ERC FUNDED PROJECTS

The brain evolves, develops, and operates in the context of animal movements. As a consequence, fundamental brain functions such as spatial perception and motor control critically depend on the precise knowledge of the ongoing body motion. An accurate internal estimate of self-movement is thought to emerge from sensorimotor integration; nonetheless, which circuits perform this internal estimation, and exactly how motor-sensory coordination is implemented within these circuits are basic questions that remain to be poorly understood. There is growing evidence suggesting that, during locomotion, motor-related and visual signals interact at early stages of visual processing. In mammals, however, it is not clear what the function of this interaction is. Recently, we have shown that a population of Drosophila optic-flow processing neurons —neurons that are sensitive to self-generated visual flow, receives convergent visual and walking-related signals to form a faithful representation of the fly’s walking movements. Leveraging from these results, and combining quantitative analysis of behavior with physiology, optogenetics, and modelling, we propose to investigate circuit mechanisms of self-movement estimation during walking. We will:1) use cell specific manipulations to identify what cells are necessary to generate the motor-related activity in the population of visual neurons, 2) record from the identified neurons and correlate their activity with specific locomotor parameters, and 3) perturb the activity of different cell-types within the identified circuits to test their role in the dynamics of the visual neurons, and on the fly’s walking behavior. These experiments will establish unprecedented causal relationships among neural activity, the formation of an internal representation, and locomotor control. The identified sensorimotor principles will establish a framework that can be tested in other scenarios or animal systems with implications both in health and disease.

1 500 000 €

Start date: 2017-11-01, End date: 2022-10-31

Parkinson’s Disease is usually characterised by motor impairment, and Autism by social difficulties. However, the co-occurrence of social and motor symptoms is critically underappreciated; Parkinson’s Disease patients exhibit social symptoms, and motor difficulties are common in Autism. At present, the biological basis of co-occurring social and motor impairment is unclear. Notably, both Autism and Parkinson’s Disease have been associated with dopamine (DA) system dysfunction and, in non-clinical populations, DA has been linked with social and motor ability. These disparate strands of research have never been combined. Brain2Bee will use psychopharmacology in typical individuals to develop a model of the relationship between DA, Motor, and Social behaviour – the DAMS model. Brain2Bee will use sophisticated genetic analysis to refine DAMS, elucidating the contributions of DA-related biological processes (e.g. synthesis, receptor expression, reuptake). Brain2Bee will then test DAMS’ predictions in patients with Parkinson’s Disease and Autism. Finally, Brain2Bee will investigate whether DAMS generalises to an animal model, the honey bee, enabling future research to unpack the cascade of biological events linking DA-related genes with social and motor behaviour. Brain2Bee will unite disparate research fields and establish the DAMS model. The causal structure of DAMS will identify the impact of dopaminergic variation on social and motor function in clinical and non-clinical populations, elucidating, for example, whether social difficulties in Parkinson’s Disease are a product of the motor difficulties caused by DA dysfunction. DAMS’ biological specificity will provide unique insight into the DA-related processes linking social and motor difficulties in Autism. Thus, Brain2Bee will determine the type of dopaminergic drugs (e.g. receptor blockers, reuptake inhibitors) most likely to improve both social and motor function.

1 783 147 €

Start date: 2018-07-01, End date: 2023-06-30

During an organism’s development it must integrate internal and external information. An example in plants, whose development stretches across their lifetime, is the coordination between environmental stimuli and endogenous cues on regulating the key hormone gibberellin (GA). The present challenge is to understand how these diverse signals influence GA levels and how GA signalling leads to diverse GA responses. This challenge is deepened by a fundamental problem in hormone research: the specific responses directed by a given hormone often depend on the cell-type, timing, and amount of hormone accumulation, but hormone concentrations are most often assessed at the organism or tissue level. Our approach, based on a novel optogenetic biosensor, GA Perception Sensor 1 (GPS1), brings the goal of high-resolution quantification of GA in vivo within reach. In plants expressing GPS1, we observe gradients of GA in elongating root and shoot tissues. We now aim to understand how a series of independently tunable enzymatic and transport activities combine to articulate the GA gradients that we observe. We further aim to discover the mechanisms by which endogenous and environmental signals regulate these GA enzymes and transporters. Finally, we aim to understand how one of these signals, light, regulates GA patterns to influence dynamic cell growth and organ behavior. Our overarching goal is a systems level understanding of the signal integration upstream and growth programming downstream of GA. The groundbreaking aspect of this proposal is our focus at the cellular level, and we are uniquely positioned to carry out our multidisciplinary aims involving biosensor engineering, innovative imaging, and multiscale modelling. We anticipate that the discoveries stemming from this project will provide the detailed understanding necessary to make strategic interventions into GA dynamic patterning in crop plants for specific improvements in growth, development, and environmental responses.

