ERC FUNDED PROJECTS

Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.

1 000 000 €

Start date: 2008-07-01, End date: 2013-06-30

A persistent challenge in unravelling mechanisms that regulate memory function is how to bridge the gap between inter-molecular dynamics of single proteins, activity of individual synapses and emerging properties of neuronal circuits. The prototype condition of disintegrating neuronal circuits is Alzheimer’s Disease (AD). Since the early time of Alois Alzheimer at the turn of the 20th century, scientists have been searching for a molecular entity that is in the roots of the cognitive deficits. Although diverse lines of evidence suggest that the amyloid-beta peptide (Abeta) plays a central role in synaptic dysfunctions of AD, several key questions remain unresolved. First, endogenous Abeta peptides are secreted by neurons throughout life, but their physiological functions are largely unknown. Second, experience-dependent physiological mechanisms that initiate the changes in Abeta composition in sporadic, the most frequent form of AD, are unidentified. And finally, molecular mechanisms that trigger Abeta-induced synaptic failure and memory decline remain elusive. To target these questions, I propose to develop an integrative approach to correlate structure and function at the level of single synapses in hippocampal circuits. State-of-the-art techniques will enable the simultaneous real-time visualization of inter-molecular dynamics within signalling complexes and functional synaptic modifications. Utilizing FRET spectroscopy, high-resolution optical imaging, electrophysiology, molecular biology and biochemistry we will determine the casual relationship between ongoing neuronal activity, temporo-spatial dynamics and molecular composition of Abeta, structural rearrangements within the Abeta signalling complexes and plasticity of single synapses and whole networks. The proposed research will elucidate fundamental principles of neuronal circuits function and identify critical steps that initiate primary synaptic dysfunctions at the very early stages of sporadic AD.

2 000 000 €

Start date: 2011-12-01, End date: 2017-09-30

Elucidating how neural circuits coordinate behaviour, and how molecules underpin the properties of individual neurons are major goals of neuroscience. Optogenetics and neural imaging combined with the powerful genetics and well-described nervous system of C. elegans offer special opportunities to address these questions. Previously, we identified a series of sensory neurons that modulate aggregation of C. elegans. These include neurons that respond to O2, CO2, noxious cues, satiety state, and pheromones. We propose to take our analysis to the next level by dissecting how, in mechanistic molecular terms, these distributed inputs modify the activity of populations of interneurons and motoneurons to coordinate group formation. Our strategy is to develop new, highly parallel approaches to replace the traditional piecemeal analysis. We propose to: 1) Harness next generation sequencing (NGS) to forward genetics, rapidly to identify a molecular ¿parts list¿ for aggregation. Much of the genetics has been done: we have identified almost 200 mutations that inhibit or enhance aggregation but otherwise show no overt phenotype. A pilot study of 50 of these mutations suggests they identify dozens of genes not previously implicated in aggregation. NGS will allow us to molecularly identify these genes in a few months, providing multiple entry points to study molecular and circuitry mechanisms for behaviour. 2) Develop new methods to image the activity of populations of neurons in immobilized and freely moving animals, using genetically encoded indicators such as the calcium sensor cameleon and the voltage indicator mermaid. This will be the first time a complex behaviour has been dissected in this way. We expect to identify novel conserved molecular and circuitry mechanisms.

2 439 996 €

Start date: 2011-04-01, End date: 2017-03-31

MAL: an actin-regulated SRF transcriptional coactivator Recent years have seen a revitalised interest in the role of actin in nuclear processes, but the molecular mechanisms involved remain largely unexplored. We will elucidate the molecular basis for the actin-based control of the SRF transcriptional coactivator, MAL. SRF controls transcription through two families of coactivators, the actin-binding MRTFs (MAL, Mkl2), which couple its activity to cytoskeletal dynamics, and the ERK-regulated TCFs (Elk-1, SAP-1, Net). MAL subcellular localisation and transcriptional activity responds to signal-induced changes in G-actin concentration, which are sensed by its actin-binding N-terminal RPEL domain. Members of a second family of RPEL proteins, the Phactrs, also exhibit actin-regulated nucleocytoplasmic shuttling. The proposal addresses the following novel features of actin biology: ¿ Actin as a transcriptional regulator ¿ Actin as a signalling molecule ¿ Actin-binding proteins as targets for regulation by actin, rather than regulators of actin function We will analyse the sequences and proteins involved in actin-regulated nucleocytoplasmic shuttling, using structural biology and biochemistry to analyse its control by changes in actin-RPEL domain interactions. We will characterise the dynamics of shuttling, and develop reporters for changes in actin-MAL interaction for analysis of pathway activation in vivo. We will identify genes controlling MAL itself, and the balance between the nuclear and cytoplasmic actin pools. The mechanism by which actin represses transcriptional activation by MAL in the nucleus, and its relation to MAL phosphorylation, will be elucidated. Finally, we will map MRTF and TCF cofactor recruitment to SRF targets on a genome-wide scale, and identify the steps in transcription controlled by actin-MAL interaction.

1 889 995 €

Start date: 2011-10-01, End date: 2017-09-30

In a changing world, one hallmark feature of human behaviour is the ability to learn about the statistics of the environment and use this prior information for action selection. Knowing about a forthcoming event allows for adjusting our actions pre-emptively, which can optimize survival. This proposal studies how the human brain learns about the uncertainty in the environment, and how this leads to flexible and efficient action selection. I hypothesise that the accumulation of evidence for future movements through learning reflects a fundamental organisational principle for action control. This explains widely distributed perceptual-, learning-, decision-, and movement-related signals in the human brain. However, little is known about the concerted interplay between brain regions in terms of effective connectivity which is required for flexible behaviour. My proposal seeks to shed light on this unresolved issue. To this end, I will use i) a multi-disciplinary neuroimaging approach, together with model-based analyses and Bayesian model comparison, adapted to human reaching behaviour as occurring in daily life; and ii) two novel approaches for testing effective connectivity: dynamic causal modelling (DCM) and concurrent transcranial magnetic stimulation-functional magnetic resonance imaging. My prediction is that action selection relies on effective connectivity changes, which are a function of the prior information that the brain has to learn about. If true, this will provide novel insight into the human ability to select actions, based on learning about the uncertainty which is inherent in contextual information. This is relevant for understanding action selection during development and ageing, and for pathologies of action such as Parkinson s disease or stroke.

1 341 805 €

Start date: 2011-06-01, End date: 2016-05-31

Relative to other species, humans are characterised by considerable biological diversity despite genetic homogeneity. This diversity is reflected in skeletal variation, but we lack sufficient understanding of the underlying mechanisms to adequately interpret the archaeological record. The proposed research will address problems in our current understanding of the origins of human variation in the past by: 1) documenting and interpreting the pattern of global hunter-gatherer variation relative to genetic phylogenies and climatic variation; 2) testing the relationship between environmental and skeletal variation among genetically related hunter-gatherers from different environments; 3) examining the adaptability of living humans to different environments, through the study of energetic expenditure and life history trade-offs associated with locomotion; and 4) investigating the relationship between muscle and skeletal variation associated with locomotion in diverse environments. This will be achieved by linking: a) detailed study of the global pattern of hunter-gatherer variation in the Late Pleistocene and Holocene with; b) ground-breaking experimental research which tests the relationship between energetic stress, muscle function, and bone variation in living humans. The first component tests the correspondence between skeletal variation and both genetic and climatic history, to infer mechanisms driving variation. The second component integrates this skeletal variation with experimental studies of living humans to, for the first time, directly test adaptive implications of skeletal variation observed in the past. ADaPt will provide the first links between prehistoric hunter-gatherer variation and the evolutionary parameters of life history and energetics that may have shaped our success as a species. It will lead to breakthroughs necessary to interpret variation in the archaeological record, relative to human dispersals and adaptation in the past.

1 911 485 €

Start date: 2014-07-01, End date: 2019-06-30

Alzheimer's disease, the most common cause of dementia in older people, is a devastating condition that is becoming a public health crisis as our population ages. Despite great progress recently in Alzheimer’s disease research, we have no disease modifying drugs and a decade with a 99.6% failure rate of clinical trials attempting to treat the disease. This project aims to develop relevant therapeutic targets to restore brain function in Alzheimer’s disease by integrating human and model studies of synapses. It is widely accepted in the field that alterations in amyloid beta initiate the disease process. However the cascade leading from changes in amyloid to widespread tau pathology and neurodegeneration remain unclear. Synapse loss is the strongest pathological correlate of dementia in Alzheimer’s, and mounting evidence suggests that synapse degeneration plays a key role in causing cognitive decline. Here I propose to test the hypothesis that the amyloid cascade begins at the synapse leading to tau pathology, synapse dysfunction and loss, and ultimately neural circuit collapse causing cognitive impairment. The team will use cutting-edge multiphoton and array tomography imaging techniques to test mechanisms downstream of amyloid beta at synapses, and determine whether intervening in the cascade allows recovery of synapse structure and function. Importantly, I will combine studies in robust models of familial Alzheimer’s disease with studies in postmortem human brain to confirm relevance of our mechanistic studies to human disease. Finally, human stem cell derived neurons will be used to test mechanisms and potential therapeutics in neurons expressing the human proteome. Together, these experiments are ground-breaking since they have the potential to further our understanding of how synapses are lost in Alzheimer’s disease and to identify targets for effective therapeutic intervention, which is a critical unmet need in today’s health care system.

