived platform chemicals to aromatic and aliphatic diols and solvents. WP3: New iron-based homogeneous catalysts for the direct, atom-economic C-O to C-N transformations. The approach taken will embrace the inherent complexity present in the renewable feedstock. A unique balance between cleavage and coupling pathways will allow to access chemical diversity in products that is necessary to achieve economic competitiveness with current fossil fuel-based pathways and will permit rapid conversion to higher value products such as functionalized amines that can enter the chemical supply chain at a much later stage than bulk chemicals derived from petroleum. The proposed high risk-high gain research will push the frontiers of sustainable and green chemistry and reach well beyond state of the art in this area. This universal, flexible and iterative approach is anticipated to give rise to a variety of similar systems targeting diverse product outcomes starting from renewables.
Project acronym CD40-INN
Project CD40 goes innate: defining and targeting CD40 signaling intermediates in the macrophage to treat atherosclerosis
Researcher (PI) Esther Lutgens Leiner
Summary Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVD), is a lipid driven, inflammatory disease of the large arteries. Despite a 25% relative risk reduction achieved by lipid-lowering treatment, the vast majority of atherosclerosis-induced CVD risk remains unaddressed. Therefore, characterizing mediators of the inflammatory aspect of atherosclerosis is a widely recognized scientific goal with great therapeutic implications. Co-stimulatory molecules are key players in modulating immune interactions. My laboratory has defined the co-stimulatory CD40-CD40L dyad as a major driver of atherosclerosis. Inhibition of CD40, and of its interaction with the adaptor molecule TRAF6 by genetic deficiency, antibody treatment or (nanoparticle based) small molecule inhibitor (SMI) treatment, is one of the most powerful therapies to reduce atherosclerosis in a laboratory setting. Although CD40-CD40L interactions are associated with adaptive immunity, I recently identified the macrophage as a driver of CD40-induced inflammation in atherosclerosis. We will use state-of-the-art in vitro experiments, live cell-, super resolution imaging, proteomics approaches and mutant mouse models to unravel the role of macrophage CD40 in atherosclerosis. Moreover, using structure based virtual ligand screening, I will develop lead SMIs targeting macrophage CD40-signaling, which I will deliver using macrophage-targeting nanoparticles. My goal is to define the role of macrophage CD40 in inflammation and immunity and disentangle how its activation affects atherosclerosis. I will finally test the feasibility of targeting macrophage CD40-signaling as a treatment for CVD. These studies will define the role of CD40-signaling in the innate immune system in health and (cardiovascular) disease. As components of macrophage CD40-signaling have the potential to be amenable to pharmacological manipulation, we will establish their feasibility as novel targets for (CVD) treatment.
Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVD), is a lipid driven, inflammatory disease of the large arteries. Despite a 25% relative risk reduction achieved by lipid-lowering treatment, the vast majority of atherosclerosis-induced CVD risk remains unaddressed. Therefore, characterizing mediators of the inflammatory aspect of atherosclerosis is a widely recognized scientific goal with great therapeutic implications. Co-stimulatory molecules are key players in modulating immune interactions. My laboratory has defined the co-stimulatory CD40-CD40L dyad as a major driver of atherosclerosis. Inhibition of CD40, and of its interaction with the adaptor molecule TRAF6 by genetic deficiency, antibody treatment or (nanoparticle based) small molecule inhibitor (SMI) treatment, is one of the most powerful therapies to reduce atherosclerosis in a laboratory setting. Although CD40-CD40L interactions are associated with adaptive immunity, I recently identified the macrophage as a driver of CD40-induced inflammation in atherosclerosis. We will use state-of-the-art in vitro experiments, live cell-, super resolution imaging, proteomics approaches and mutant mouse models to unravel the role of macrophage CD40 in atherosclerosis. Moreover, using structure based virtual ligand screening, I will develop lead SMIs targeting macrophage CD40-signaling, which I will deliver using macrophage-targeting nanoparticles. My goal is to define the role of macrophage CD40 in inflammation and immunity and disentangle how its activation affects atherosclerosis. I will finally test the feasibility of targeting macrophage CD40-signaling as a treatment for CVD. These studies will define the role of CD40-signaling in the innate immune system in health and (cardiovascular) disease. As components of macrophage CD40-signaling have the potential to be amenable to pharmacological manipulation, we will establish their feasibility as novel targets for (CVD) treatment.