1 499 616 €

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

In 380 CE, the Emperor Theodosius (d. 395) ordered all Roman subjects to follow Catholic Christianity and limited imperial patronage to the Catholic Church. Theodosius was the last ruler to reign over a united empire. At his death the realm was divided into two halves, and by the end of Gregory the Great’s papacy (d. 604), a mosaic of independent kingdoms had replaced the western part of the empire. Yet despite the political division, during this period western clerics built a supra-regional ecclesiastical structure with substantial levels of hierarchy and cohesion. Up to the 1950s historians have largely conceived of these ecclesiastical institutions as organizations with widely accepted power. More recent scholarship, however, has revealed the social origin and fallibility of clerical authority. Nonetheless, this move away from the study of institutions has left unanswered the fundamental questions of how a ‘universal’ church was built at a time of political fragmentation, and how the transition from informal mutual aid to more formal hierarchical structures of law- and policy-making came about. With innovative methods of social inquiry we can offer new answers to these historiographical questions. Our project (CONNEC) will use social network analysis and new institutional theory to trace four processes: how clerical networks adapted to the new secular contexts, how these interactions shaped the development of ecclesiastical law, how clerics constructed and disseminated discourses that supported different structures of the church, and how networks fostered compliance and a sense of accountability among clerics. CONNEC’s use of state-of-the-art methods will be enhanced by the implementation of cutting-edge digital technologies, adapting network analysis software for late antique sources. By bringing together digital tools with qualitative textual analysis, CONNEC will provide a more nuanced understanding of a key process of world history.

1 465 316 €

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

Civil emergencies such as flooding, terrorist attacks, fire, etc., can have devastating impacts on people, infrastructure, and economies. Knowing how to best respond to an emergency can be extremely difficult because building a clear picture of the emerging situation is challenging with the limited data and modelling capabilities that are available. Agent-based modelling (ABM) is a field that excels in its ability to simulate human systems and has therefore become a popular tool for simulating disasters and for modelling strategies that are aimed at mitigating developing problems. However, the field suffers from a serious drawback: models are not able to incorporate up-to-date data (e.g. social media, mobile telephone use, public transport records, etc.). Instead they are initialised with historical data and therefore their forecasts diverge rapidly from reality. To address this major shortcoming, this research will develop dynamic data assimilation methods for use in ABMs. These techniques have already revolutionised weather forecasts and could offer the same advantages for ABMs of social systems. There are serious methodological barriers that must be overcome, but this research has the potential to produce a step change in the ability of models to create accurate short-term forecasts of social systems. The project is largely methodological, and will evidence the efficacy of the new methods by developing a cutting-edge simulation of a city – entitled the Dynamic Urban Simulation Technique (DUST) – that can be dynamically optimised with streaming ‘big’ data. The model will ultimately be used in three areas of important policy impact: (1) as a tool for understanding and managing cities; (2) as a planning tool for exploring and preparing for potential emergency situations; and (3) as a real-time management tool, drawing on current data as they emerge to create the most reliable picture of the current situation.