2 000 000 €

Start date: 2016-11-01, End date: 2021-10-31

Within a 12 month period, 20% of adults will meet criteria for one or more clinical anxiety disorders (ADs). These disorders are hugely disruptive, placing an emotional burden on individuals and their families. While both cognitive behavioural therapy and pharmacological treatment are widely viewed as effective strategies for managing ADs, systematic review of the literature reveals that only 30–45% of patients demonstrate a marked response to treatment (anxiety levels being reduced into the nonaffected range). In addition, a significant proportion of initial responders relapse after treatment is discontinued. There is hence a real and marked need to improve upon current approaches to AD treatment. One possible avenue for improving response rates is through optimizing initial treatment selection. Specifically, it is possible that certain individuals might respond better to cognitive interventions while others might respond better to pharmacological treatment. Recently it has been suggested that there may be two or more distinct biological pathways disrupted in anxiety. If this is the case, then specification of these pathways may be an important step in predicting which individuals are likely to respond to which treatment. Few studies have focused upon this issue and, in particular, upon identifying neural markers that might predict response to cognitive (as opposed to pharmacological) intervention. The proposed research aims to address this. Specifically, it tests the hypothesis that there are at least two mechanisms disrupted in ADs, one entailing amygdala hyper-responsivity to cues that signal threat, the other impoverished recruitment of frontal regions that support cognitive and emotional regulation. Two series of functional magnetic resonance imaging experiments will be conducted. These will investigate differences in amygdala and frontal function during (a) attentional processing and (b) fear conditioning. Initial clinical experiments will investigate whether Generalised Anxiety Disorder and Specific Phobia involve differing degrees of disruption to frontal versus amygdala function during these tasks. This work will feed into training studies, the goal being to characterize AD patient subgroups that benefit from cognitive training.

1 708 407 €

Start date: 2011-04-01, End date: 2016-08-31

The Hippocratic Aphorisms have exerted a singular influence over generations of physicians both in the East and in the West. Galen (d. c. 216) produced an extensive commentary on this text, as did other medical authors writing in Greek, Latin, Arabic, and Hebrew. The Arabic tradition is particularly rich, with more than a dozen commentaries extant in over a hundred manuscripts. These Arabic commentaries did not merely contain scholastic debates, but constituted important venues for innovation and change. Moreover, they impacted on medical practice, as the Aphorisms were so popular that both doctors and their patients knew them by heart. Despite their importance for medical theory and practice, previous scholarship on them has barely scratched the surface. Put succinctly, the present project breaks new ground by conducting an in-depth study of this tradition through a highly innovative methodology: it approaches the available evidence as a corpus, to be constituted electronically, and to be analysed in an interdisciplinary way. We propose to survey the manuscript tradition of the Arabic commentaries on the Hippocratic Aphorisms, beginning with Ḥunayn ibn ʾIsḥāq’s Arabic translation of Galen’s commentary. On the basis of this philological survey that will employ a new approach to stemmatics, we shall produce provisional electronic XML editions of the commentaries. These texts will constitute the corpus, some 600,000 words long, that we shall investigate through the latest IT tools to address a set of interdisciplinary problems: textual criticism of the Greek sources; Graeco-Arabic translation technique; methods of quotation; hermeneutic procedures; development of medical theory; medical practice; and social history of medicine. Both in approach and scope, the project will bring about a paradigm shift in our study of exegetical cultures in Arabic, and the role that commentaries played in the transmission and transformation of scientific knowledge.

1 499 968 €

Start date: 2012-02-01, End date: 2017-07-31

ATM is the protein kinase that is mutated in the hereditary autosomal recessive disease ataxia telangiectasia (A-T). A-T patients display immune deficiencies, cancer predisposition and radiosensitivity. The molecular role of ATM is to respond to DNA damage by phosphorylating its substrates, thereby promoting repair of damage or arresting the cell cycle. Following the induction of double-strand breaks (DSBs), the NBS1 protein is required for activation of ATM. But ATM can also be activated in the absence of DNA damage. Treatment of cultured cells with hypotonic stress leads to the activation of ATM, presumably due to changes in chromatin structure. We have recently described a second ATM cofactor, ATMIN (ATM INteractor). ATMIN is dispensable for DSBs-induced ATM signalling, but ATM activation following hypotonic stress is mediated by ATMIN. While the biological role of ATM activation by DSBs and NBS1 is well established, the significance, if any, of ATM activation by ATMIN and changes in chromatin was up to now completely enigmatic. ATM is required for class switch recombination (CSR) and the suppression of translocations in B cells. In order to determine whether ATMIN is required for any of the physiological functions of ATM, we generated a conditional knock-out mouse model for ATMIN. ATM signaling was dramatically reduced following osmotic stress in ATMIN-mutant B cells. ATMIN deficiency led to impaired CSR, and consequently ATMIN-mutant mice developed B cell lymphomas. Thus ablation of ATMIN resulted in a severe defect in ATM function. Our data strongly argue for the existence of a second NBS1-independent mode of ATM activation that is physiologically relevant. While a large amount of scientific effort has gone into characterising ATM signaling triggered by DSBs, essentially nothing is known about NBS1-independent ATM signaling. The experiments outlined in this proposal have the aim to identify and understand the molecular pathway of ATMIN-dependent ATM signaling.

1 499 881 €

Start date: 2012-02-01, End date: 2018-01-31

Long-term studies of free-living vertebrate populations have proved a rich resource for understanding evolutionary and ecological processes, because individuals’ life histories can be measured by tracking them from birth/hatching through to death. In recent years the ‘animal model’ has been applied to pedigreed long-term study populations with great success, dramatically advancing our understanding of quantitative genetic parameters such as heritabilities, genetic correlations and plasticities of traits that are relevant to microevolutionary responses to environmental change. Unfortunately, quantitative genetic approaches have one major drawback – they cannot identify the actual genes responsible for genetic variation. Therefore, it is impossible to link evolutionary responses to a changing environment to molecular genetic variation, making our picture of the process incomplete. Many of the best long-term studies have been conducted in passerine birds. Unfortunately genomics resources are only available for two model avian species, and are absent for bird species that are studied in the wild. I will fill this gap by exploiting recent advances in genomics technology to sequence the entire transcriptome of the longest running study of wild birds – the great tit population in Wytham Woods, Oxford. Having identified most of the sequence variation in the great tit transcriptome, I will then genotype all birds for whom phenotype records and blood samples are available This will be, by far, the largest phenotype-genotype dataset of any free-living vertebrate population. I will then use gene mapping techniques to identify genes and genomic regions responsible for variation in a number of key traits such as lifetime recruitment, clutch size and breeding/laying date. This will result in a greater understanding, at the molecular level, how microevolutionary change can arise (or be constrained).

1 560 770 €

Start date: 2008-10-01, End date: 2014-06-30

Neurons make long-distance connections with synaptic targets via axons. These axons survive throughout the lifetime of an organism, often many years in mammals, yet how axons are maintained is not fully understood. Recently, we provided in vivo evidence that local mRNA translation in mature axons is required for their maintenance. This new finding, along with in vitro work from other groups, indicates that promoting axonal protein synthesis is a key mechanism by which trophic factors act to prevent axon degeneration. Here we propose a program of research to investigate the importance of ribosomal proteins (RPs) in axon maintenance and degeneration. The rationale for this is fourfold. First, recent genome-wide studies of axonal transcriptomes have revealed that protein synthesis (including RP mRNAs) is the highest functional category in several neuronal types. Second, some RPs have evolved extra-ribosomal functions that include signalling, such as 67LR which acts both as a cell surface receptor for laminin and as a RP. Third, mutations in different RPs in vertebrates cause unexpectedly specific defects, such as the loss of optic axons. Fourth, preliminary results show that RP mRNAs are translated in optic axons in response to trophic factors. Collectively these findings lead us to propose that locally synthesized RPs play a role in axon maintenance through either ribosomal or extra-ribosomal function. To pursue this proposal, we will perform unbiased screens and functional assays using an array of experimental approaches and animal models. By gaining an understanding of how local RP synthesis contributes to axon survival, our studies have the potential to provide novel insights into how components conventionally associated with a housekeeping role (translation) are linked to axon degeneration. Our findings could provide new directions for developing therapeutic tools for neurodegenerative disorders and may have an impact on more diverse areas of biology and disease.

