Source: https://erc.europa.eu/projects-figures/erc-funded-projects/results?destination=projects-figures/erc-funded-projects/canbuild&f%5B0%5D=country%3ASwitzerland&f%5B1%5D=funding_scheme%3AConsolidator%20Grant%20%28CoG%29&f%5B2%5D=call_year%3A2016
Timestamp: 2019-04-22 16:35:15+00:00

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Summary While the crisis of the territorial nation-state in the Middle East has once again been brought to a head by the wars in Iraq and Syria, it cannot be simply understood as the logical consequence of an imported political construction. Based on two epistemological notions – borderlands as histoire-problème (history-as-problem) and the co-production of borders between state and society – this research project proposes to rethink the classical historical narrative about the emergence of the post-Ottoman Middle East. Taking its cue from trans-border phenomena and thus paying attention to the circulation of people, goods and ideas as well as to everyday encounters between local actors and state representatives, the project will be guided by four principle objectives to offer: •	A socio-historical analysis of state violence in the borderlands of the Middle East; •	An examination of the capacity of border populations to create the history of the borderlands, nation-states, and the region as a whole; •	A study of the frontier effects based around the notions of subjectivity, space and time, and involving various levels of observation (macro, meso and micro) in order to identify the ruptures and continuities evoked by the delineation of new borderlines; and •	A historical lens through which to make sense of current events in Syria and Iraq, and possibly orient conflict-resolution practitioners. Through the exploitation of a wide range of sources (diplomatic, administrative and military records, missionary documents, newspapers) and by looking at the social construction of international frontiers at the borderlands located between Turkey, Iraq and Syria in the interwar era, the research project will provide a much more holistic yet finely-grained understanding of the formation of the territorial state in the region in the aftermath of the First World War as well as a historical perspective on the on-going armed conflicts.
While the crisis of the territorial nation-state in the Middle East has once again been brought to a head by the wars in Iraq and Syria, it cannot be simply understood as the logical consequence of an imported political construction. Based on two epistemological notions – borderlands as histoire-problème (history-as-problem) and the co-production of borders between state and society – this research project proposes to rethink the classical historical narrative about the emergence of the post-Ottoman Middle East. Taking its cue from trans-border phenomena and thus paying attention to the circulation of people, goods and ideas as well as to everyday encounters between local actors and state representatives, the project will be guided by four principle objectives to offer: •	A socio-historical analysis of state violence in the borderlands of the Middle East; •	An examination of the capacity of border populations to create the history of the borderlands, nation-states, and the region as a whole; •	A study of the frontier effects based around the notions of subjectivity, space and time, and involving various levels of observation (macro, meso and micro) in order to identify the ruptures and continuities evoked by the delineation of new borderlines; and •	A historical lens through which to make sense of current events in Syria and Iraq, and possibly orient conflict-resolution practitioners. Through the exploitation of a wide range of sources (diplomatic, administrative and military records, missionary documents, newspapers) and by looking at the social construction of international frontiers at the borderlands located between Turkey, Iraq and Syria in the interwar era, the research project will provide a much more holistic yet finely-grained understanding of the formation of the territorial state in the region in the aftermath of the First World War as well as a historical perspective on the on-going armed conflicts.
Summary Successful social interactions require social decision making, the ability to guide our actions in line with the goals and expectations of the people around us. Disordered social decision making – e.g., associated with criminal activity or psychiatric illnesses – poses significant financial and personal challenges to society. However, the brain mechanisms that enable us to control our social behavior are far from being understood. Here I will take decisive steps towards a causal understanding of these mechanisms by elucidating the role of functional interactions in the brain networks responsible for steering strategic, prosocial, and norm-compliant behavior. I will employ a unique multi-method approach that integrates computational modeling of social decisions with new combinations of multimodal neuroimaging and brain stimulation methods. Using EEG-fMRI, I will first identify spatio-temporal patterns of functional interactions between brain areas that correlate with social decision processes as identified by computational modeling of behavior in different economic games. In combined brain stimulation-fMRI studies, I will then attempt to affect – and in fact enhance – these social decision-making processes by modulating the identified brain network patterns with novel, targeted brain stimulation protocols and measuring the resulting effects on behavior and brain activity. Finally, I will examine whether the identified brain network mechanisms are indeed related to disturbed social decisions in two psychiatric illnesses characterized by maladaptive social behavior (post-traumatic stress disorder and autism spectrum disorder). My proposed work plan will generate a causal understanding of the brain network mechanisms that allow humans to control their social decisions, thereby elucidating a biological basis for individual differences in social behavior and paving the way for new perspectives on how disordered social behavior may be identified and hopefully remedied.
