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CIPHER will launch the global research initiative, Hip Hop Interpellation, pilot a new semantic digital/ethnographic web methodology, and codify the emergent discipline of global hip hop studies. It addresses the central question: why has this highly localized and authenticizing African American music translated so easily to far-flung communities and contexts around the globe? Through this specific question the project attempts to understand the foundational and broadly transferable question: how are globalization and localization related? To answer these questions CIPHER posits the Hip Hop Interpellation thesis, that hip hop spreads not as a copy of an African American original, but, through its performance of knowledge, emerges as an always already constituent part of local knowledge and practice. The theorization thus moves beyond the “hailing practices” described by Althusser’s theory of interpellation—the discursive webs that coerce ideological incorporation—to describing an interpolation that locates other histories within and through hip hop’s performed knowledges. CIPHER’s semantic web methodology tests this thesis, tracking how hip hop memes—slogans, anthems, and icons—are simultaneously produced by people and produce people. This research clears the conceptual impasse of structural “cultural imperialism” vs. agentic “cultural appropriation” debates and instrumentalizes the methodological distance between ethnographic specificity and big data generality. It does so by creating a feedback loop between digital humanities methods (crowd sourcing, semantic tagging, computational stylometry) and ethnographic fieldwork techniques (interviews, musical analysis, participant observation). The result will be an iterative map of Hip Hop Interpellation/Interpolation created by stakeholders that is transformational of our understanding of culture and/as cultural production and transferable to pressing questions about globalization and l’exception culturelle.

Immunotherapy holds the potential to dramatically improve the curative prognosis of cancer patients. However, despite significant progress, a huge gap remains to be bridged to gain board success in the clinic. A first limiting factor in cancer immunotherapy is the low response rate in large fraction of the patients and an unmet need exists for more efficient - potentially synergistic - immunotherapies that improve upon or complement existing strategies. The second limiting factor is immune-related toxicity that can cause live-threatening situations as well as seriously impair the quality of life of patients. Therefore, there is an urgent need for safer immunotherapies that allow for a more target-specific engineering of the immune system. Strategies to engineer the immune system via a materials chemistry approach, i.e. immuno-engineering, have gathered major attention over the past decade and could complement or replace biologicals, and holds promise to contribute to resolving the current issues faced by the immunotherapy field. I hypothesize that synthetic biomaterials can play an important role in anti-cancer immunotherapy with regard to synergistic, safe, but potent, instruction of innate and adaptive anti-cancer immunity and to revert the tumor microenvironment from an immune-suppressive into an immune-susceptible state. Hereto, the overall scientific objective of this proposal is to fully embrace the potential of immuno-engineering and develop several highly synergistic biomaterials strategies to engineer the immune system to fight cancer. I will develop a series of biomaterials and address a number of fundamental questions with regard to optimal biomaterial design for immuno-engineering. Based on these findings, I will elucidate those therapeutic strategies that lead to synergistic engineering of innate and adaptive immunity in combination with remodeling the tumor microenvironment from an immune-suppressive into an immune-susceptible state.

What is the origin of the electromagnetic (EM) counterparts of gravitational waves observed from compact binary mergers? What makes short gamma ray bursts (GRBs)? What are the sources of IceCube’s high-energy neutrinos? Are all core-collapse supernovae exploding via the same mechanism? These are some of the puzzles that have emerged with the rapid progress of time domain astronomy. Relativistic jets in compact binary mergers and GRBs, and their interaction with the surrounding media hold the key to these, and other, seemingly unrelated broad-impact questions. Here I propose a new forefront study of how relativistic jets interact with their surrounding media and of its numerous implications, focusing on compact binary mergers and GRBs. The goal of this project is to study, first, the jet-media interaction, and the microphysics of the radiation-mediated shocks that it drives. I will then use the results, together with available observations, to learn about compact binary mergers, GRBs and SNe, sheding light on the questions listed above, and probing the nature of relativistic jets in general. Important goals will include: (i) General models for the propagation of relativistic jets in various media types. (ii) Modeling of the EM signal generated by jet-media interaction following compact binary mergers. (iii) Estimates of the neutrino signal from jet-media interaction in GRBs and SNe. (iv) Constraint the role of jets in SN explosions. This project is timey as it comes at the beginning of a new multi-messenger era where the EM counterparts of GW sources are going to be detected on a regular basis and where the face of transient astrophysics is going to be changed by a range of large scale surveys such as LSST, the SKA, and more. This project will set the theoretical base for understanding numerous known and yet-to be discovered transients that will be detected in the next decade.