2 426 573 €

Start date: 2013-03-01, End date: 2018-09-30

" Why do people convert to Islam? The contemporary relevance of this question is immediately apparent.""Becoming Muslim"" will transform our knowledge about Islamisation processes and contexts through archaeological research in Harar, Eastern Ethiopia, and examine this in comparison to other regions in sub-Saharan Africa via publication and a major conference. Assessing genuine belief is difficult, but the impact of trade, Saints, Sufis and Holy men, proselytisation, benefits gained from Arabic literacy and administration systems, enhanced power, prestige, warfare, and belonging to the larger Muslim community have all been suggested. Equally significant is the context of conversion. Why were certain sub-Saharan African cities key points for conversion to Islam, e.g. Gao and Timbuktu in the Western Sahel, and Harar in Ethiopia? Archaeological engagement with Islamisation processes and contexts of conversion in Africa is variable, and in parts of the continent research is static. This exciting 4-year project explores, for the first time, Islamic conversion and Islamisation through focusing on Harar, the most important living Islamic centre in the Horn of Africa, and its surrounding region. Islamic archaeology has been neglected in Ethiopia, and is wholly non-existent in Harar. Excavation at 5 key sites: 2 shrines, 2 abandoned settlements, 1 urban site, will permit evaluation of urban Islam, the veneration of saints, pilgrimage and shrine based practices, rural Islam, architecture and jihad, changes in lifeways, and early and comparative evidence for Islam and long-distance trade, through analysis of, e.g. architecture, epigraphy, burial orientation, imported artifacts, and faunal and botanical remains. Although it is fully acknowledged that conversion to Islam and Islamisation processes are not universal, my project is groundbreaking in developing and applying a transferable methodology for the archaeological explanation of ""Becoming Muslim"" in sub-Saharan Africa."

1 031 105 €

Start date: 2016-09-01, End date: 2020-08-31

Pericytes, located at intervals along capillaries, have recently been revealed as major controllers of brain blood flow. Normally, they dilate capillaries in response to neuronal activity, increasing local blood flow and energy supply. But in pathology they have a more sinister role. After artery block causes a stroke, the brain suffers from the so-called “no-reflow” phenomenon - a failure to fully reperfuse capillaries, even after the upstream occluded artery has been reperfused successfully. The resulting long-lasting decrease of energy supply damages neurons. I have shown that a major cause of no-reflow lies in pericytes: during ischaemia they constrict and then die in rigor. This reduces capillary diameter and blood flow, and probably degrades blood-brain barrier function. However, despite their crucial role in regulating blood flow physiologically and in pathology, little is known about the mechanisms by which pericytes function. By using blood vessel imaging, patch-clamping, two-photon imaging, optogenetics, immunohistochemistry, mathematical modelling, and live human tissue obtained from neurosurgery, this programme of research will: (i) define the signalling mechanisms controlling capillary constriction and dilation in health and disease; (ii) identify the relative contributions of neurons, astrocytes and microglia to regulating pericyte tone; (iii) develop approaches to preventing brain pericyte constriction and death during ischaemia; (iv) define how pericyte constriction of capillaries and pericyte death contribute to Alzheimer’s disease; (v) extend these results from rodent brain to human brain pericytes as a prelude to developing therapies. The diseases to which pericytes contribute include stroke, spinal cord injury, diabetes and Alzheimer’s disease. These all have an enormous economic impact, as well as causing great suffering for patients and their carers. This work will provide novel therapeutic approaches for treating these diseases.

2 499 954 €

Start date: 2017-09-01, End date: 2022-08-31

Energy, supplied in the form of oxygen and glucose in the blood, is essential for the brain s cognitive power. Failure of the energy supply to the nervous system underlies the mental and physical disability occurring in a wide range of economically important neurological disorders, such as stroke, spinal cord injury and cerebral palsy. Using a combination of two-photon imaging, electrophysiological, molecular and transgenic approaches, I will investigate the control of brain energy supply at the vascular level, and at the level of individual neurons and glial cells, and study the deleterious consequences for the neurons, glia and vasculature of a failure of brain energy supply. The work will focus on the following fundamental issues: A. Vascular control of the brain energy supply (1) How important is control of energy supply at the capillary level, by pericytes? (2) Which synapses control blood flow (and thus generate functional imaging signals) in the cortex? B. Neuronal and glial control of brain energy supply (3) How is grey matter neuronal activity powered? (4) How is the white matter supplied with energy? C. The pathological consequences of a loss of brain energy supply (5) How does a fall of energy supply cause neurotoxic glutamate release? (6) How similar are events in the grey and white matter in energy deprivation conditions? (7) How does a transient loss of energy supply affect blood flow regulation? (8) How does brain energy use change after a period without energy supply? Together this work will significantly advance our understanding of how the energy supply to neurons and glia is regulated in normal conditions, and how the loss of the energy supply causes disorders which consume more than 5% of the costs of European health services (5% of ~1000 billion euro/year).

2 499 947 €

Start date: 2010-04-01, End date: 2016-03-31

My lab's work ranges from basic science, querying brain plasticity and sensory integration, to technological developments, allowing the blind to be more independent and even “see” using sounds and touch similar to bats and dolphins (a.k.a. Sensory Substitution Devices, SSDs), and back to applying these devices in research. We propose that, with proper training, any brain area or network can change the type of sensory input it uses to retrieve behaviorally task-relevant information within a matter of days. If this is true, it can have far reaching implications also for clinical rehabilitation. To achieve this, we are developing several innovative SSDs which encode the most crucial aspects of vision and increase their accessibility the blind, along with targeted, structured training protocols both in virtual environments and in real life. For instance, the “EyeMusic”, encodes colored complex images using pleasant musical scales and instruments, and the “EyeCane”, a palm-size cane, which encodes distance and depth in several directions accurately and efficiently. We provide preliminary but compelling evidence that following such training, SSDs can enable almost blind to recognize daily objects, colors, faces and facial expressions, read street signs, and aiding mobility and navigation. SSDs can also be used in conjunction with (any) invasive approach for visual rehabilitation. We are developing a novel hybrid Visual Rehabilitation Device which combines SSD and bionic eyes. In this set up, the SSDs is used in training the brain to “see” prior to surgery, in providing explanatory signal after surgery and in augmenting the capabilities of the bionic-eyes using information arriving from the same image. We will chart the dynamics of the plastic changes in the brain by performing unprecedented longitudinal Neuroimaging, Electrophysiological and Neurodisruptive approaches while individuals learn to ‘see’ using each of the visual rehabilitation approaches suggested here.

1 499 900 €

Start date: 2013-09-01, End date: 2018-08-31

This project will study how calendars evolved in late antique and medieval societies towards ever increasing standardization and fixation. The study of calendars has been neglected by historians as a technical curiosity; but in fact, the calendar was at the heart of ancient and medieval culture, as a structured concept of time, and as an organizing principle of social life. The history of calendars in late Antiquity and the Middle Ages was a complex social and cultural process, closely related to politics, science, and religion. The standardization and fixation of calendars was related in Antiquity to the rise of large, centralized empires in the Mediterranean and Near East, and in the Middle Ages, to the rise of the monotheistic, universalist religions of Christianity and Islam. The standardization and fixation of calendars contributed also, more widely, to the formation of a unified and universal culture in the ancient and medieval worlds. The standardization and fixation of ancient and medieval calendars will be analyzed by focusing on four, specific manifestations of this process: (1) the diffusion and standardization of the seven-day week in the Roman Empire; (2) the production of hemerologia (comparative calendar tables) in late Antiquity; (3) the use of Jewish calendar fixed cycles in medieval manuscripts; (4) the production and diffusion of monographs on the calendar by medieval Muslim, Christian, and Jewish scholars, especially al-Biruni’s Chronology of the Ancient Nations and Isaac Israeli’s Yesod Olam. Study of these four research areas will enable us to formulate a general interpretation and explanation of how and why calendars became increasingly standardized and fixed. This will be the first ever study of calendars on this scale, covering a wide range of historical periods and cultures, and involving a wide range of disciplines: social history, ancient and medieval astronomy and mathematics, study of religions, literature, epigraphy, and codicology.

