- Total grants
- Total funders
- Total recipients
- Earliest award date
- 10 Apr 2001
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
The metazoan Hsp70 disaggregase system is the only known human protein complex capable of resolubilising aggregated protein, conferring a protective phenotype for a range of pathologies. Disaggregation occurs through the dynamic assembly of a Hsp70/110 complex, initiated by J-protein recruitment of substrate. The structure of the active complex is currently unknown, as is the mechanism of disaggregation. This project will employ an interdisciplinary approach to structurally characterise the disaggregation of alpha-synuclein amyloid fibres in vitro by the human proteins DNAJB1 (J-protein), Hsc70 (Hsp70) and Apg2 (Hsp110). There will be a primary focus on understanding two particular elements of disaggregation. Firstly, how do J-proteins recruit substrate to activate disaggregation? This will be investigated using electron tomography, taking advantage of the recent "resolution revolution" in the electron microscopy field. Secondly, what is the mechanism of the active disaggregase complex as it is resolubilising aggregates? To answer this, we aim to track individual alpha-synuclein fibres by atomic force microscopy and total internal reflection fluorescence microscopy as they are solubilised during disaggregation. Given the role of aggregation in a broad range of debilitating diseases, increasing the understanding of disaggregation in humans has the potential to eventually lead to significant public health benefits.
Feeling Flesh: Pain, Emotion and the Self in the Understanding of Insanity’s Tortured Bodies and Fractured Minds, c.1880-1930 02 May 2017
This study draws attention to the ambiguities and conflicts surrounding embodiment and pain in late-nineteenth and early-twentieth century understanding of the experience of ‘insanity’. Engaging with concepts of embodied cognition, the history of emotion and phenomenology, it considers the relationship between the body, culture, and language in the experience and construction of disorder. Deconstructing boundaries drawn around the ‘shell-shocked body’ in historical discourse draws attention to the ambiguous but shifting position occupied by the hypersensitive uncontrollable or pained body to reveal the experience of mental illness as shaped by a complex interaction of body, language, and culture. Resistant reading of patient case-notes and published treatises on insanity will be used in conjunction with a consideration of representations of the ‘insane body’ in the visual arts (including photography and film). Arguing for a biopsychosocial approach to mental health, this research emphasises the importance of historicising the ways in which the experience of ‘disorder’ is filtered through textual and visual discourse; asking how patients have communicated sensation and considers the ways in which doctors have sought to record or understand it.
Fascism, the Corruption of Psychiatry and the Coercion and Confinement of LGBT People in Italy, 1922 - 1943 02 May 2017
My doctoral thesis will draw together substancial archives records and will analyse the complex and intricate behind-the-scenes dialogue between psychiatric hospitals directors, public security forces, local authorities, mental health patients and their families during the fascist regime in Italy (1922-1943). Analysing and comparing the correspondence between these institutions and individuals, together with doctors' and nurses' notes, in four different locations, it will shed light on how repression of so-called sexual inversion was implemented. This fragmented and choral dialogue will be revealing of broader social attitudes towards homosexuality and will challenge the stereotype of cohesive Italian families that was so central in fascist propaganda. It will unravel mechanisms of power and authority during the regime and will show to what extent its rhetoric had entered everyday life. Finally, it will demonstrate how the law and its representatives accommodated the regime's need to isolate and punish non-conforming individuals, and how psychiatry offered its knowledge to this project, thus becoming its most effective tool of repression.
Establishing objective measures for identifying children with Autism Spectrum Disorders using eye-tracking technology in the UK and India 09 Nov 2016
Autism Spectrum Disorders (ASD) contribute significantly to total years lived with disability globally. Most people with ASD in low-income countries are belatedly or never diagnosed, mainly due to the paucity of mental health specialists - hence critical years for treatment are missed. Objective measures for ASD detection are needed. Multiple cognitive markers of ASD have been identified using eye-tracking technology; testing these markers in combination holds promise for effective identification of children with ASD. This proposal aims to establish objective measures for identifying children with ASD using eye-tracking technology in high and low-income settings. Stage 1 will analyse existing eye-tracking data from the British Autism Study of Infant Siblings, to establish a combination of eye-tracking tasks that has the highest probability of identifying children with an ASD diagnosis. Stage 2 will be a case control pilot study to determine whether the same combination of markers identifies children with an ASD diagnosis in India. The feasibility and acceptability of these eye-tracking tasks will also be assessed in an Indian context. Establishing effective, acceptable and feasible methods for objectively identifying children with ASD will improve detection in these settings and translate into a greater number of children benefiting from early interventions worldwide.