1 499 840 €

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

This project will investigate the origins, acquisition, and evolution of linguistic tone: the use of pitch to distinguish between the meaning of words. Despite the typological ubiquity of tone, there is still no phonetic, structural, or psychological model that explains how and why tones emerge (or fail to emerge) in language after language, nor how they evolve once they are formed. This is because there has never been a systematic analysis of the principles that govern the evolution of tone systems. EVOTONE will provide the first comprehensive study of tonal emergence and evolution, combining detailed phonetic and perceptual studies of Himalayan and Southeast Asian minority languages with innovative experimental methodologies and large-scale computational analysis of the structural principles correlated with the emergence of tone. EVOTONE is guided by a novel hypothesis that, if correct, will have important repercussions for the study of sound change. The core idea is deceptively simple: rather than being the result of small, incremental changes in pronunciation, features like tone come about due to a sudden failure to articulate a particular aspect of a sound. If the risk of focusing on tone is to overemphasize a single feature, the potential reward is enormous: an opportunity to transform our understanding of how physical and cognitive pressures interact to shape human behavior and language change. The outcomes of this project will provide a new empirical foundation for the typology and evolution of tone systems; break new ground in the study of how structural and phonetic factors interact in sound change; and establish, for the first time, an empirically grounded set of principles of tonal evolution. In addition to resolving a number of outstanding questions about tonogenesis, the results will substantially advance our more general understanding of how language changes over time.

1 481 154 €

Start date: 2018-06-01, End date: 2023-05-31

Food Security is a grand challenge of our time, but three factors inhibit our ability to meet global targets. First, interdisciplinary approaches incorporating ecological, social, and health sciences are fundamental, but lacking. Second, a disproportionate focus on food quantity overlooks ‘hidden hunger’, or micronutrient deficiencies, which are implicated in over a million deaths annually. Third, small-scale fisheries (SSF) reach 100s of millions of people in the developing world, hold potential for achieving food security, but remain ‘forgotten food’ in global discourse. Consequently, an interdisciplinary approach that tackles hidden hunger within SSF is a critical frontier for food security research. Fish are particularly high in many micronutrients, but a systematic understanding of which species have the greatest concentrations of key nutrients is needed. Inadequate access to nutritious food is one of the most significant problems of the modern age, which can be illuminated through analyses of power. The failure to realise the tremendous potential for improving food security through fisheries stems from a lack of understanding of how social drivers exacerbate or ameliorate nutritional inequalities. Consequently, an in-depth analysis that quantifies how key social drivers impact nutritional inequality, is essential. FAIRFISH will address these gaps to uncover the ecological and socio-cultural determinants of the contributions SSF make to human health: 1. Establish the ecological and environmental determinants of nutrient availability among fish species using a traits based approach. 2. Advance social practice theory, by integrating an analysis of power, to determine what power relations enable or constrain access to nutritious food. 3. Progress interdisciplinary science, by integrating findings from 1 and 2, to quantify the impact of key social drivers on nutritional inequality, and uncover opportunities to meet nutritional needs.

1 493 605 €

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

In recent years, conservationists have engaged in heated debates about whether and how conservation should respond to the challenges posed by ‘the Anthropocene’—a term increasingly used to encapsulate the overwhelming, transformative impact of human activity on the Earth system. How are these debates—and the wider ‘Anthropocenic’ awareness they embody—reshaping conservation philosophy, strategy and practice? How are they manifested in and across diverse contexts? How, conversely, are global conservation developments and ‘Anthropocenic’ phenomena apprehended and reshaped on the ground? This project explores such urgent questions through an unprecedented study of the global nexus of orangutan conservation at a unique historical juncture marked by flux and uncertainty. Combining in-depth ethnography and multiply-scaled cross-cultural comparison, it approaches orangutan conservation as a sprawling, uneven terrain across which the rapidly-evolving relationship between conservation and ‘the Anthropocene’ is being played out. Its objectives are 1) to examine if and how contemporary conservation is being ‘scaled up’ and re(con)figured in and for ‘the Anthropocene’; and 2) to cut ‘the Anthropocene’ down to size by exploring how it is experienced, conceptualized, contested or indeed refused across multiple conservation settings. Comprising four interlinked studies to be carried out simultaneously at the main nodes of orangutan conservation, this project seeks to pioneer a new synchronic, multi-sited approach to the analysis of global conservation and lay the groundwork for an empirically-driven, theoretically ambitious new field of scholarship on conservation in/for ‘the Anthropocene’—one that will revitalize social scientific understandings of conservation while adding much-needed empirical depth and nuance to emerging cross-disciplinary discussions about ‘the Anthropocene’.