2 499 006 €

Start date: 2013-02-01, End date: 2018-01-31

A critical question in neuroscience is to understand how neurons wire up to form a functional network. During the wiring of the brain it is important to establish mechanisms that act as safeguards to control and stabilize neuronal excitability in the face of large, chronic changes in neuronal or network activity. This is especially true for developing systems that undergo rapid and large scale forms of plasticity, which could easily lead to large imbalances in activity. If left unchecked, they could lead the network to its extremes: a complete loss of signal or epileptic-like activity. For this reason neurons employ different strategies to maintain their excitability within reasonable bounds. This proposal will focus on two crucial sites for neuronal information processing and integration: the synapse and the axon initial segment (AIS). Both sites undergo important structural and functional rearrangements in response to chronic activity changes, thus controlling the input-output function of a neuron and allowing the network to function efficiently. This proposal will explore novel forms of plasticity that occur during development and which are key to establishing a functional network. They range from understanding the role of activity during synapse formation to how pre- and postsynaptic structure and function become matched during development. Finally, it tackles a novel form of plasticity that lies downstream of synaptic inputs and is responsible for setting the threshold of action potential firing: the axon initial segment. Here, chronic changes in network activity results in a physical relocation of the AIS along the axon, which in turn alters the excitability of the neuron. This proposal will focus on the central issue of how a neuron alters both its input (synapses) and output (AIS) during development to maintain its activity levels within a set range and allow a functional network to form.

1 500 000 €

Start date: 2012-03-01, End date: 2017-02-28

'Coastal Frontiers' will involve the Principal Investigator, Dr Sunil Amrith, and a post-doctoral research assistant, in a study of the Bay of Bengal’s coastal rim from the late-nineteenth century to the present. This project will illuminate the entangled political and ecological history of the coastal arc stretching from India’s southern tip to the edge of the Malay Peninsula. It will combine macro-level perspectives on environmental change, contingent histories of transformations in political sovereignty, and local histories of coastal peoples. It seeks to examine how people have actually inhabited the coastal borderlands of Asia, and the contrasting ways these worlds appear through the eyes of states, or in the minds of coastal ecologists. It will focus on key coastal sites at the frontiers of ecological change, at the frontiers between empires and nations, at the frontiers between terrestrial and maritime law. The project will examine the deeper history of environmental change and political conflict in a region that is now particularly vulnerable to climate change, and at the fault-lines of strategic conflict between India and China. The project will build on the Principal Investigator’s recent work at the frontiers of scholarship in Asian history, through his studies of the links between South and Southeast Asia’s histories of migration and oceanic connection. It is time, now, to root this re-conceptualization of Asia’s regional frontiers in a closer study of environmental change, but to do so in a way that does not lose sight of the experiences and consciousness of individuals. This represents a new departure in scholarship, combining environmental history with the history of transnational flows, bridging insights from the humanities and ecological science. This ambitious project seeks new ways for historians to engage with questions of planetary change, without losing the fine-grained detail and hard archival research that has characterised our discipline.

606 655 €

Start date: 2012-01-01, End date: 2015-06-30

"Communication between the nervous and the immune system is pivotal for maintaining homeostasis and ensuring rapid and efficient reaction to stress and infection insults. The emergence of microRNAs (miRs) as regulators of gene expression and of acetylcholine (ACh) signalling as regulator of anxiety and inflammation provides a model for studying this interaction. My hypothesis is that 1) a specific sub-group of miRs, designated ""CholinomiRs"", may silence multiple target genes in the neuro-immune interface; 2) these miRs compete with each other on the interaction with their targets, and 3) mutations interfering with miR binding lead to inherited susceptibility to anxiety and inflammation disorders by modifying these interactions. Our preliminary findings have shown that by targeting acetylcholinesterase (AChE), CholinomiR-132 can intensify acute stress, resolve intestinal inflammation and change post-ischemic stroke responses. Further, we have identified clustered single nucleotide polymorphisms (SNPs) interfering with AChE silencing by several miRs which associate with elevated trait anxiety, blood pressure and inflammation. To further study miR regulators of ACh signalling, I plan to: (1) Identify anxiety and inflammation-induced changes in CholinomiRs and their targets in challenged brain and immune cells. (2) Establish the roles of these targets for one selected CholinomiR by tissue-specific manipulations. (3) Study primate-specific CholinomiRs by continued human DNA screens to identify SNPs and in ""humanized"" mice with knocked-in human AChE and transgenic CholinomiR-608. (4) Test if therapeutic modulation of aberrant CholinomiR expression can restore homeostasis. This research will clarify how miRs interact with each other in health and disease, introduce the dimension of complexity of multi-target competition and miR interactions and make a conceptual change in miRs research while enhancing the ability to intervene with diseases involving impaired ACh signalling."

2 375 600 €

Start date: 2013-03-01, End date: 2018-02-28

A PubMed search for ‘epigenetic’ identifies nearly 35,000 entries, yet the molecular mechanisms by which chromatin modification and gene expression patterns are actually inherited during chromosome replication — mechanisms which lie at the heart of epigenetic inheritance of gene expression — are still largely uncharacterised. Understanding these mechanisms would be greatly aided if we could reconstitute the replication of chromosomes with purified proteins. The past few years have seen great progress in understanding eukaryotic DNA replication through the use of cell-free replication systems and reconstitution of individual steps in replication with purified proteins and naked DNA. We will use these in vitro replication systems together with both established and novel chromatin assembly systems to understand: a) how chromatin influences replication origin choice and timing, b) how nucleosomes on parental chromosomes are disrupted during replication and are distributed to daughter chromatids, and c) how chromatin states and gene expression patterns are re-established after passage of the replication fork. We will begin with simple, defined templates to learn basic principles, and we will use this knowledge to reconstitute genome-wide replication patterns. The experimental plan will exploit our well-characterised yeast systems, and where feasible explore these questions with human proteins. Our work will help explain how epigenetic inheritance works at a molecular level, and will complement work in vivo by many others. It will also underpin our long-term research goals aimed at making functional chromosomes from purified, defined components to understand how DNA replication interacts with gene expression, DNA repair and chromosome segregation.

1 983 019 €

Start date: 2015-11-01, End date: 2020-10-31

The unexpected connection between the primary cilium and cell-to-cell signalling is one of the most exciting discoveries in cell and developmental biology in the last decade. In particular, the Hedgehog (Hh) pathway relies on the primary cilium to fulfil its fundamental functions in orchestrating vertebrate development. This microtubule-based antenna, up to 5 µm long, protrudes from the plasma membrane of almost every human cell and is the essential compartment for the entire Hh signalling cascade. All its molecular components, from the most upstream transmembrane Hh receptor down to the ultimate transcription factors, are dynamically localised and enriched in the primary cilium. The aim of this proposal, which combines structural biology and live cell imaging, is to understand the function and signalling consequences of the multivalent interactions between Hh signal transducer proteins as well as their spatial and temporal regulation in the primary cilium. The key questions my laboratory will address are: What are the rules for assembly of Hh signal transduction complexes? How dynamic are these complexes in size and organisation? How are these processes linked to the transport and accumulation in the primary cilium? I will combine state-of-the art structural biology techniques (with an emphasis on X-ray crystallography) to study the molecular architecture of binary and higher-order Hh signal transduction complexes and live cell fluorescence microscopy (for protein localisation and direct protein interactions). These two approaches will allow me to identify and define specific protein-protein interfaces at the atomic level and test their functional consequences in the cell in real time. My goal is to consolidate a world-class morphogen signal transduction laboratory, deciphering fundamental biological insights. Importantly, my results and reagents can potentially feed into the development of novel anti-cancer therapeutics and reagents promoting stem cell therapy.

1 727 456 €

Start date: 2015-08-01, End date: 2020-07-31

Over the last 8000 years, the Fertile Crescent of the Near East has seen the emergence of cities, states and empires. Climate fluctuations are generally considered to be a significant factor in these changes because in pre-industrial societies they directly relate to food production and security. In the short term, ‘collapse’ events brought about by extreme weather changes such as droughts have been blamed for declines in population, social complexity and political systems. More broadly, the relationships between environment, settlement and surplus drive most models for the development of urbanism and hierarchical political systems. Studies seeking to correlate social and climatic changes in the past tend either to focus on highly localised analyses of specific sites and surveys or to take a more synthetic overview at much larger, even continental, scales. The CLaSS project will take a ground breaking hybrid approach using archaeological data science (or ‘big data’) to construct detailed, empirical datasets at unprecedented scales. Archaeological settlement data and archaeobotanical data (plant and tree remains) will be collated for the entire Fertile Crescent and combined with climate simulations derived from General Circulation Models using cutting edge techniques. The resulting datasets will represent the largest of their kind ever compiled, covering the period between 8000BP and 2000BP and an area of 600,000km2. Collecting data at this scale will enable us to compare population densities and distribution, subsistence practices and landscape management strategies to investigate the question: What factors have allowed for the differential persistence of societies in the face of changing climatic and environmental conditions? This ambitious project will provide insights into the sustainability and resilience of societies through both abrupt and longer term climate changes, leveraging the deep time perspective only available to archaeology.