Successful social interactions require social decision making, the ability to guide our actions in line with the goals and expectations of the people around us. Disordered social decision making – e.g., associated with criminal activity or psychiatric illnesses – poses significant financial and personal challenges to society. However, the brain mechanisms that enable us to control our social behavior are far from being understood. Here I will take decisive steps towards a causal understanding of these mechanisms by elucidating the role of functional interactions in the brain networks responsible for steering strategic, prosocial, and norm-compliant behavior. I will employ a unique multi-method approach that integrates computational modeling of social decisions with new combinations of multimodal neuroimaging and brain stimulation methods. Using EEG-fMRI, I will first identify spatio-temporal patterns of functional interactions between brain areas that correlate with social decision processes as identified by computational modeling of behavior in different economic games. In combined brain stimulation-fMRI studies, I will then attempt to affect – and in fact enhance – these social decision-making processes by modulating the identified brain network patterns with novel, targeted brain stimulation protocols and measuring the resulting effects on behavior and brain activity. Finally, I will examine whether the identified brain network mechanisms are indeed related to disturbed social decisions in two psychiatric illnesses characterized by maladaptive social behavior (post-traumatic stress disorder and autism spectrum disorder). My proposed work plan will generate a causal understanding of the brain network mechanisms that allow humans to control their social decisions, thereby elucidating a biological basis for individual differences in social behavior and paving the way for new perspectives on how disordered social behavior may be identified and hopefully remedied.
Summary The terahertz (THz) portion of the electromagnetic spectrum is the junction between optics and electronics. THz is a gate to sensing applications and spectroscopy as well as appealing for material inspection, non-invasive imaging for safety and medical applications and short-range high data rate wireless communication which are being extended to higher frequencies entering the THz range. Optical frequency combs have dominated the scene of laser physics in the last 10 years revolutionizing many fields of optics from metrology to high precision spectroscopy. Optical frequency combs act as rulers in the frequency domain and are characterized by their perfectly equally spaced and coherent modes. An extremely appealing application of optical frequency combs is the so-called dual-comb spectroscopy where multi-heterodyne detection is performed allowing Fourier transform spectroscopy with high resolution, high sensitivity and no moving parts. The objective of this proposal is to create on-chip, self-referenced frequency combs operating in the spectral region from 1.5-5-5 THz. Two main approaches will be followed: direct generation with THz QC lasers (cryogenically cooled) and room temperature non-linear generation by means of Mid-IR QCL combs. Such devices will be groundbreaking since they will allow high resolution THz spectroscopy and they will pave the way to high-rate local data transmission and coherent communication. We recently demonstrated octave spanning lasing from a THz QCL: this will constitute the foundation of our efforts. The developed combs will be implemented in the extremely powerful dual-comb scheme with innovative on-chip self-stabilization and detection of the multi-heterodyne signals. The self-referencing and the independence from an external detector makes the proposed devices disruptive due to their extreme compactness, intrinsic stability and large bandwidth.