1 407 676 €

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

GRIEVANCE seeks to make significant advances in increasing our understanding, and thereby reducing the risk, of extremist violence against non-combatants. An inter-disciplinary project underpinned by crime prevention principles is needed to help quantify the risk of such offences. The barbarity of such violent acts, coupled with the fact that participation in them is characterised by an extremely low base rate, has led researchers to seek out individual qualities of the offender with a particular focus upon what radicalisation is and how its drivers can be countered. This search has proven unproductive and impractical. In fact, it has most likely limited and unduly narrowed a wider consideration of the ways in which social scientists can bring what conceptual tools we have to bear on the problem of controlling and managing such behaviour. By doing so, this project shifts the focus from individual qualities (what we think terrorists and other similar offenders “are”) to a consideration of the situational qualities of their behaviour – in other words, what violent offenders do and how they do it (Horgan, 2009: 143). This is consistent with developments in the area of crime control (Cornish and Clarke, 1986; Brantingham & Brantingham, 1981) and crime science more generally. More specifically, GRIEVANCE will utilise a number of unique datasets to understand the risk of extremist violence across a number of phases of analysis. GRIEVANCE characterises risk in terms of a process and dedicates a work package (WP) to each stage of the process from the risk of radicalisation (WP1), to the risk of recruitment (WP2), to the risk of violent action (WP3), to the temporal (WP4) and spatial (WP5) risk of offending behaviour followed by an assessment of the risk of adverse consequences from intervention (WP6). GRIEVANCE will both synthesise the existing knowledge within the literature and produce innovative new findings by utilising cutting edge inter-disciplinary research methods.

1 458 345 €

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

What does mean to be heterosexual? How do you know if you are heterosexual? Though much research has investigated what it means to be *homosexual* very little empirical research has investigated the meaning of heterosexuality. Furthermore, most people who consider themselves heterosexual have never given this question much thought. However, a number of recent, tragic events (e.g., the murder of Gwen Araujo and the deadly attack by Omar Mateen) show that our perceptions of heterosexuality can have profound ramifications for our self-image and our treatment of transgender individuals, gay men and lesbians. My prior research has pointed to two lay models of heterosexuality that can have important consequences for anti-LGBT prejudice – a model of heterosexuality as a form of biological-purity and a model of heterosexuality as a form of moral purity. Across 14 studies (4 large-scale, representative surveys in multiple countries, and 10 lab-based genuine experiments), this proposed research will verify the biological-purity and moral-purity models of heterosexuality, identify the predictors and associated consequences of these models (Studies 1 – 4), investigate the consequences of the biological-purity model for anti-transgender prejudice (Studies 5 – 7), investigate the consequences of the moral-purity model for anti-gay prejudice (Studies 8 – 12), and investigate whether and how individuals strategically adopt or abandon these models to preserve their values and self-image (Studies 13 – 14). Together, these studies will add meaningfully to our theoretical understanding of sexual orientation and some of the causes of anti-gay and anti-transgender prejudice. On a practical level, they will point to new ways of combating anti-LGBT prejudice, even in some of the most severely prejudiced societies, and have implications for a number of real-world issues such as legal protection and gay conversion therapy.

746 048 €

Start date: 2018-05-01, End date: 2023-04-30

I will establish how abnormal B cell behaviour contributes to the generation of HIV neutralising antibodies by studying B cell biology: Previous studies show that broadly neutralising HIV antibodies are the most highly-mutated human antibodies ever isolated, with unusually long binding loops and polyreactivity, suggestive of changes to B cell tolerance and germinal centre selection mechanisms. These remarkable antibodies develop only during HIV infection, concurrent with immune dysfunction, not following vaccination. Crucially, the cellular processes whereby these antibodies arise need to be elucidated and I hypothesize that doing so using RNAseq, flow cytometry and imaging B cell activation will answer why only a minority of HIV+ individuals develop neutralization breadth. Moreover, B cell dysfunction is associated to a range of malignancies and autoimmune diseases and, while much has been learnt from model antigens in mouse models, HIV infection provides a uniquely well-characterised human model to study B cell regulation. Another fundamental question is whether strain-specific antibodies are a stepping-stone to breadth, or a detour that must be eliminated in vaccination. I have shown that the best serum neutralization activity induced via stabilized HIV envelope protein immunization predominantly targets a strain-specific glycan hole, similar to many early responses observed in infection before broad neutralising activity develops. Therefore, I will determine whether non-neutralising and strain-specific antibodies affect the development of breadth by isolating a range of antibodies raised during viral infection from individual donors and comparing binding affinities, clonal ontogenies and B cell receptor activation. Defining the impact of competition between antibody specificities during HIV infection will be directly translatable to developing vaccines for other pathogens where cross-reactivity is a key factor such as Influenza, Dengue and Zika viruses.