1 498 650 €

Start date: 2019-01-01, End date: 2023-12-31

A highly significant division in present-day Europe is between two types of legal system: the Continental with foundations in Civil Law (law with an ultimately Roman law basis), and English Common Law. Both trace their continuous history back to the twelfth century. The present project re-evaluates this vital period in legal history, by comparing not just English Common Law and Continental Civil Law (or “Ius commune”), but also the customary laws crucially important in Continental Europe even beyond the twelfth century. Such laws shared many features with English law, and the comparison thus disrupts the simplistic English:Continental distinction. The project first analyses the form, functioning and development of local, national, and supra-national laws. Similarities, differences, and influences will then be examined from perspectives of longer-term European legal development. Proper historical re-examination of the subject is very timely because of current invocation of supposed legal histories, be it Eurosceptic celebration of English Common Law or rhetorical use of Ius commune as precedent for a common European Law. F. W. Maitland wrote that ‘there is not much “comparative jurisprudence” for those who do not know thoroughly well the things to be compared’. A comparative project requires collaboration – PI, senior researcher, post-doctoral and doctoral researchers, and Advisory Board. It also needs an integrated approach, through carefully selected areas, themes, and sources. The purpose is not just to provide geographical and thematic coverage but to assemble scholars who overcome divisions of approach in legal historiography: between lawyers and historians, between national traditions, between Common Law and Civil Law. The project is thus very significant in developing methods for writing comparative legal history - and legal history and comparative law more widely - in terms of uncovering patterns, constructing narratives, and testing theories of causation.

2 161 502 €

Start date: 2017-05-01, End date: 2022-04-30

All forms of life adjust themselves to the daily rhythms of their environments using endogenous oscillators collectively referred to as circadian clocks. Peripheral and central body clocks exist, which both require extrinsic information (e.g. light or temperature changes) to keep in sync with the geophysical cycle (entrainment). In addition, intrinsic cues (e.g. activity levels) have been linked to clock entrainment. Recently, we could show that activation of proprioceptors is sufficient to entrain the central clock of the fruit fly Drosophila melanogaster. Proprioceptors are mechanosensors that monitor the positions, and relative movements, of an animal’s own body parts. The existence of proprioceptive entrainment pathways has significant implications; it implies that an animal’s ‘clock time’ is computed by integrating, and weighting, various external and internal conditions, suggesting the existence of external and internal time. Using Drosophila, I will investigate the relationship between mechanosensory and circadian systems in a dual, and bidirectional, approach. The project’s first aim is to dissect the neurobiological bases of proprioceptive clock entrainment (i) identifying the specific stimulus requirements for effective entrainment, (ii) determining its mechanosensory pathways and, in a combined computational and experimental strategy, (iii) quantifying the precise contributions of an animal’s activity to its sense of time. The project’s second aim, in turn, is to unravel the roles of the clock, and clock genes, for the function of mechanosensory systems. Previous studies have linked the clock to noise vulnerability in mammalian ears, and clock genes to regeneration in avian ears. Our own preliminary data reveal severe mechanosensory defects in flies mutant for core clock genes. I will use the Drosophila ear as a unifying model to analyse the specific roles of the clock, and clock genes, for the function of mechanotransducer systems.

1 899 549 €

Start date: 2015-09-01, End date: 2021-08-31

A key question in neuroscience is how information is processed by sensory systems to guide behavior. Most of our knowledge about sensory processing is based on presentation of simple isolated stimuli and recording corresponding neural activity in relevant brain areas. Yet sensory stimuli in real life are never isolated and typically not simple. How the brain processes complex stimuli, simultaneously arising from multiple objects is unknown. Our daily experience (as well as well-controlled experiments) shows that only parts of a complex sensory scene can be perceived - we cannot listen to more than one speaker in a party. Importantly, one can easily choose what is important and should be processed and what can be ignored as background. These observations lead to the prevalent hypothesis that feedback projections from ‘higher’ brain areas to more peripheral sensory areas are involved in processing of complex stimuli. However experimental analysis of signals conveyed by feedback projections in behaving animals is scarce. The nature of these signals and how they relate to behavior is unknown. Here I propose a cutting edge approach to directly record feedback signals in the olfactory system of behaving mice. We will use chronically implanted electrodes to record the modulation of olfactory bulb (OB) principal neurons by task related context. Additionally, we will record from piriform cortical (PC) neurons that project back to the OB. These will be tagged with channelrhodopsin-2 and identified by light sensitivity. Finally, we will express the spectrally distinct Ca++ indicators GCaMP6 and RCaMP2 in PC neurons and in olfactory sensory neurons, respectively, and use 2-photon microscopy to analyze the spatio-temporal relationship between feedforward and feedback inputs in the OB. This comprehensive approach will provide an explanation of how feedforward and feedback inputs are integrated to process complex stimuli.

1 500 000 €

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

The ComPAg research program will produce the first global comparative synthesis of the convergent evolution of domesticated plants and early agricultural systems based primarily on empirical archaeobotanical data. We will produce ground-breaking data on the earliest crop packages across large parts of Eurasia and Africa, comparisons of the nature of early cultivation inferred from associated weed floras, quantified time series data on evolution of domestication traits for over 30 crops, including both primary and secondary domestications. This program will pursue primary archaeobotanical research in East and Southeast Asia, India, and parts of Africa, with synthesis of existing evidence from Southwest Asia and Europe. We aim to achieve a new framework for explaining the multiple routes from foraging to agriculture on a global scale. The origins of agriculture is widely regarded as the most significant ecological and economic change in the history of human populations, constituting the basis of a fundamental demographic transition towards higher and denser human populations. Plant cultivation is common to all instances of food production that supported sedentism, and thus the origins of crop agriculture is a core issue of socioeconomic evolution in long-term human history. This program will pursue cutting edge research to produce a new critical understanding of early agricultural transformations.

2 041 992 €

Start date: 2013-06-01, End date: 2018-05-31

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

The neural assembly underlying the formation of functional networks in the cerebral cortex is conceivably the most complex biological system that exists. Much of this complexity arises during development through the interaction of dozens of different neuronal populations, which belong to two general classes: excitatory glutamatergic pyramidal cells and inhibitory gamma-aminobutyric containing (GABAergic) interneurons. Perhaps the most fascinating aspect of the assembly of cortical circuits is that pyramidal cells and interneurons are generated in distant germinal zones. Pyramidal cells are born locally from progenitors located in the cortical anlage, while interneurons derive from progenitors in the embryonic subpallium. Much progress has been made recently in understanding the molecular mechanisms that regulate the migration of interneurons towards the cortex, but how interneurons find their appropriate partners to build cortical networks with balanced excitation and inhibition remains an enigma. The general goal of this project is to identify the mechanisms controlling the precise allocation of different classes of interneurons into specific layers of the cortex, where they assemble into neural circuits. We also aim to determine how the allocation of interneurons into specific cortical layers influences their function. This project is now possible due to the unique combination of our detailed know-how on the early development of cortical interneurons, including a variety of genetically modified mice available to us, and the application of new technologies to specifically target synchronically generated populations of interneurons. Our multidisciplinary approach, combining mouse genetics, in vivo functional genomics and electrophysiological methodologies represents a technological breakthrough that should accelerate our understanding of the general principles guiding the assembly of neuronal circuits in the cerebral cortex.

2 493 481 €

Start date: 2012-04-01, End date: 2017-09-30

I propose to bridge the gap between simple in vitro measurements of biological processes, and the complexities of the cellular environment. This requires reduced in vitro systems that are sufficiently complex to reproduce the subtleties of the in vivo biological phenomenon, but sufficiently controllable to test how quantitative changes in a particular property affects function. The challenge is to step beyond the most simple and straightforward in vitro mimics of the cell membrane, and create model systems that more closely reproduce the conditions in vivo. I propose to tackle two specific, but interrelated membrane phenomena, that are currently not captured in artificial bilayers and create new complex mimics of the cell membrane capable of tackling these systems; namely (1) protein crowding and the cytoskeleton, and (2) lateral forces and membrane curvature. Testing our synthetic mimics with models that we understand in vivo is vital. This benchmarking will ensure that the mimics we create are relevant and will help ensure the more ambitious later goals of the this proposal are successful.We will then take these tools to go on and aim to create a synthetic mimic of the bacterial membrane. However we are not limited to creating purely natural duplicates, and we can exploit a much wider range of building material than nature. In addition to creating complex mimics, we will also create totally new synthetic systems inspired by the properties of the cell membrane, but possessing unique properties.