Project acronym CFS modelling
Project Chromosomal Common Fragile Sites: Unravelling their biological functions and the basis of their instability
Researcher (PI) Andres Joaquin Lopez-Contreras
Summary Cancer and other diseases are driven by genomic alterations initiated by DNA breaks. Within our genomes, some regions are particularly prone to breakage, and these are known as common fragile sites (CFSs). CFSs are present in every person and are frequently sites of oncogenic chromosomal rearrangements. Intriguingly, despite their fragility, many CFSs are well conserved through evolution, suggesting that these regions have important physiological functions that remain elusive. My previous background in genome editing, proteomics and replication-born DNA damage has given me the tools to propose an ambitious and comprehensive plan that tackles fundamental questions on the biology of CFSs. First, we will perform a systematic analysis of the function of CFSs. Most of the CFSs contain very large genes, which has made technically difficult to dissect whether the CFS role is due to the locus itself or to the encoded gene product. However, the emergence of the CRISPR/Cas9 technology now enables the study of CFSs on a more systematic basis. We will pioneer the engineering of mammalian models harbouring large deletions at CFS loci to investigate their physiological functions at the cellular and organism levels. For those CFSs that contain genes, the cDNAs will be re-introduced at a distal locus. Using this strategy, we will be able to achieve the first comprehensive characterization of CFS roles. Second, we will develop novel targeted approaches to interrogate the chromatin-bound proteome of CFSs and its dynamics during DNA replication. Finally, and given that CFS fragility is influenced both by cell cycle checkpoints and dNTP availability, we will use mouse models to study the impact of ATR/CHK1 pathway and dNTP levels on CFS instability and cancer. Taken together, I propose an ambitious, yet feasible, project to functionally annotate and characterise these poorly understood regions of the human genome, with important potential implications for improving human health.
Cancer and other diseases are driven by genomic alterations initiated by DNA breaks. Within our genomes, some regions are particularly prone to breakage, and these are known as common fragile sites (CFSs). CFSs are present in every person and are frequently sites of oncogenic chromosomal rearrangements. Intriguingly, despite their fragility, many CFSs are well conserved through evolution, suggesting that these regions have important physiological functions that remain elusive. My previous background in genome editing, proteomics and replication-born DNA damage has given me the tools to propose an ambitious and comprehensive plan that tackles fundamental questions on the biology of CFSs. First, we will perform a systematic analysis of the function of CFSs. Most of the CFSs contain very large genes, which has made technically difficult to dissect whether the CFS role is due to the locus itself or to the encoded gene product. However, the emergence of the CRISPR/Cas9 technology now enables the study of CFSs on a more systematic basis. We will pioneer the engineering of mammalian models harbouring large deletions at CFS loci to investigate their physiological functions at the cellular and organism levels. For those CFSs that contain genes, the cDNAs will be re-introduced at a distal locus. Using this strategy, we will be able to achieve the first comprehensive characterization of CFS roles. Second, we will develop novel targeted approaches to interrogate the chromatin-bound proteome of CFSs and its dynamics during DNA replication. Finally, and given that CFS fragility is influenced both by cell cycle checkpoints and dNTP availability, we will use mouse models to study the impact of ATR/CHK1 pathway and dNTP levels on CFS instability and cancer. Taken together, I propose an ambitious, yet feasible, project to functionally annotate and characterise these poorly understood regions of the human genome, with important potential implications for improving human health.