1 499 269 €

Start date: 2018-06-01, End date: 2023-05-31

Lymph node swelling is a classical hallmark of immunity. This expansion is observed by doctors, researchers and patients, yet as obvious as this process is, our understanding of the remodelling mechanisms involved are in their infancy. Lymph node remodelling is rapid and yet completely reversible, occurring countless times throughout our lifetimes. The purpose of this proposal is to understand how lymph node remodelling occurs and is resolved, repeatedly; to understand immunity in a whole organ context. The architecture of lymphoid organs is key to the effective operation of our immune system and is dictated by structures formed by non-haematopoetic stromal cells, including endothelial cells, and fibroblasts. Beyond their structural roles, stromal cells play an active role in immune responses, and the field of stromal immunology has become one of the most dynamic and exciting areas of immunology research. In this proposal I focus on the changing behaviour of fibroblastic reticular cells (FRCs) throughout cycles of lymph node remodelling. Fibroblastic reticular cells (FRCs) are the most abundant lymphoid stromal cell population, and form an interconnected network spanning the full volume of the tissue. FRCs are highly contractile and are able to relax and stretch during early phases of lymph node remodelling. FRCs proliferate during later phases of lymph node growth but are then removed as homeostasis is restored. Throughout this proposal I will use an extensive range of systems, ranging from proteomics and biochemistry to intravital imaging. I aim to: 1) To discover how spreading and stretching of the existing fibroblastic reticular network is directed in the acute phase of expansion: 2) To discover the cellular cues inducing the switch from stretching to proliferation and growth of the fibroblastic reticular network and 3) understand how homeostasis is regained as immune responses are resolved.

1 500 000 €

Start date: 2018-03-01, End date: 2023-02-28

MESG explores how the notion of a collective European-North African cultural memory has been articulated through music for different sociopolitical ends in colonial and postcolonial contexts. Based on the notion of convivencia (the alleged coexistence between Christians, Jews and Muslims in Islamic Spain), music has been employed as a means of social control and representation during French-Spanish colonialism in North Africa (1912–56) and as a model for multiculturalism among North African communities in Europe today. Current scholarship on musical exchange between Europe and North Africa is fragmented, often focusing on isolated geographical case studies. There is limited understanding of how a collective cultural memory has shaped musical practice and discourse in the colonial past and the postcolonial present. In contrast, MESG offers a comparative study of music and colonialism in the Maghreb. By examining colonial music scholarship, policy and education, and musical encounters between different cultural groups, MESG probes the social dynamics of musical interaction at this time, framed by issues of race, imperialism and cultural memory. Second, MESG explores how the idea of a collective cultural memory is invoked through musical collaboration today, by focusing on various genres such as Arab-Andalusian music and flamenco. Rather than separating these historical periods, however, MESG analyses how modern-day practices of musical exchange in the region are shaped by discourses and networks formed during colonialism. Musical exchange will be read against the wider context of multiculturalism, immigration and cultural diplomacy that underpins postcolonial relations between Europe and North Africa. Combining archival and ethnographic research, this groundbreaking project brings together for the first time different geographical, linguistic and musical specialisms, leading towards a fuller understanding of musical exchange in the region.