1 498 523 €

Start date: 2013-02-01, End date: 2018-10-31

The human genome is highly transcribed, with over 90% of sequences contributing to the production of RNA. The function of the vast majority of these RNAs is unknown. Evidence over many years has revealed that transcription factors and chromatin regulators are associated with a variety of non-coding (nc)RNAs, but their function remains largely unknown. There are a few cases where a role has been ascribed for ncRNAs in transcription, but no clear mechanistic insight has been defined yet. We predict that many of the newly identified ncRNAs emanating from the genome will play a role in transcriptional processes. We intend to identify and characterise such ncRNAs. This will take place in two phases. In the first phase we will use biochemical approaches to identify ncRNAs involved in the regulation of chromatin and transcription. Our investigations will focus on proteins leading to the induction of pluripotency and oncogenesis. ncRNAs associated with such proteins will be identified using targeted screens. In the second phase, the importance of these RNAs in determining pluripotency and oncogenesis will be analysed. In addition, a variety of molecular approaches will be used to investigate the mechanism by which these ncRNAs regulate the function of the proteins or complexes they associate with. One particular hypothesis we will explore is that such ncRNAs play a role in guiding proteins to DNA sequences, via the formation of RNA/DNA triplexes. This concerted and focused analysis will provide mechanistic insights into the functions of ncRNAs in transcriptional regulation and validate their role in key biological processes. The identification of such new ncRNA-regulated pathways may open up new avenues for therapeutic intervention.

2 141 470 €

Start date: 2011-05-01, End date: 2017-04-30

In eukaryotic cells, DNA replication is tightly regulated to ensure that the genome is duplicated only once per cell cycle. Errors in the control mechanisms that regulate chromosome ploidy cause genomic instability, which is linked to the development of cellular abnormalities, genetic disease and the onset of cancer. Recent reconstitution experiments performed with purified proteins revealed that initiation of eukaryotic genome duplication requires three distinct steps. First, DNA replication start sites are identified and targeted for the loading of an inactive MCM helicase motor, which encircles the double helix. Second, MCM activators are recruited, causing duplex-DNA untwisting. Third, upon interaction with a firing factor, the MCM ring opens to eject one DNA strand, leading to unwinding of the replication fork and duplication by dedicated replicative polymerases. These three events are not understood at a molecular level. Structural investigations so far aimed at imaging artificially isolated replication steps and used simplified templates, such as linear duplex DNA to study helicase loading or pre-formed forks to understand unwinding. However, the natural substrate of the eukaryotic replication machinery is not DNA but rather chromatin, formed of nucleosome arrays that compact the genome. Chromatin plays important regulatory roles in all steps of DNA replication, by dictating origin start-site selection and stimulating replication fork progression. Only by studying chromatin replication, we argue, will we understand the molecular basis of genome propagation. To this end, we have developed new protocols to perform visual biochemistry experiments under the cryo-electron microscope, to image chromatin duplication at high resolution, frozen as it is being catalysed. Using these strategies we want to generate a molecular movie of the entire replication reaction. Our achievements will change the way we think about genome stability in eukaryotic cells.

2 000 000 €

Start date: 2019-03-01, End date: 2024-02-29

This project aims to explore the effects of human settlement intensity on desert ecological community structure, focusing on the hitherto unstudied phenomenon of trophic cascades in antiquity. Its key research question is whether human-induced changes in arid land biodiversity can feedback to affect natural resources important for human subsistence, such as pasture and wood. The role of such feedback effects in ecological systems is increasingly acknowledged in recent years in the biological literature but has not been addressed in the study of human past. The research question will be approached using bioarchaeological methods applied to the uniquely-preserved material record from the middle and late Holocene settlement sequence (approximately 4,500 BCE to 700 CE) of the Dead Sea Ein Gedi Oasis, and to the contemporary palaeontological assemblages from caves located in the surrounding Judean Desert. The proposed research is expected to bridge between aspects of current thinking on ecosystem dynamics and the study of human past by exploring the role of trophic cascades as an invisible dimension of Anthropocene life in marginal environments. The study of the history of human impact on such environments is important to resource management planning across a rapidly expanding ecological frontier on Earth, as climate deterioration brings more people in contact with life-sustaining and sensitive arid land ecosystems.

1 499 563 €

Start date: 2019-01-01, End date: 2023-12-31

What is the fundamental unit of computation in the brain? Answering this question is crucial not only for understanding how the brain works, but also for building accurate models of brain function, which require abstraction based on identification of the essential elements for carrying out computations relevant to behaviour. We will directly test the possibility that single dendritic branches may act as individual computational units during behaviour, challenging the classical view that the neuron is the fundamental unit of computation. We will address this question using a combination of electrophysiological, anatomical, imaging, molecular, and modeling approaches to probe dendritic integration in pyramidal cells and Purkinje cells in mouse cortex and cerebellum. We will define the computational rules for integration of synaptic input in dendrites by examining the responses to different spatiotemporal patterns of excitatory and inhibitory inputs. We will use computational modeling to extract simple rules describing dendritic integration that captures the essence of the computation. Next, we will determine how these rules are engaged by patterns of sensory stimulation in vivo, by using various strategies to map the spatiotemporal patterns of synaptic inputs to dendrites. To understand how physiological patterns of activity in the circuit engage these dendritic computations, we will use anatomical approaches to map the wiring diagram of synaptic inputs to individual dendrites. Finally, we will manipulate dendritic function using molecular tools, in order to provide causal links between specific dendritic computations and sensory processing. These experiments will provide us with deeper insights into how single neurons act as computing devices, and how fundamental computations that drive behaviour are implemented on the level of single cells and neural circuits.

2 416 078 €

Start date: 2010-06-01, End date: 2016-05-31

The mammalian neocortex consists of discrete, but highly interconnected, functional areas that collectively encode features of the environment, form associations between stimuli and drive behaviour by transforming sensory input into motor output. All neocortical areas are organised into six layers containing two major classes of neurons, excitatory glutamatergic pyramidal cells and inhibitory GABAergic interneurons. However, each area has distinctive cytoarchitectonical features and inputs that largely determine its computational capabilities. As pyramidal cells comprise the large majority of neurons in the cerebral cortex, much emphasis has been made on their contribution to the differential organisation of cortical areas. In contrast, interneurons have received little attention in the context of the functional specialisation of cortical areas, even though their distribution is highly heterogeneous. The central tenet of this research proposal is that distinct patterns of inhibitory connectivity may accompany, and perhaps even determine, the functional specialisation of neocortical areas. We hypothesise that interneurons play an important role in the tuning of circuits in each cortical area, and therefore that quantitative differences in the relative distribution of specific classes of interneurons, which arise during development, reflect functional specialisations. The overall aim of this research project is to understand how developmental mechanisms ‘sculpting’ the distribution of inhibitory neurons across different neocortical areas contribute to their functional specialisation. This project has the potential to transform our understanding of the organisation of inhibitory circuits in the mammalian neocortex.

2 500 000 €

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

The communities of the Western Sephardic Diaspora were founded in the 16th and 17th centuries by New Christians from Iberia who returned to Judaism that had been abandoned by their ancestors in the late Middle Ages. This project will concentrate on the changes in the religious conceptions and behavior as well as the cultural patterns of the communities of Amsterdam, Hamburg, Leghorn, London, and Bordeaux. We will analyze the vigorous activity of their leaders to set the boundaries of their new religious identity in comparison to the policy of several Christian “communities of belief,” which went into exile following religious persecution in their homelands. We will also examine the changes in the attitude toward Judaism during the 17th century in certain segments of the Sephardic Diaspora: rather than a normative system covering every area of life, Judaism came to be seen as a system of faith restricted to the religious sphere. We will seek to explain the extent to which this significant change influenced their institutions and social behaviour. This study will provide us with better understanding of the place of the Jews in European society. At the same time, we will subject a central series of concepts in the historiographical discourse of the Early Modern Period to critical analysis: confessionalization, disciplinary revolution, civilizing process, affective individualism, etc. This phase of the research will be based on qualitative and quantitative analysis of many hundreds of documents, texts and the material remains of these communities. Using sociological and anthropological models, we will analyze ceremonies and rituals described at length in the sources, the social and cultural meaning of the architecture of the Sephardic synagogues of that time, and of other visual symbols.