The terahertz (THz) portion of the electromagnetic spectrum is the junction between optics and electronics. THz is a gate to sensing applications and spectroscopy as well as appealing for material inspection, non-invasive imaging for safety and medical applications and short-range high data rate wireless communication which are being extended to higher frequencies entering the THz range. Optical frequency combs have dominated the scene of laser physics in the last 10 years revolutionizing many fields of optics from metrology to high precision spectroscopy. Optical frequency combs act as rulers in the frequency domain and are characterized by their perfectly equally spaced and coherent modes. An extremely appealing application of optical frequency combs is the so-called dual-comb spectroscopy where multi-heterodyne detection is performed allowing Fourier transform spectroscopy with high resolution, high sensitivity and no moving parts. The objective of this proposal is to create on-chip, self-referenced frequency combs operating in the spectral region from 1.5-5-5 THz. Two main approaches will be followed: direct generation with THz QC lasers (cryogenically cooled) and room temperature non-linear generation by means of Mid-IR QCL combs. Such devices will be groundbreaking since they will allow high resolution THz spectroscopy and they will pave the way to high-rate local data transmission and coherent communication. We recently demonstrated octave spanning lasing from a THz QCL: this will constitute the foundation of our efforts. The developed combs will be implemented in the extremely powerful dual-comb scheme with innovative on-chip self-stabilization and detection of the multi-heterodyne signals. The self-referencing and the independence from an external detector makes the proposed devices disruptive due to their extreme compactness, intrinsic stability and large bandwidth.
Summary Cholera is one of the oldest infectious diseases known and remains a major burden in many developing countries. The World Health Organization estimates that up to 4 million cases of cholera occur annually. The transmission of cholera by contaminated water, particularly under epidemic conditions, was first reported in the 19th century. However, early volunteer studies suggested that an incredibly high infectious dose (ID) is required to produce disease symptoms, in contrast to most other intestinal pathogens. Therefore, the mechanism of infection of index cases at the onset of an outbreak is unclear. This proposal aims to fill this knowledge gap by studying how the environmental lifestyle of the causative agent of the disease, the bacterium Vibrio cholerae, may prime the pathogen for intestinal colonization. We hypothesize that one of the natural niches of the bacterium (chitinous surfaces) fosters biofilm formation and provides a competitive advantage over co-colonizing bacteria. As an adaptive trait, passage of chitin-attached sessile V. cholerae through the acidic environment of the human stomach might be vastly facilitated compared to planktonic bacteria. Moreover, interbacterial warfare exerted by V. cholerae on these biotic surfaces may help the pathogen overcome the colonization barrier imposed by the human microbiota upon ingestion. The mechanism by which V. cholerae leaves the sessile lifestyle and the regulatory circuits involved in this process will also be investigated in this project. In summary, our goal is to elucidate the environmental community structures of V. cholerae that may enhance transmissibility from the ecosystem to humans in endemic areas resulting in the infection of index cases.
Cholera is one of the oldest infectious diseases known and remains a major burden in many developing countries. The World Health Organization estimates that up to 4 million cases of cholera occur annually. The transmission of cholera by contaminated water, particularly under epidemic conditions, was first reported in the 19th century. However, early volunteer studies suggested that an incredibly high infectious dose (ID) is required to produce disease symptoms, in contrast to most other intestinal pathogens. Therefore, the mechanism of infection of index cases at the onset of an outbreak is unclear. This proposal aims to fill this knowledge gap by studying how the environmental lifestyle of the causative agent of the disease, the bacterium Vibrio cholerae, may prime the pathogen for intestinal colonization. We hypothesize that one of the natural niches of the bacterium (chitinous surfaces) fosters biofilm formation and provides a competitive advantage over co-colonizing bacteria. As an adaptive trait, passage of chitin-attached sessile V. cholerae through the acidic environment of the human stomach might be vastly facilitated compared to planktonic bacteria. Moreover, interbacterial warfare exerted by V. cholerae on these biotic surfaces may help the pathogen overcome the colonization barrier imposed by the human microbiota upon ingestion. The mechanism by which V. cholerae leaves the sessile lifestyle and the regulatory circuits involved in this process will also be investigated in this project. In summary, our goal is to elucidate the environmental community structures of V. cholerae that may enhance transmissibility from the ecosystem to humans in endemic areas resulting in the infection of index cases.