Project acronym CHEMCHECK
Project CHECKPOINTS IN CHECK: Novel Chemical Toolbox for Local Cancer Immunotherapy
Researcher (PI) Martijn Verdoes
Summary Cancer evades the immune system by generating an immunosuppressive tumour-microenvironment through various mechanisms to enable unhampered growth. Recent breakthroughs in blocking one of these mechanisms – the so called 'immune checkpoints' – put cancer immunotherapy back in the spotlights. Although promising, clinical benefits of these checkpoint inhibitors as single treatment has been limited to a subset of patients and goes along with unwanted systemic autoimmune toxicity. I hypostasize, that attacking the tumour microenvironment from multiple immunological angles simultaneously by local, conditional, and multimodal immunomodulation will greatly improve success of cancer immunotherapy and patient wellbeing. To achieve this, I will develop a highly defined synergistic chemistry-based molecular therapeutic toolbox to specifically attack cancer, acting on effector T cells, macrophages as well as tumour cells simultaneously. In this highly multidisciplinary endeavour I will (i) generate novel multifunctional dendritic cell targeted anti-cancer vaccines to 'educate' the patient's immune system to recognise the tumour, (ii) I will develop conditional, targeted immune checkpoint inhibitors to release the immunosuppressive break specifically within the tumour microenvironment without the risk of autoimmunity and (iii) I will generate chemical tools to locally eliminate the tumour-associated macrophages to tear down a major immunosuppressive barrier. I will do so utilizing the novel ModimAb technology which I developed to obtain functionalized antibody fragments. These individual therapeutic tools will allow me and my research team to explore uncharted tumour immunological territories in vitro as well as in vivo, greatly advancing the field of cancer immunotherapy. But above all, together they will form a highly dedicated symbiotic immunotherapeutic regime which will be extremely effective without systemic side effects, dramatically improving patient care.
Cancer evades the immune system by generating an immunosuppressive tumour-microenvironment through various mechanisms to enable unhampered growth. Recent breakthroughs in blocking one of these mechanisms – the so called 'immune checkpoints' – put cancer immunotherapy back in the spotlights. Although promising, clinical benefits of these checkpoint inhibitors as single treatment has been limited to a subset of patients and goes along with unwanted systemic autoimmune toxicity. I hypostasize, that attacking the tumour microenvironment from multiple immunological angles simultaneously by local, conditional, and multimodal immunomodulation will greatly improve success of cancer immunotherapy and patient wellbeing. To achieve this, I will develop a highly defined synergistic chemistry-based molecular therapeutic toolbox to specifically attack cancer, acting on effector T cells, macrophages as well as tumour cells simultaneously. In this highly multidisciplinary endeavour I will (i) generate novel multifunctional dendritic cell targeted anti-cancer vaccines to 'educate' the patient's immune system to recognise the tumour, (ii) I will develop conditional, targeted immune checkpoint inhibitors to release the immunosuppressive break specifically within the tumour microenvironment without the risk of autoimmunity and (iii) I will generate chemical tools to locally eliminate the tumour-associated macrophages to tear down a major immunosuppressive barrier. I will do so utilizing the novel ModimAb technology which I developed to obtain functionalized antibody fragments. These individual therapeutic tools will allow me and my research team to explore uncharted tumour immunological territories in vitro as well as in vivo, greatly advancing the field of cancer immunotherapy. But above all, together they will form a highly dedicated symbiotic immunotherapeutic regime which will be extremely effective without systemic side effects, dramatically improving patient care.
Project acronym CHILDROBOT
Project Children and social robots: An integrative framework
Researcher (PI) Jochen Peter
Host Institution (HI) UNIVERSITEIT VAN AMSTERDAM
Summary Robots used to be made for labor; now, they are increasingly also made for relationships. Social robots can learn from us, teach us, play with us, and assist us. With the market for social robots expected to grow substantially in the next 20 years, social robots are likely to become a life-changing technology similar to personal computers or smart phones. Still, we still know little about one of the most intriguing, relevant, and timely issues in this process – children's interaction with social robots. Children are not only increasingly recognized and targeted as early adopters of new technologies; they may also be more susceptible to potential effects of interacting with robots than are adults. As research on child-robot interaction (CRI) is still a fragmented field, the main aim of the proposed project is to develop an integrative framework of CRI. This framework synthesizes theories and concepts from communication research, human-robot-interaction, as well as developmental and social psychology in an entirely new way. It will focus (1) on the antecedents of children's acceptance of social robots; (2) the con-sequences of CRI for children's learning of social skills from social robots and their relationship formation with them; and (3) the processes that explain why such effects emerge. The project combines survey and experimental research, thereby bringing an unprecedented, but much needed multi-methodological approach to the field of CRI. Focusing on 8-9 year-old children, the project will also provide two crucial methodological innovations: (a) the creation an inventory of standardized measures for CRI and (b) new procedures and research designs to study long-term CRI. In its pioneering focus on a disruptive new technology, its theoretically unifying character, and its original methodological contributions, the project will not only define the field of CRI, but will also present a completely new agenda for it.