1 671 200 €

Start date: 2012-03-01, End date: 2018-02-28

This project involves developing and applying new methods in palaeography, bringing digital resources to bear in innovative ways. It comprises three components: a web resource, a database, and a monograph. The web resource will allow the study of medieval script in the context of the manuscripts and charters that preserve it. It will focus on discovery and citation, allowing users to retrieve digital images, verbal descriptions, and detailed characterisations of the writing, as well as the larger context including the content and structure of the manuscript or charter. It will incorporate different ways of exploring the material such as images, maps and timelines as well as text-based browse and search. It will provide a flexible, extensible framework to integrate external data-sources and so applies to any period or area of palaeography. It will therefore enable new developments in palaeographical method which have been discussed in theory but not yet achieved in practice. To demonstrate these methods, content will be provided for handwriting from England in the vernacular, particularly that of AD 990-1100. This period saw rapid change in vernacular script despite relative stability in that of Latin, something that has never been fully explained. This problem will be addressed by integrating existing datasets but also by producing and incorporating an entirely new database of scripts. The result will provide access to the complete corpus of surviving examples of the script for the first time, bringing an unprecedented rigour to palaeographical analysis. A monograph will then draw on this research, demonstrating the new methods in practice and providing the first comprehensive account of English vernacular script from the period. The work will address issues in Digital Humanities (integration, interface design, visualisation and standards), in palaeographical method (quantitative methods, terminology and evidential rigour), and in the history of vernacular script

995 531 €

Start date: 2010-10-01, End date: 2014-09-30

We aim to understand the relationship between dynamic changes in physical landscapes and patterns of human dispersal and development in prehistory, paying particular attention to the impact of active tectonics and sea-level change. We will: • Introduce and develop concepts and techniques of tectonic geomorphology and mapping to analyse the relationship between geological instability, complex topographies, and archaeological remains at a variety of geographical scales • Focus on the western Arabian Peninsula and the Red Sea coast, a key, but little known, intermediary region between Africa and Eurasia, and draw on a wider comparative sample of key site-regions throughout the main axes of early dispersal in Africa, SW Asia and S Europe. • Develop strategies to explore the submerged landscapes and archaeology of the continental shelf, now recognised as a major gap in our understanding of the human story • Analyse the shell mounds of recent millennia to develop a detailed benchmark for what constitutes the archaeological signature of a coastal economy, and a guide to the interpretation of more vestigial data from earlier periods and the search for material on submerged coastlines when sea levels were lower • Synthesise the results with existing palaeoclimatic and palaeoenvironmental data • Tackle the fundamental but hitherto unresolved technical challenge of how to distinguish in distributions of archaeological sites between genuine patterns of human habitat preference and geological effects of differential visibility • Produce a case study that demonstrates how long-term human engagement with the material world of a changing physical landscape and the cumulative palimpsests of archaeological deposits can give rise to new adaptations and new strategies of social action

2 550 000 €

Start date: 2011-04-01, End date: 2016-03-31

Our genetic material is continually subjected to damage, either from endogenous sources such as reactive oxygen species, produced as by-products of oxidative metabolism, from the breakdown of replication forks during cell growth, or by agents in the environment such as ionising radiation or carcinogenic chemicals. To cope with DNA damage, cells employ elaborate and effective repair processes that specifically recognise a wide variety of lesions in DNA. These repair systems are essential for the maintenance of genome integrity. Unfortunately, some individuals are genetically predisposed to crippling diseases or cancers that are the direct result of mutations in genes involved in the DNA damage response. For several years our work has been at the forefront of basic biological research in the area of DNA repair, and in particular we have made significant contributions to the understanding of inheritable diseases such as breast cancer, Fanconi anemia, and the neurodegenerative disorder Ataxia with Oculomotor Apraxia (AOA). The focus of this ERC proposal is: (i) to determine the mechanism of action and high-resolution structure of the BRCA2 tumour suppressor, and to provide a detailed picture of the interplay between BRCA2, PALB2, RAD51AP1 and the RAD51 paralogs, in terms of RAD51 filament assembly, using biochemical, electron microscopic and cell biological approaches, (ii) to determine the biological role of a unique structure-selective tri-nuclease complex (SLX1-SLX4-MUS81-EME1-XPF-ERCC1), with particular emphasis on its roles in DNA crosslink repair and Fanconi anemia, and (iii) to understand the actions of Senataxin, which is defective in AOA2, in protecting against genome instability in neuronal cells. These three distinct and yet inter-related areas of the research programme will provide an improved understanding of basic mechanisms of DNA repair and thereby underpin future therapeutic developments that will help individuals afflicted with these diseases.

2 203 153 €

Start date: 2015-09-01, End date: 2020-08-31

Documenting Multiculturalism will investigate comprehensively and systematically the coexistence of the diverse confessional, ethnic and linguistic communities of the island of Sicily under its Norman and Hohenstaufen rulers — Arabic-speaking Muslims and Jews, Greek Christians, and Latin Christians. It will investigate: the legal foundations upon which the coexistence of the subject communities rested; the nature, extent and results of cultural, linguistic and social interactions between them; and variation in the above, from time to time c. 1060 – c. 1266, and from place to place within the island. The ambitious objective is to create the fundamental tools to study, and to begin to write, the history of the subject communities of Norman Sicily from the bottom up, using documentary rather than narrative sources, and illustrating as far as possible the full variety in space and time. The Project will do this by making new critical editions of all of the administrative and legal documents for Norman Sicily, in the three principal administrative languages — Arabic, Greek and Latin. These texts will populate a database, to which further data from the non-documentary sources will be added. The database will then be used to generate a series of powerful electronic research tools, which will be both the means to meet the ends of this particular project, and ends in themselves that will revolutionise the future study of all aspects of the history of Norman Sicily. At the end of the Project, a series of summative studies will document, analyse and discuss different aspects of coexistence and popular multiculturalism in Norman Sicily, and set the case of Sicily in the wider Mediterranean context. What is distinctive about this Project is that not only the publication of its research objectives, but also the tools that it will create in order to achieve them, will revolutionise the future study of all aspects of the cultural, economic and social history of Norman Sicily.

2 467 965 €

Start date: 2018-10-01, End date: 2023-09-30

The survival of our most active tissues, such as the brain and heart, throughout decades of a human lifespan presents an extraordinary biological challenge. Mitochondria are central to the life and death of these tissues. They provide the cellular energy required by these cells and protect them by buffering potentially lethal levels of cytoplasmic calcium, while at the same time mitochondria produce much of the molecules that cause cellular damage and contain a lethal arsenal of apoptotic cell death machinery. These organelles require exquisite maintenance processes to keep them intact and prevent potentially catastrophic disruption. Failure in mitochondrial homeostasis is strongly linked to age-related conditions such as neurodegeneration. This subject has garnered intense interest recently with emergence that two genes linked to Parkinson's disease, PINK1 and parkin, regulate the autophagic degradation of mitochondria (mitophagy). Mitophagy is coordinated with mitochondrial dynamics, processes vital to neuronal health. While recent work has uncovered the basic mechanisms of PINK1/parkin-induced mitophagy, many questions and caveats surround the current knowledge. Most notably, all studies to date have used in vitro approaches and non-physiological manipulations. Thus, we still have a poor understanding of this process in a physiological context. I will principally use the powerful genetic techniques of Drosophila to investigate the influence of mitochondrial dynamics on maintaining normal neuronal function and survival, and its impact on neurodegeneration, in the context of an intact animal system. I will also use molecular, cell biology and biochemical approaches in mammalian cells to complement our in vivo findings and verify their relevance to human biology. These insights will deliver a greater understanding of the role of mitochondrial dynamics in the health and dysfunction of the nervous system in a physiological context and guide therapeutic developments.

1 486 761 €

Start date: 2013-01-01, End date: 2018-12-31

Emotions influence social relations; consequently, they are socially relevant, subject to scrutiny, judgment, and normative intervention. The manifestation, perception and treatment of emotions are subject to social interventions and to the influence of cultural change. Emotions in the Classical world have been primarily studied in the light of their representation in literature and art. Such studies have provided important insights; yet, they are based on works primarily created in a few major urban centres, almost exclusively by educated men of a higher status. This project is based on an analysis of documentary sources (inscriptions and papyri, c. 800 BC-c. 500 AD). Although they provide abundant, diverse, and representative evidence, they have never been studied in connection with this subject. As compared to literature and art, these sources represent a wide range of social strata and age-classes, originate in both genders, and are widely disseminated over time and space. These sources will be analysed both diachronically (history of particular emotions) and synchronically (manifestations of emotions in defined historical contexts). Selected literary sources and archaeological material will also be taken into consideration. The project pursues the following objectives: to contribute to a more reliable, nuanced, and comprehensive history of emotions in the Greek world; to increase awareness of the importance of emotions in Classical studies; to contribute to the transdisciplinary study of emotions through the presentation of paradigms from Classical antiquity; to enhance the dialogue between historical, social, and natural sciences; and to make documentary sources accessible to scholars working on the history of emotions and, more generally, on the history of mentality.