Summary Striking morphological transformations are a hallmark of any cell division cycle. During nuclear division chromatin is compacted into distinctive rod-shaped chromatids in preparation of chromosome segregation by the spindle apparatus. Multi-subunit SMC protein complexes and a large number of regulatory factors are at the heart of this elementary process. SMC complexes also play key roles during other aspects of genome function such as the control of gene expression and the repair of damaged DNA. They are thought to act as chromatin linkers with exquisite specificity for certain pairs of DNA fibres. However, the underlying molecular mechanisms are not understood. Active extrusion of DNA loops by the SMC complex has been proposed to be the mechanistic basis for the establishment of long-range, intra-chromatid DNA bridges. Here, I put forward a multi-pronged research programme that aims to elucidate fundamentally conserved features of SMC protein function and action using the prokaryotic SMC condensin complex in Bacillus subtilis as a tractable model system. We will conduct a combined structural, biochemical and cell biology approach (including crystallography, electron paramagnetic resonance, ChIP-Seq and ‘native’ HiC) to uncover how the SMC complex acts at the higher levels of organization of the bacterial chromosome to promote the efficient individualization of sister DNA molecules. We will reveal the molecular and structural bases for the association between the SMC complex and the bacterial chromosome at different stages of the loading reaction – each representing a crucial intermediate in a sophisticated chromosome organization process. For the first time, we will be able to map the paths of chromosomal DNA through an SMC complex. Our in-depth mechanistic insights will likely have implications for the understanding of various pathological conditions and have the potential to contribute to the development of novel antibacterial compounds.
Striking morphological transformations are a hallmark of any cell division cycle. During nuclear division chromatin is compacted into distinctive rod-shaped chromatids in preparation of chromosome segregation by the spindle apparatus. Multi-subunit SMC protein complexes and a large number of regulatory factors are at the heart of this elementary process. SMC complexes also play key roles during other aspects of genome function such as the control of gene expression and the repair of damaged DNA. They are thought to act as chromatin linkers with exquisite specificity for certain pairs of DNA fibres. However, the underlying molecular mechanisms are not understood. Active extrusion of DNA loops by the SMC complex has been proposed to be the mechanistic basis for the establishment of long-range, intra-chromatid DNA bridges. Here, I put forward a multi-pronged research programme that aims to elucidate fundamentally conserved features of SMC protein function and action using the prokaryotic SMC condensin complex in Bacillus subtilis as a tractable model system. We will conduct a combined structural, biochemical and cell biology approach (including crystallography, electron paramagnetic resonance, ChIP-Seq and ‘native’ HiC) to uncover how the SMC complex acts at the higher levels of organization of the bacterial chromosome to promote the efficient individualization of sister DNA molecules. We will reveal the molecular and structural bases for the association between the SMC complex and the bacterial chromosome at different stages of the loading reaction – each representing a crucial intermediate in a sophisticated chromosome organization process. For the first time, we will be able to map the paths of chromosomal DNA through an SMC complex. Our in-depth mechanistic insights will likely have implications for the understanding of various pathological conditions and have the potential to contribute to the development of novel antibacterial compounds.
Summary Transient multivalent interactions are critical for biological processes such as signaling pathways controlling chromatin function. Chromatin, the nucleoprotein complex organizing the genome, is dynamically regulated by post-translational modifications (PTMs) of the chromatin fiber. Protein effectors interact with combinations of these PTMs through multivalent interactions, deposit novel PTMs, thereby propagate signaling cascades and remodel chromatin structure. To reveal the underlying molecular mechanisms, methods outside classical biochemistry are required, in particular due to the combinational complexity of chromatin PTMs and the transient supramolecular interactions crucial for their recognition. Here, we develop a novel approach, where we synthesize arrays of chemically defined designer chromatin fibers and use dynamic multiplex single-molecule imaging to dissect multivalent signaling processes in chromatin. Our studies target a key pathway, the DNA damage response (DDR), which regulates DNA repair processes central to cell survival and is critically implicated in cancer. Detailed knowledge is of utmost importance to develop targeted therapeutic interventions. We thus employ advanced peptide and protein chemistry to generate libraries of chromatin fibers of a defined PTM state that is encoded in the chromatin DNA. With the library immobilized in a flow cell, we use single-molecule detection to directly observe signaling processes by key DDR effectors in real time. Subsequent in situ polony decoding allows the identification of each chromatin fiber’s modification state, enabling broad sampling of signaling outcomes. Finally, we use dynamic computational models to integrate the effector-chromatin interaction network and test key mechanisms in cancer-based cell culture. Together, these methods will yield fundamental insight into chromatin and DDR signaling and will be of broad use for chemical and biomedical research with applications beyond the chromatin field.