1 498 013 €

Start date: 2018-04-01, End date: 2023-03-31

Prejudice and discrimination are pressing social problems. Across Europe, the far right is on the rise, and individuals are often discriminated against on the basis of their race, gender or sexual orientation. The origins of these problematic attitudes and behaviours appear early in development, suggesting that we are passing on our biases to our children. Yet, our knowledge of the complex psychological processes by which these biases are learned remains rudimentary. MINDTOMIND experimentally investigates how children encode, select and transmit biased social information, and so provides a framework for understanding how intergroup attitudes are perpetuated across generations. Until now, artificial boundaries between different areas of psychology have prevented theoretical and empirical progress on this important subject. MINDTOMIND synthesizes cutting-edge research on cognitive development and experimental research on cultural transmission and intergroup psychology in order to provide a comprehensive account of this process. The series of experiments to test the proposed framework will answer three key questions. First, how do children respond to biased information they receive from others? Second, how do children select which social information to consume? Third, how do children transmit biased information to others in their social networks? MINDTOMIND will examine how learning, social motivation and cognitive biases interact to produce prejudice and discrimination. It will demonstrate how negative intergroup attitudes can emerge, become radicalised and spread through children’s social networks. In doing so, it will provide a step-change in our understanding of social cognitive development. In addition to far-reaching theoretical implications, this work will have broad societal implications. It will pave the way towards the development of research-led interventions that can reduce intergroup bias and thus contribute to a fairer and more egalitarian society.

1 223 054 €

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

The brain plays a central role in the production of adaptive behaviour. It must extract and integrate the most relevant sensory cues from the environment, and combine this information with memories of past experience to trigger appropriate behavioural responses. To fully understand the origins of behavioural novelty we need a detailed understanding of how behavioural differences are generated, both across evolutionary time and during development. This requires the integration of behavioural and neuroanatomical variation, and their genomic and developmental bases. Mushroom bodies (MBs) are the most enigmatic structures in the insect brain. They have ‘higher order’ functions, integrating sensory information and storing memories of past experience. MBs share a conserved ground plan, but their size and structure varies extensively across species. MB morphology is determined by the number of MB neurons, and the nature and extent of connections they make with other brain regions. As such, they provide a model for asking fundamental questions about how selection, development and functional constraints shape brain evolution. This project will establish a new study system in evolutionary neuroscience, Heliconius butterflies. MB volume in Heliconius is among the highest across insects, 3-4 times larger than typical for Lepidoptera, including closely related genera. The proposal represents a synthesis of four key objectives that will provide a cohesive understanding of MB expansion in Heliconius, encompassing both proximate and ultimate causes. Specifically, I will ask: i) How does MB expansion enhance behavioural function? ii) How do volumetric changes relate to differences in neuron number, density and connectivity? iii) What developmental mechanisms control region specific changes in neural proliferation? And iv) what is the genetic basis of MB expansion? Addressing these questions will provide profound advances in our understanding of brain evolution.

1 499 940 €

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

This proposal seeks to understand the molecular and circuit mechanisms used to store information in parallel memory units, and how these memories are integrated to guide action selection. We will use the Drosophila mushroom body (MB), a key center for associative learning in insect brains, as a model system. We recently generated intersectional genetic drivers that allowed us to draw a comprehensive anatomical map and selectively manipulate nearly all of the MB’s ~60 cell types. Sparse activity in the 2,000 Kenyon cells of the MB represents the identity of sensory stimuli. Along the parallel axonal fibers of Kenyon cells, we have shown that dopaminergic neurons and MB output neurons form 16 matched compartmental units. These anatomically defined units are also units of associative learning: reward and punishment activate distinct subsets of dopaminergic neurons. Our latest optogenetic activation experiments demonstrate that individual dopaminergic neurons independently write and update memories in each unit with cell-type-specific rules. We find extensive differences in the rate of memory formation, decay dynamics, storage capacity and flexibility to learn new associations across different units. Thus individual memory units within the mushroom body store different information about the same learning event. Together, these memories cooperatively or competitively represent the predictive value of sensory cues. We will now identify molecules and cell biological features that enable dopamine neurons to produce diverse forms of synaptic plasticity underlying distinct learning rules in different memory units. We will anatomically identify downstream neurons of the mushroom body output neurons that integrate information from parallel memory units, and make genetic drivers for them. Then, we will probe functions of these downstream neurons by imaging or manipulating their activity while flies retrieve and integrate memories for action selection.