1 593 945 €

Start date: 2009-01-01, End date: 2013-12-31

Excising a membrane protein from its natural environment, preserving the lipid bilayer, and characterising the lipids that surround it is the ‘holy grail’ of membrane protein biophysics. However, with some 40,000 different lipid structures the challenges we face in understanding selective binding arise not just from the complexity and dynamics of the lipidome, but also from the transient nature of protein lipid interactions. To overcome these challenges we will take mass spectrometry (MS) into a new era, allowing, for the first time, the study of proteins in an environment as close as possible to the natural one. To do this we will (i) characterise protein lipid interactions by employing a high resolution Orbitrap mass spectrometer developed in-house, specifically for membrane proteins, (ii) capture the native lipid environment in vehicles suitable for use in conjunction with MS, and (iii) establish a new platform to be known as integral membrane protein desorption electrospray ionization (impDESI). Designed and built in-house impDESI is capable of releasing membrane proteins from surfaces directly into the mass spectrometer (MS). We will develop impDESI for membrane mimetics, and subsequently portions of natural membranes, enabling us to extract proteins with oligomeric state preserved and native lipid binding intact. The development of impDESI, in conjunction with high resolution Orbitrap MS, and coupled with the optimisation of membrane mimetics, has the potential to radically transform our understanding of native lipid binding, not only directly, but also temporally and spatially. Together these advances will answer key questions about how lipids modulate protein interfaces, occupy different binding sites, modulate membrane protein structure and modify function in vivo. Given the importance of membrane proteins as potential drugs targets understanding their modulation by lipids would be a major step towards more effective drug development.

2 481 744 €

Start date: 2016-06-01, End date: 2021-05-31

The five-year EngLaId project will look at the long-term history of the English landscape from 1500 BC to AD 1086, combining evidence on landscape features, such as track-ways,fields and settlements, with the distribution of metalwork. The project aims to understand how people built relations with each other and broader cosmological forces from the start of the settled landscape to the early Medieval world. The project will combine a mass of digital data on landscapes and artefacts to uncover both continuity and change over 2500 years throwing a new light on the nature of pre-modern communities, contributing method and theory which can have model value in other areas of Europe.

2 059 935 €

Start date: 2011-08-01, End date: 2016-12-31

Interactions between bacteria and their viruses (bacteriophages) have led to the evolution of a wide range of bacterial mechanisms to resist viral infection. The exploitation of such systems has produced true revolutions in biotechnology; firstly, the restriction-modification (RM) enzymes for genetic engineering, and secondly, CRISPR-Cas9 for gene editing. This project aims to unravel the mechanisms and consequences of prokaryotic immune systems that target covalently-modified DNA, such as base methylation, hydroxymethylation and glucosylation. Very little is known about these Type IV restriction enzymes at a mechanistic level, or about their importance to the coevolution of prokaryotic-phage communities. I propose a unique interdisciplinary approach that combines biophysical and single-molecule analysis of enzyme function, nucleoprotein structure determination, prokaryotic evolutionary ecology, and epigenome sequencing, to link the molecular mechanisms of prokaryotic defence to individual, population and community-level phenotypes. This knowledge is vital to a full understanding of how bacterial immunity influences horizontal gene transfer, including the spread of virulence or antimicrobial resistance. In addition, a deeper analysis of enzyme function will support our reengineering of these systems to produce improved restriction enzyme tools for the mapping of eukaryotic epigenetics markers.

2 196 414 €

Start date: 2018-08-01, End date: 2023-07-31

In each cell cycle, eukaryotic cells must faithfully replicate large genomes in a relatively short time. This is accomplished by initiating DNA replication from many replication origins distributed along chromosomes. Ensuring that each origin is efficiently activated once and only once per cell cycle is crucial for maintaining the integrity of the genome. Recent evidence indicates that defects in the regulation of origin firing may be important contributors to genome instability in cancer. Strict once per cell cycle DNA replication is achieved by a two-step mechanism. DNA replication origins are first licensed by loading an inactive DNA helicase (Mcm2-7) into pre-replicative complexes (pre-RCs). This can only occur during G1 phase. Initiation then occurs during S phase, triggered by cyclin dependent kinases (CDKs) and Dbf4-dependent kinase (DDK), which promote recruitment of proteins required for helicase activation and replisome assembly. Research proposed herein will lead to a deeper understanding of the mechanism and regulation of DNA replication. We have reconstituted the licensing reaction with purified proteins which will be used to characterise the mechanism of licensing and the mechanism by which licensing is regulated in the cell cycle. We will also use this system to reconstitute events leading to the initiation of DNA replication. We will use genetic and biochemical approaches to characterise the mechanisms by which perturbed licensing causes gross chromosome rearrangements. We will also explore mechanisms involved in regulating the temporal programme of origin firing and how origin firing is regulated in response to DNA damage. Work in budding yeast and mammalian cells will be pursued in parallel to exploit the specific advantages of each system.

2 449 999 €

Start date: 2010-05-01, End date: 2015-04-30

The biological response to stress is concerned with the maintenance of homeostasis in the presence of real or perceived challenges. This process requires numerous adaptive responses involving changes in the central nervous and neuroendocrine systems. When a situation is perceived as stressful, the brain activates many neuronal circuits linking centers involved in sensory, motor, autonomic, neuroendocrine, cognitive, and emotional functions in order to adapt to the demand. However, the details of the pathways by which the brain translates stressful stimuli into the final, integrated biological response are presently incompletely understood. Nevertheless, it is clear that dysregulation of these physiological responses to stress can have severe psychological and physiological consequences, and there is much evidence to suggest that inappropriate regulation, disproportional intensity, or chronic and/or irreversible activation of the stress response is linked to the etiology and pathophysiology of anxiety disorders and depression. Understanding the neurobiology of stress by focusing on the brain circuits and genes, which are associated with, or altered by, the stress response will provide important insights into the brain mechanisms by which stress affects psychological and physiological disorders. This is an integrated multidisciplinary project from gene to behavior using state-of-the-art moue genetics and animal models. We will employ integrated molecular, biochemical, physiological and behavioral methods, focusing on the generation of mice genetic models as an in vivo tool, in order to study the central pathways and molecular mechanisms mediating the stress response. Defining the contributions of known and novel gene products to the maintenance of stress-linked homeostasis may improve our ability to design therapeutic interventions for, and thus manage, stress-related disorders.

1 500 000 €

Start date: 2011-04-01, End date: 2016-03-31

"This project will investigate the transmission of farming and associated technological innovations (landscape use, pottery, lithics) in the western Balkans during the 6th and 5th millennium BC through a combination of new data collection (archaeological field work, access to museum collections and literature survey), analysis and agent-based modelling. The research area provides a unique opportunity to observe the creation and initial dispersal of the two cultural streams (inland and maritime) responsible for the introduction of farming across much of Europe. This project will be the first one to consider explicitly this process from the point of view of the transmission of innovations, that is how one becomes a farmer. The analytical work will characterise the competences and knowledge required for the transmission of each selected technological innovation. The agent-based modelling will aim at comparing these technologies together and weighing their respective impact in shaping the variability between the inland and maritime streams of neolithisation. Thanks to its combination of robust analytical work and modelling, this project will achieve the difficult balance between reflecting the complexity inherent to each technology, and the need for abstraction required for comparison."

1 499 832 €

Start date: 2012-10-01, End date: 2017-09-30

By the time of the Norman Conquest in 1066, England’s population was again comparable to that of Roman Britain and included substantial urban centres. By 1200, England was more densely populated than ever before. Such population growth was mirrored across much of Europe. It drove the expansion of towns and markets and was fed, literally, by an increase in agricultural productivity that involved a fundamental reorganization of the countryside. The social, economic and demographic consequences of this reorganization were so far-reaching that it has often been described as an ‘agricultural revolution’. At the heart of this proposal is the question, how and when was this revolution achieved? FeedSax will effect a breakthrough in understanding this critically important period in Europe’s agricultural history by generating new, direct evidence for changing land-use from the excavated remains of crops, animals and farms. The timing and nature of the ‘cerealisation’ of England have been debated for over a century, with arguments focusing on the origins of open fields. These arrays of strip fields were communally cultivated, requiring collective decision-making and sharing of resources. Peasant households therefore had to live close together, giving rise to the nucleated villages that remain such a striking feature of the landscape. Fields thus created communities, reconfiguring both landscapes and social geography. The spread of open fields laid the foundations for the modern countryside and is widely regarded as one of the transformative changes of the Middle Ages, yet theories about when and how this unprecedented type of agriculture emerged and spread are based on limited, indirect written and archaeological evidence. FeedSax breaks new ground by integrating scientific methods such as stable isotope and pollen analysis, radiocarbon dating, archaeobotany and archaeozoology with structural remains to resolve this hitherto intractable problem.

1 933 165 €

Start date: 2017-09-01, End date: 2021-08-31