Transient multivalent interactions are critical for biological processes such as signaling pathways controlling chromatin function. Chromatin, the nucleoprotein complex organizing the genome, is dynamically regulated by post-translational modifications (PTMs) of the chromatin fiber. Protein effectors interact with combinations of these PTMs through multivalent interactions, deposit novel PTMs, thereby propagate signaling cascades and remodel chromatin structure. To reveal the underlying molecular mechanisms, methods outside classical biochemistry are required, in particular due to the combinational complexity of chromatin PTMs and the transient supramolecular interactions crucial for their recognition. Here, we develop a novel approach, where we synthesize arrays of chemically defined designer chromatin fibers and use dynamic multiplex single-molecule imaging to dissect multivalent signaling processes in chromatin. Our studies target a key pathway, the DNA damage response (DDR), which regulates DNA repair processes central to cell survival and is critically implicated in cancer. Detailed knowledge is of utmost importance to develop targeted therapeutic interventions. We thus employ advanced peptide and protein chemistry to generate libraries of chromatin fibers of a defined PTM state that is encoded in the chromatin DNA. With the library immobilized in a flow cell, we use single-molecule detection to directly observe signaling processes by key DDR effectors in real time. Subsequent in situ polony decoding allows the identification of each chromatin fiber’s modification state, enabling broad sampling of signaling outcomes. Finally, we use dynamic computational models to integrate the effector-chromatin interaction network and test key mechanisms in cancer-based cell culture. Together, these methods will yield fundamental insight into chromatin and DDR signaling and will be of broad use for chemical and biomedical research with applications beyond the chromatin field.
Summary Neurodegenerative diseases (NDs) are incurable, debilitating conditions, arise mid-late in life, represent an enormous health and socioeconomic burden and no therapies exist. An enigmatic finding in NDs is the early and selective alteration in intrinsic excitability of vulnerable neurons paralleling changes in its circuitry. However, a gap in understanding exists in ND field about the cause of these alterations and whether these modifications regulate degenerative pathomechanisms. Our recent study, examining mechanisms of Purkinje cell (PC) degeneration in Spinocerebellar ataxia type 1 (SCA1) revealed that the earliest cerebellar alterations occur in the major excitatory inputs onto PCs, the climbing fibers (CFs). Based on this, we propose a novel three-step model of neurodegeneration: First, suboptimal functioning of the presynaptic inputs initiates signaling deficits in target PCs. Second, those alterations trigger maladaptive responses such as altered intrinsic PC excitability, thus amplifying pathogenic cascades. Third, at network level progressive dysfunction triggers compensatory synaptic modifications within the cerebellar circuitry. In this proposal, we will test our new hypothesis for NDs on SCA1 and this will be the first study to test circuit-dependency in NDs by selectively silencing presynaptic inputs and examining molecular responses in the postsynaptic neuron. Specifically, we will 1) Identify the dysfunctional CF associated molecular signature in PCs. 2) Elucidate mechanisms involved in altering intrinsic PC excitability. 3) Map the connectome for a structural correlate of the pathology. Using conditional mouse models, pharmacogenetics, transcriptomics, proteomics and connectomics, we will delineate molecular alterations that govern disease from compensatory alterations. Our systematic approach will not only impact SCA related therapies but the entire spectrum of NDs and has the potential to change the conceptual approach of future studies on NDs.
Neurodegenerative diseases (NDs) are incurable, debilitating conditions, arise mid-late in life, represent an enormous health and socioeconomic burden and no therapies exist. An enigmatic finding in NDs is the early and selective alteration in intrinsic excitability of vulnerable neurons paralleling changes in its circuitry. However, a gap in understanding exists in ND field about the cause of these alterations and whether these modifications regulate degenerative pathomechanisms. Our recent study, examining mechanisms of Purkinje cell (PC) degeneration in Spinocerebellar ataxia type 1 (SCA1) revealed that the earliest cerebellar alterations occur in the major excitatory inputs onto PCs, the climbing fibers (CFs). Based on this, we propose a novel three-step model of neurodegeneration: First, suboptimal functioning of the presynaptic inputs initiates signaling deficits in target PCs. Second, those alterations trigger maladaptive responses such as altered intrinsic PC excitability, thus amplifying pathogenic cascades. Third, at network level progressive dysfunction triggers compensatory synaptic modifications within the cerebellar circuitry. In this proposal, we will test our new hypothesis for NDs on SCA1 and this will be the first study to test circuit-dependency in NDs by selectively silencing presynaptic inputs and examining molecular responses in the postsynaptic neuron. Specifically, we will 1) Identify the dysfunctional CF associated molecular signature in PCs. 2) Elucidate mechanisms involved in altering intrinsic PC excitability. 3) Map the connectome for a structural correlate of the pathology. Using conditional mouse models, pharmacogenetics, transcriptomics, proteomics and connectomics, we will delineate molecular alterations that govern disease from compensatory alterations. Our systematic approach will not only impact SCA related therapies but the entire spectrum of NDs and has the potential to change the conceptual approach of future studies on NDs.