1 500 000 €

Start date: 2018-07-01, End date: 2023-06-30

This proposal aims to provide insight into persister resuscitation. Persisters are multidrug-tolerant cells that are transiently non-growing and able to generate viable offspring by resuming growth when antibiotic pressure is removed. Despite their implication in relapses of many infectious diseases, and progress in understanding how persisters form through the action of toxin-antitoxin modules, the mechanisms underlying resuscitation of these persisters are still unknown. The interaction between Salmonella and host macrophages has proven to be a powerful and relevant model to study persister biology since the bacteria specifically respond to engulfment by the host defence cells by forming high proportions of persisters. Upon encounter with the host, Salmonella activates 14 toxins to arrest growth and persist in this environment. With the recent discovery of a detoxifying enzyme (Pth) counteracting the action of a persister-inducing toxin (TacT), thus allowing growth resumption of Salmonella persisters, we can now begin to address the pending question of persister regrowth. The consolidation of my research group around the experimental plan proposed here, will enable us to dissect the balance between intoxication vs. detoxification or entry vs. exit from persistence induced by Tact and Pth respectively. This is the first couple of toxin/detoxifying enzymes to be identified. I intend to extend this knowledge to the whole repertoire of toxins involved in Salmonella persister formation through systematic identification and characterization of the detoxifying mechanisms allowing resuscitation. Additionally I will investigate the lag phase leading to regrowth of persisters; and target the toxins involved in persister formation to force persisters out of growth arrest. This work will unravel persister resuscitation and could ultimately provide ways to force persisters out of that state so they become re-sensitized to antibiotics.

1 499 996 €

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

"The focus of the SIRI project is on the desirability and feasibility of targeting research, and the idea of ""serendipity"" in research and innovation (SIRI). This is the notion that research leads to unexpected valuable outcomes and, since the outcomes of research are impossible to predict, research itself is difficult (perhaps even impossible) to manage or direct towards specific social ends. Research may be uncertain, but it is not random, and we know that industrial R&D managers fund research in areas where they expect returns and organise research to maximise its impact. With public policy, the scenario is slightly different, but there is limited evidence to draw on to support policy making. Thus, SIRI asks whether EU science can be better managed in ways that enhance the social and economic value of serendipity. The project will undertake a mix of fundamental basic research on the nature of serendipity and its measurement, its history and influence on research policy, together with applied policy-focused research on issues of direct relevance to government policy makers, medical charities and industrial R&D managers. It will deploy mixed quantitative and qualitative methods to generate large scale evidence as well detailed cases studies. It will then focus on developing theory and implications to inform future policy on research and innovation."

1 423 228 €

Start date: 2018-06-01, End date: 2023-05-31

Stem cell (SC) proliferation during development requires tight spatial and temporal regulation to ensure correct cell number and right cell types are formed at the proper positions. Currently very little is known about how SCs are regulated during development. Specifically, it is unclear how SC waves of proliferation are regulated and how the fate of their progeny changes during development. In addition, it has recently become evident that metabolism provides additional complexity in cell fate regulation, highlighting the need for integrating metabolic information across physiological levels. This project will answer the question of how the combination of metabolic state and temporal cues (animal developmental stage) regulate SC fate. I will use Drosophila melanogaster, an animal complex enough to be similar to higher eukaryotes and yet simple enough to dissect the mechanistic details of cell regulation and its impact on the organism. Drosophila neural stem cells, the neuroblasts (NB), are a fantastic model of temporally and metabolically regulated cells. NB lineage fate changes with time, directing the generation of a stereotypical set of neurons, after which they disappear. I have previously found that metabolism is an important regulator of NB cell cycle exit, which occurs in response to an increase in levels of oxidative phosphorylation. Using a multidisciplinary approach combining genetics, cell type/age sorting, multi-omics analysis, fixed and 3D-live NB imaging and metabolite dynamics, I propose an integrative approach to investigate how NBs are regulated in the developing animal. First I will dissect the mechanisms by which metabolism regulates NB fate. Second, I will investigate how metabolism contributes to NB unlimited proliferation and brain tumors. Finally, we will address how temporal transcription factors and hormones dynamically affect cell fate decisions during development.