Robots used to be made for labor; now, they are increasingly also made for relationships. Social robots can learn from us, teach us, play with us, and assist us. With the market for social robots expected to grow substantially in the next 20 years, social robots are likely to become a life-changing technology similar to personal computers or smart phones. Still, we still know little about one of the most intriguing, relevant, and timely issues in this process – children's interaction with social robots. Children are not only increasingly recognized and targeted as early adopters of new technologies; they may also be more susceptible to potential effects of interacting with robots than are adults. As research on child-robot interaction (CRI) is still a fragmented field, the main aim of the proposed project is to develop an integrative framework of CRI. This framework synthesizes theories and concepts from communication research, human-robot-interaction, as well as developmental and social psychology in an entirely new way. It will focus (1) on the antecedents of children's acceptance of social robots; (2) the con-sequences of CRI for children's learning of social skills from social robots and their relationship formation with them; and (3) the processes that explain why such effects emerge. The project combines survey and experimental research, thereby bringing an unprecedented, but much needed multi-methodological approach to the field of CRI. Focusing on 8-9 year-old children, the project will also provide two crucial methodological innovations: (a) the creation an inventory of standardized measures for CRI and (b) new procedures and research designs to study long-term CRI. In its pioneering focus on a disruptive new technology, its theoretically unifying character, and its original methodological contributions, the project will not only define the field of CRI, but will also present a completely new agenda for it.


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Conferences \ Biofluid Biopsies and Companion Diagnostics 2014
Biofluid Biopsies and Companion Diagnostics 2014
Date: Monday, 27 October 2014 - Tuesday, 28 October 2014
Michael Heller
Distinguished Scientist - Knight Cancer Institute at Oregon Health & Science University (OHSU), Center for Cancer Early Detection and Research (CEDAR); Professor, University of California-San Diego
Executive Director, Amgen Inc
Nicholas Dracopoli
Vice President/Head, Johnson & Johnson
Walter Koch
Vice President, Roche Molecular Systems
Klaus Pantel
Chairman, Department of Tumor Biology, University Medical Center Hamburg-Eppendorf
Oscar Puig
Biomarker Leader, Hoffmann La Roche
Ruth Katz
Professor of Pathology, Chief Image Analysis Laboratory, Chief Research Cytopathology, MD Anderson Cancer Center
David Hoon
Professor, Director Department of Translational Molecular Medicine, John Wayne Cancer Institute
Robert Wassman
Chief Medical Officer, Rosetta Genomics
Yoshiya Oda
President, Eisai Inc
Martin Siaw
Associate Scientific Director, Quest Diagnostics Nichols Institute
Biofluid Biopsies and Companion Diagnostics 2014 brings together academic researchers, industry researchers, as well as biotechnology and pharmaceutical companies to explore the expanding and evolving field whereby Circulating Biomarkers of various classes are being evaluated for their potential to be developed into diagnostics for cancer as well as other disease classes.
The Biofluid Biopsies Conference Track focuses primarily on blood-based molecular biomarkers, such as circulating tumor DNA (ctDNA) as well as circulating tumor cells (CTCs), and protein-based circulating biomarkers. There is much interest in the potential of ctDNA for developing biological fluid-based biopsies (such as using plasma, urine, or other biofluids) and the presenters in this track bring together the most up-to-date information and current state-of-the-field.