Summary We are witnessing transformative results in the clinical application of both cancer immunotherapies and gene transfer technologies. Tumor vaccines are a specific modality of cancer immunotherapy. Similar to vaccination against pathogens, tumor vaccines are designed to elicit a specific immune response against cancer. They are based on the administration of inactivated cancer cells or tumor antigens, or the inoculation of antigen-presenting cells (APCs) previously exposed to tumor antigens. In spite of significant development and testing, tumor vaccines have largely delivered unsatisfactory clinical results. Indeed, while some patients show dramatic and durable cancer regressions, many do not respond, highlighting both the potential and the shortcomings of current vaccination strategies. Hence, identifying and abating the barriers to effective cancer vaccines is key to broadening their therapeutic reach. The goal of EVOLVE (EVirs to Optimize and Leverage Vaccines for cancer Eradication) is to propel the development of effective APC-based tumor vaccines using an innovative strategy that overcomes several key hurdles associated with available treatments. EVOLVE puts forward a novel APC engineering platform whereby chimeric receptors are used to both enable the specific and efficient uptake of cancer-derived extracellular vesicles (EVs) into APCs, and to promote the cross-presentation of EV-associated tumor antigens for stimulating anti-tumor immunity. EVOLVE also envisions a combination of ancillary ‘outside of the box’ interventions, primarily based on further APC engineering combined with innovative pre-conditioning of the tumor microenvironment, to facilitate the deployment of effective APC-driven, T-cellmediated anti-tumor immunity. Further to preclinical trials in mouse models of breast cancer and melanoma, our APC platform will be used to prospectively identify novel human melanoma antigens and reactive T cell clones for broader immunotherapy applications.
We are witnessing transformative results in the clinical application of both cancer immunotherapies and gene transfer technologies. Tumor vaccines are a specific modality of cancer immunotherapy. Similar to vaccination against pathogens, tumor vaccines are designed to elicit a specific immune response against cancer. They are based on the administration of inactivated cancer cells or tumor antigens, or the inoculation of antigen-presenting cells (APCs) previously exposed to tumor antigens. In spite of significant development and testing, tumor vaccines have largely delivered unsatisfactory clinical results. Indeed, while some patients show dramatic and durable cancer regressions, many do not respond, highlighting both the potential and the shortcomings of current vaccination strategies. Hence, identifying and abating the barriers to effective cancer vaccines is key to broadening their therapeutic reach. The goal of EVOLVE (EVirs to Optimize and Leverage Vaccines for cancer Eradication) is to propel the development of effective APC-based tumor vaccines using an innovative strategy that overcomes several key hurdles associated with available treatments. EVOLVE puts forward a novel APC engineering platform whereby chimeric receptors are used to both enable the specific and efficient uptake of cancer-derived extracellular vesicles (EVs) into APCs, and to promote the cross-presentation of EV-associated tumor antigens for stimulating anti-tumor immunity. EVOLVE also envisions a combination of ancillary ‘outside of the box’ interventions, primarily based on further APC engineering combined with innovative pre-conditioning of the tumor microenvironment, to facilitate the deployment of effective APC-driven, T-cellmediated anti-tumor immunity. Further to preclinical trials in mouse models of breast cancer and melanoma, our APC platform will be used to prospectively identify novel human melanoma antigens and reactive T cell clones for broader immunotherapy applications.

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