1 697 493 €

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

What is Tuberculosis (TB)? How does a person go from infection to disease, and what does this mean at the population level? For a disease that has caused over two billion deaths in human history, and is the biggest cause of death from an infection today, the natural history of TB remains stubbornly elusive. In this ERC award I will challenge current paradigms by exploring the implications of new empirical insights from basic science on our understanding of TB epidemiology and its control using mathematical modelling techniques. My hypothesis is that the prevailing paradigm of TB natural history is overly simple, and one of the key drivers of inaccuracy in projections made by mathematical models thus far. Current models of disease typically account for two distinct stages of infection and disease, with mostly one-directional progression between them. Instead, data has shown that individuals experience a range of stages of disease intensity. Moreover, over time individuals can move between stages through a dynamic interplay between immune induced repression and disease progression. In this ERC award I will first focus on collating the best available data to parameterize a new mathematical model of TB with unprecedented flexibility to capture the required trends. I will settle on the best model structure and understand its behavior. In the second stage, I will use the model to explore critical questions in two areas of TB research that require the detail of the new paradigm: the challenge of addressing latent tuberculosis infection; and incorporating the impact of changes in socio-economic indicators on TB trends. The consequences of such a paradigm shift to better reflect new insights from basic science and epidemiology are important. Initial modelling of intermediate disease states and the potential for progression and regression suggests that the projected impact of diagnostic strategies is substantially reduced, both in the immediate and longer-term.

1 499 819 €

Start date: 2018-03-01, End date: 2023-02-28

Everything that lives must die. Yet when it comes to the world's forests, we know much more about the processes governing their life than those governing their death. Global forests hold enormous amounts of carbon in their biomass, which has absorbed about 20% of anthropogenic carbon dioxide emissions over recent decades. Whether the size of this sink will persist, intensify, decrease or even become a source is highly uncertain, yet knowing this is crucial to the calculation of carbon emission budgets consistent with limiting global temperature rise. One of the most compelling explanations for this uncertainty is a lack of knowledge of how tree mortality affects forest carbon storage on a global scale. Mortality rates and mechanisms are closely tied to forest structure and composition, and thus the storage of carbon in biomass, but mechanistic complexity and the difficulty of measurement have hindered understanding, resulting in a striking lack of consensus in existing assessments. TreeMort will remedy this, combining newly available sources of data with appropriate conceptualisation and innovative modelling, to provide quantifications of the rates and causes of tree death, and their relation to environmental drivers, that set new standards for robustness, comprehensiveness and consistency at the global scale. This breaking-out of the narrower foci of previous work will be a game-changer, finally enabling globally-comprehensive investigation of the extent to which whole forest structure and function are governed by and interact with mortality, and their likely evolution under environmental change. TreeMort will assess this using state-of-the-art ecosystem modelling, which will then be employed to make a fundamental reassessment of the current and future carbon storage capacity of global forests. TreeMort will thus bring us significantly closer to understanding fully how forests interact with the global carbon cycle, assisting efforts to mitigate climate change.

1 493 970 €

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

Poverty is frequently perceived to be the root cause of illegal natural resource use – the hunting or extraction of wildlife not sanctioned by the state. When unsustainable, such activities threaten conservation of ecosystems and endangered species. However, understanding what motivates individuals involved is a major challenge; understandably few are willing to discuss their motives for fear of punishment [1]. Furthermore, severe, multifaceted poverty overlaps with regions prioritised for their globally important biodiversity [2]. This association exacerbates the problem that illegal activities pose for policy-makers responsible for managing and policing the use of nature. The dominant approach to conserving biodiversity is to establish protected areas [3] which typically restrict resource use and manage infractions through law enforcement [4]. However, the designation of such areas does not guarantee compliance, as demonstrated by ongoing infractions [5] and its conspicuous profile on global policy agendas. This includes the 2030 Agenda for Sustainable Development which calls for urgent action to halt biodiversity loss and hunting of protected species [6]. Solving this problematic cocktail of poverty, exclusion from resources and drivers of illegal resource use requires a new approach to understanding why people break rules and to what extent poverty underpins behaviour. Recent advances in cutting-edge techniques for asking sensitive questions are paving the way towards a more accurate understanding of the prevalence and drivers of illegal acts [7]. Combining conservation social science with development studies, criminology and social psychology, this project will examine, for the 1st time, the relative importance of multidimensional poverty and socio-psychological characteristics in dictating people’s involvement in illegal resource use which will be contextualised by histories of national park establishment and how the idea of illegality shifts through time.

1 458 770 €

Start date: 2018-06-01, End date: 2023-05-31