Major theme of this conference track is to explore the potential of various circulating biomarker classes, such as circulating-free DNA (cfDNA), CTCs, and Extracellular Vesicles (EVs), for Biofluid-based Biopsies and Patient Monitoring.
The Companion Diagnostics Conference Track brings together presenters from around the world to offer a comprehensive picture from research, commercial, and regulatory perspectives as to the deployment of biomarkers for precision medicine, and technical as well as economic and regulatory considerations in the development of companion diagnostics for the different cancer sub-classes as well as other disease areas.
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redpajama_set_name: RedPajamaCommonCrawl


Fall is always a little bit tough to call in Flagstaff, some years the leaves change and temperatures drop and it all makes sense, other years it skips fall and goes straight to winter, from warm to bitter cold. This year however, summer never really seemed to leave, the only difference being the days have gotten shorter and the temperatures only a little bit cooler. This has been a blessing and a curse for me, there's something to be said for wet wading and fishing foam grasshoppers in November, however some snow would be incredible at this point!
This fall has held some fun trips and given me time to explore some new spots. Some of the new spots are just new stretches of familiar creeks, while others are totally new to me. Fishing new areas always seems to be very rewarding if a little nervous to begin with. It is all too easy to return to the same stretch of creek you know will always produce good fish rather than explore a new stretch or little blue line on the map. Even when those lines turn out to hold no fish or are dry (we are in Arizona), the trip to a new area is always worth it. Even if that area is a fishless trickle of water surrounded by black berries and locust trees.
If I had stuck to the familiar this fall there is no way I would have been able to get into two of my favorite fish of the fall. The first came from XXXXX Lake outside of XXXXX (sorry I promised not to spill the beans on this spot). I had been told the area held some nice brown trout, however due to the relatively small size of the lake when I arrived I had my doubts the water had stayed cold enough all summer to support trout. With no surface activity I began stripping woolly buggers and nymphs along the reeds and felt a few fish halfheartedly nibble on the tails of the bugger. I continued fishing for the next few hours without any other success and got into the "I'll tie this fly on because I like it" mode rather than try and match what fish were eating. On this rare occasion it worked. Despite not seeing a single sign of crawdads I tied on a crawbugger and began trying different retrieve rates.
Finally a fish hit while I was stripping in quickly! The fish jumped once or twice and I saw what I believed at a distance to be a rainbow, or at least for sure not a brown trout. As it got closer I realized it definitely was not a rainbow but something else. Finally I got the fish into the net and realized it was a silvery colored brook trout! Not what I had expected at all! The fish was not huge, however it is the biggest brook trout I have caught so far in Arizona!
After a few quick photos the fish darted back into the mud cloud we had created. That was the only fish of the day but it was definitely a nice surprise!
My other two scouting trips involve familiar creeks, but new areas. Both had their rewards in larger fish, if not necessarily high numbers of fish caught. I checked the first of the two areas out in the beginning of October on a 70 degree weekend (not much to complain about there). I began the day as I usually do on small creeks in October, with a grasshopper of course! The familiar pools and runs at the bottom held a few fish and my two friends I was with and I pulled a few small fish out as we moved up the creek. The fishing was consistent but not every cast like I know this area can be.
As we moved up creek the water began to flow both above, and below the rocks. It was wild having the creek lose and regain half of its flow every couple hundred feet! This section had beautiful pools and there was a crazy hatch going on at one point where the cloud of midges was so thick it looked unpleasant to walk through. Naturally the fish were not rising at all but would come up for the grasshopper.. match the hatch? I guess these ones really don't care about that kind of thing.
And not a single rise was seen until the hopper hit the water.. Who woulda guessed??
In this section of water the size of the fish began to increase, and when I say size I don't mean monsters, but far larger and more wily fish than lower down. The 3 weight rod and 6X tippet was never truly put to the test, however every once in a while one of these browns would take you on a journey around every stick, rock and log in their little homes.