Most advanced economies have struggled to deliver inclusive growth in recent decades. Many people are fearful about the impact on their lives of technological change, large-scale immigration, and a shifting balance of power in the labour market that seems to have benefitted employers at the expense of workers. There is a widening gap in economic fortunes between ex-industrial areas and dynamic cities with service-based economies. The stakes are high: we should not be surprised if some voters no longer support growth-enhancing policies if they do not anticipate benefitting from that growth. While it is easy to identify the problems, diagnosing the causes and finding effective solutions has been more difficult. This proposal aims to improve our analytical tools for thinking about these problems and to develop appropriate policies to respond. On the impact of technology, it will extend our understanding of the link between job polarization and inequality and analyse the appropriate skills policy. On immigration it will develop models of the impact of migration in which employers play a pro-active role as they do in many labour markets. This will be done by integrating models of migration with models of imperfectly competitive labour markets. The empirical content of these models and the implications for migration policies will be explored. On labour market competition the project will provide better estimates of how responsive recruitment is to wages offered by firms, and better measures of the gap between wages and productivity and how this varies across different types of labour markets. The intention is that the proposal will help to develop practical policies to improve people’s lives. But it also aims to provide improved models and empirical methodologies to make a more lasting intellectual contribution, to equip us with the tools to analyse and develop policy not just for the problems we face today but the new ones we will undoubtedly face in the future.

Bacterial secretion systems release effectors into the extra-cellular milieu or directly into foreign cells. They represent fundamental mechanisms by which bacteria modulate their environment and induce human infection. Here we study two related and complementary secretion systems, the bacterial type II secretion system (T2SS) and the Tad secretion system (TdSS). The T2SS secretes effectors and toxins involved in cell adherence, biofilm formation and host cell death. The TdSS drives cell adherence and colonization through extra-cellular pilus formation. Both secretion systems constitute multi-component complexes with many shared components that span the cell envelope of Gram-Negative bacteria. The overall goal is to determine the molecular mechanism underlying T2SS and TdSS operation. Key aims for the T2SS include showing how substrate is recruited, how inner membrane components are organised, and how pseudo-pilus assembly is coordinated. The repertoire of K. pneumoniae T2SS virulence factors will also be expanded. For the TdSS, key aims include structure-function studies on the outer membrane secretin with its associated pilotin and pilus. Comparison of T2SS and TdSS structures will reveal common mechanistic and evolutionary principles. By understanding how the T2SS and TdSS function and promote pathogenesis, this research has the potential to facilitate drug development and combat anti-microbial resistance. Some bacteria cause infections in humans that kill millions of people annually. To trigger the infection, the bacteria contain nanomachines within their cell surface that act like miniature pumps. These are secretion systems. One role of secretion systems is to deliver harmful proteins from inside the bacteria to outside environments like your cells. These harmful proteins act as molecular weaponry in many ways. They can form grappling hooks to help the bacteria attach to environments like your intestine or as molecular malware that maliciously reprogram your cells. We use a powerful technique called cryo-electron microscopy, which allows us to visualize the precise position of the atoms within the secretion systems. In this way we can learn the 3D structure and chemistry of the secretion systems. By understanding how the secretion systems work we have a much greater chance of developing medicines that stop the secretion systems from causing human illness.

Mucus-Penetrating Microbiota: Characterization, Mechanism and Therapeutic in Metabolic Disease Humanity is facing an epidemic of inter-related metabolic disorders, including obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hepatic steatosis, that altogether have major impact on the promotion of cardiovascular diseases. The increasing incidence of these complex metabolic disorders and their highly morbid, chronic and costly downstream diseases threatens to overwhelm the world’s health care systems and economies, making it a top public health priority in dire need of investigation. The intestinal tract is inhabited by a large and diverse community of bacteria, collectively referred to as the intestinal microbiota. When stably maintained at an appropriately safe distance from the epithelial cell monolayer, the microbiota provides important benefits to its host. However, disturbance of the microbiota-host relationship, promoted by genetic or non-genetic factors, can alter intestinal homeostasis and drive chronic low-grade intestinal inflammation, ultimately leading to metabolic abnormalities. We previously reported that a ubiquitous class of food additives, emulsifiers, detrimentally impact the microbiota resulting in its encroachment into the mucus layer that associated with low-grade inflammation and development of metabolic disorders. The central goal of this proposal is to investigate the hypothesis that bacteria that penetrate the inner part of the mucus layer, referred as invaders, promote development of metabolic alterations. We herein propose to identify mucus-invaders, in preclinical models and clinical conditions, and investigate mechanisms by which they promote inflammatory and metabolic abnormalities. Furthermore, we propose to define original approaches to modulate the intestinal microbiota in order to counteract microbiota encroachment and protect against associated metabolic abnormalities.

For many years, lymphatic vessels have been viewed as inert fluid conduits whose open structure allows for passive flow of antigens, proteins and cells from peripheral tissues to lymphoid organs. Yet, recent discoveries highlighting novel functions and heterogeneous origins of the lymphatic endothelium, call for reevaluation of the passive lymphatic-vessel paradigm. During the past decade, we have used the zebrafish (ZF) to detail the cellular and molecular events underlying the development of the lymphatic system. Our discoveries have greatly contributed to our understanding of the origins, specification and mechanisms of formation of lymphatic endothelial cells (LECs) in the developing embryo. In line with our past achievements, we now aim towards novel directions- to transform the adult ZF into an equally convenient model for the study of lymphatic diversity. The overall goal of LymphMap is to reveal the multiple regulatory levels that coordinate the formation and functionality of lymphatic vessels in health and disease. To this end, we will carry out a comprehensive research program characterizing four distinct aspects of lymphatic biology: 1.Cellular origins and molecular signature of LECs 2.Formation and specialization of organotypic lymphatics 3.Lymphatic vessels during organ regeneration 4.Lymphatic involvement in human disease Our experimental strategy involves the combination of high-resolution imaging, global expression profiling and regeneration models in adult ZF, with analyses of human-derived LECs in various clinical settings. The important and unique aspects of our approach are the focus on in vivo dynamics, and the cross-organ comparative analysis, which will likely provide the much-needed knowledge on lymphatic diversity in health and disease. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving lymphatics as passive bystanders, but rather as orchestrators of tissue morphogenesis and regeneration.

The four fundamental interactions and their symmetries, the fundamental constants as well as the properties of elementary particles like masses and moments, determine the basic structure of the universe and are the basis for our so well tested Standard Model (SM) of physics. Performing stringent tests on these interactions and symmetries in extreme conditions at lowest energies and with highest precision by comparing e.g. the properties of particles and their counterpart, the antiparticles, will allow us to search for physics beyond the SM. Any improvement of these tests beyond their present limits will require novel experimental techniques. To this end, we propose ambitious Penning-trap based single-ion experiments and measurements of magnetic moments and atomic masses to substantially improve the to-date best limits on some of the key SM predictions. While the measurement technique in determining the eigenfrequencies of the stored particles with unprecedented precision will be identical to the technique used in the past ERC grant by the PI (MEFUCO - MEasurements of FUndamental COnstants), the novel ion preparation and cooling techniques to be developed as well as the physics questions to be addressed are completely different. The new findings will enable us to perform stringent tests of fundamental symmetries like charge-parity-time reversal symmetry (CPT theorem) with (anti)protons or of the energy-mass equivalence principle as well as tests of interactions like quantum electrodynamics in strong fields by using highly charged ions. This will enable us to set new limits on SM predictions or even to reveal their failures. To meet these challenges, advanced charge breeding and cooling techniques will make it possible for us to achieve among other advances a ten-fold improved test of E = mc2, and thus of Einstein’s special theory of relativity and the most stringent CPT test in the baryonic sector by comparing the magnetic moments of the proton and the antiproton.

Endocrine disruptors (EDs) are defined as exogenous chemicals that alter functions of the endocrine system, thereby causing adverse health effects in an organism or its progeny. Historically, the field of ED research has focused on reproductive endocrinology and related hormones, which is reflected in the regulatory test methods assessing endocrine effects of xenobiotics. However, recent evidence links increased incidence of metabolic syndrome (a cluster of metabolic risk factors including abdominal obesity, dyslipidemia, elevated blood pressure, and elevated fasting glucose) to EDs, increasing the incidence of atherosclerosis and type 2 diabetes. Despite these findings, adequate testing methods for metabolic effects of EDs are lacking. The project “Metabolic effects of Endocrine Disrupting Chemicals: novel testing METhods and adverse outcome pathways” (EDCMET) brings together experts in various research fields, including systems toxicologists, experimental biologists with a thorough understanding of the molecular mechanisms of metabolic disease and comprehensive in vitro and in vivo methodological skills and ultimately, epidemiologists linking environmental exposure to adverse metabolic outcomes. This proposal focuses on developing novel test methods and models to assess the metabolic effects of EDs. Combined in silico methods, in vitro and in vivo methods are developed with an emphasis on liver and adipose tissue and endocrine pathways related to their metabolism. In addition, epidemiological and field monitoring data is used to gain information regarding the exposure to chemicals and ED-related metabolic effects. The interdisciplinary approach and complementary expertise of the participants will identify novel mechanisms of action, and in collaboration with the European Commission Joint Research Centre (JRC) providing an interface between the programme and European regulatory agencies, novel validated test methods for regulatory purposes will be generated.

The dominantly inherited spinocerebellar ataxias (SCAs) are rare neurodegenerative disorders which primarily affect the cerebellum, the area of the brain responsible for motor coordination. Patients suffering from SCAs experience a progressive loss of coordination as the cerebellum degenerates. Key cerebellar cells known as Purkinje cells (PCs) are particularly affected, but not enough is known about the disease mechanisms and there is currently no cure. This project aims to investigate the role of two key proteins – TRPC3 and mGluR1 – in the molecular pathways underlying these disorders. mGluR1 is a cell-surface membrane protein which responds to the neurotransmitter glutamate at synapses and leads to activation of TRPC3, an ion channel which allows positively charged ions such as calcium into the cell. Mutations in both proteins have been identified in different subtypes of SCA; these mutations lead to increased protein activity and a subsequent toxic increase of intracellular calcium. Using computational techniques, in vitro studies, and a novel mGluR1 mutant mouse model, I will investigate the impact of mutant TRPC3 and mGluR1 on PCs, as well as the effects of novel TRPC3 inhibitors, to better understand the molecular mechanisms underlying SCAs and work towards new therapeutic approaches.