After switching to a smaller fly (not catching anything) and back to the hopper (worked immediately) we moved into a section with a beautiful plunge pool colored a light bluish color. Unfortunately the fish in this pool seemed wise to our tricks, but just downstream of pools outlet Sean managed to hook a beautiful lightly colored brown that was almost all gold in color. We stopped just upstream of this pool but not before I snuck up to one last little pool. Without much hope I cast blindly around the corner of a rock and saw a splash. A hard fighting little brown went speeding under the rock it came out of, seemingly trying to bury itself in the bank. After a short but spirited fight the fish came to hand and after a few brief pictures it swam back under its rock home. Despite it being a small fish with only a 5 foot pool to run in, this little brown had gotten my hands shaking!
All in all an amazing little creek to fish and very glad I headed into some new spots in familiar water!
Finally a beadhead copper john managed to bring a fish to hand. The fish had a beautiful, buttery belly and gave a good account of himself with two jumps and a strong run across current. Thankfully Ryan was able to get him in the net before he was gone!
Despite the day being slow it is always nice to get a nice walk in along the creek. This fishery is a fickle one and a spot a may never truly master, but it sure is fun trying!


My Househusband is Octoarts films' entry this year to the Manila Film Festival. Unlike most entries which rely on the tried and tested dramatics or slapstick tactics of recent local movies, My Househusband banks itself on a witty script, talented actors and an amazing director full of imagination.
This latest presscon of My Househusband was held in Guilly's Tomas Morato where all of its topbilling actors were present sans Direk Joey who was missed at the event.
The presence of Eugene Domingo during this presscon really turned the affair into a relaxed and hilarious afternoon. I swear, she is one of the funniest people I've ever encountered and it seems to come so naturally to her.
Judyanne on the other hand has this aura around her that is so strong you know that it can only be reserved for a few, special people; true superstars in their own right. I've met several actors and actresses in the industry but few carry this type of enigma and "star power".
The movie revolves around Rod (Ryan Agoncillo), a bank manager who suddenly lost his job and his wife Mia (Judy Ann Santos) who had to take on a job to provide for their family. WhileMia continuously excels on her job at the insurance agency, Rodadjusts to doing domesticated houseworks. In the process, he befriends their neighbor Aida (Eugene Domingo), who everybody in the neighborhood knows is "the other woman" of a rich man.
It's a story of a couple who goes through the changes and trials of role reversal in the family. A story of a mistress who needed to realize her self-worth as a woman, and a human being.
My Househusband is the first movie that Ryan and Juday have starrred in as a couple since they tied the knot thus bringing to the screen a genuine understanding of their roles which is ver much evident in their acting.
Dear, I looove your new hair! Nice to see you! Direk was looking for you during the Eugene Domingo presscon! LOL!


A bunch of low-res images of Bryan Singer's X-Men: Apocalypse characters have popped up in the new issue of Entertainment Weekly, giving audiences the first official look at new villains and heroes alike. The title villain, played by an unrecognizable Oscar Isaac, looms over his co-stars, which include the new addition of Olivia Munn's Psylocke and a re-invented costume for Michael Fassbender's Magneto. All that and more appear below. Be sure to let us know your thoughts in the comments!
X-Men: Apocalypse features returning actors Jennifer Lawrence, James McAvoy, and Nicholas Hoult, and will introduce Storm (Alexandra Shipp), Cyclops (Tye Sheridan), Jean Grey (Sophie Turner), and Nightcrawler (Kodi Smit-McPhee), among others when it opens May 27, 2016.


Very vigorous habit and high yielding.
Excellent resistance to Spring frosts as well as Summer droughts.
Harvest late July / August.
One of the most common and widespread varieties which is resistant to both Spring frosts and drought.
The vigorous bushes are very high yielding with the branches often bending under heavy crops of fruit. Ripening starts late July / August. The flowers are very delicate and pretty. The light blue berries are large, firm and gathered in clusters.
Commercially Bluecrop is regarded as one of the the best varieties.
Blueberries are classified as a superfruit and as such are extremely good for you.
Self Fertile - though to ensure good pollination, plant with one or two other Blueberries - ideally different varieties.