Toddlerlab CAVE Neuroimaging Facilities 05 Jul 2018
The Centre for Brain and Cognitive Development (CBCD) has been at the forefront of developing behavioural, electrophysiological, and functional Near Infrared Spectroscopy (fNIRS) methods for use in early development. We propose to assemble the world’s first audiovisually contingent, fully immersive multiuser Cave Automatic Virtual Environment (CAVE) incorporating real-time synchronised brain recordings of electrical activity, blood oxygenation, and motor functioning (motion tracking, EMG), all using wearable or wireless technology enabling natural toddler and pre-school child interactions to be recorded. This will be achieved by building a completely new dedicated facility incorporating state of the art behavioural and neuroimaging capabilities. The proposed automated end-to-end pipeline will provide an unconstrained solution that will allow toddlers and pre-school children to be studied in comparable ways to infant and animal studies, affording direct validation of existing animal models of cognitive development to neurotypical development, as well as to emerging disorders, such as ADHD, Autism Spectrum Disorder, Down syndrome, and Williams syndrome. This facility will allow us to join the dots between early neurocognitive development, which is relatively well understood, and later development in middle childhood that will enable the direct translation of advances in basic bioscience to practical clinical and social solutions.
History of Medicine: Minds, Bodies and Cultures 30 Jun 2018
Recent historical work has begun to grapple with the ways in which representations of epidemics in the Global South have impacted both popular understandings and policies towards afflicted countries. Previous studies such as David Campbell’s ‘The Iconography of Famine’ have shown how visual culture has played an important role in both presenting the Global South as inferior to the West and in prompting government actions. There is, however, a need for more scholarly attention to be focused on historical representations of Ebola epidemics and the impact that such representations have had in social and political spheres. By contextualising my close analysis of Ebola photography within a diverse selection of textual sources, this project will fulfil the following three objectives: 1. Explore the ways in which photographs of the Ebola epidemic in British popular culture have historically shaped attitudes and policies towards afflicted countries. 2. Produce a peer-reviewed article that will examine the history of photographic representations of Ebola in Britain. 3. Submit an opinion piece to Guardian Science that will explore visual imagery in relation to current debates over public-health and immigration policies. Further, a policy report will be produced for History & Policy.
Waiting Times 01 Feb 2017
This project brings together an interdisciplinary team to investigate waiting as a cultural and psychosocial concept, and an embodied and historical experience, in order to understand the temporalities of healthcare. It represents a fundamental rethinking of the relation between time and care through a critical analysis of waiting in the modern period. Working across Medical Humanities and Psychosocial Studies, we will uncover the history, cultural representation, and psychosocial organisation of delayed and impeded time, from 1860 to the present. This work will underpin focused investigations of ‘watchful waiting’ in current general practice, psychotherapy, and end of life care. We ask which models of time operate within healthcare practices and develop new models of durational temporality to conceptualise how waiting can operate as a form of careful attention, historically and in the present. Contextualising these healthcare practices within broader social organisations of time, we open up the meanings, potentialities, and difficulties of waiting in current times. Through academic publications and extensive public engagement, we will reframe debates about waiting in and for healthcare, moving beyond the urgent need to reduce waiting times in the NHS, towards a more comprehensive understanding of the relation between waiting, care, and changing experiences of time.
Conference: Hospitals and the Patient Experience: Architecture, Art, Music and Treatment, WT Centre for HOM, London, 16 February, 2007. The conference: a select number of conferences have previously considered patient experience, but this theme has formed merely a small section of the proceedings and the emphasis has fallen upon either modern historical studies or research into current medical practice. Examples of such conferences include: 'From Western Medicine to Global Medicine: The Hospital Beyond the West' (Wellcome Unit for the History of Medicine, University of Oxford, 2004), 'Patients and Pathways: Cancer Therapies in Historical and Sociological Perspective' (Wellcome Unit for the History of Medicine, University of Manchester, 2005); 'Music and Medicine' (Society for Education, Music and Psychology Research, University of Edinburgh, forthcoming, October 2006. This conference, 'Hospitals and Patient Experience' is unique not only because the focus is centred firmly upon the patient for the first time, but also because it is a major aim to include papers which cover a broad chronological and geographical area. The use of the INHH website for short abstracts and discussion boards will allow debate concerning this topic to reach unprecedented heights. Breaking away from internalist histories of hospitals, this conference will highlight the latest, innovative historical approaches. Particular emphasis will be placed on material culture, physical environment and music - important topics which have hitherto been neglected in historical studies. This conference will be divided into four key themes: 1. Architecture (the physical environment) 2. Art, material culture and healing 3. Music as therapy 4. The experience of treatment: medicines and apothecaries. A major aim is also to give new, young scholars experience of speaking in a friendly, supportive environment, with experts in the field.
The Corporeal Territories of War: Representing Disfigurement and Death in World War One Britain. 14 Jun 2007
The three pieces of work that I am proposing to complete during this period of research leave will deepen our understanding of the emotional and corporeal terrain of the Great War by focusing on representations and perceptions of injury, disfigurement and death. To what extent are our responses to these states of embodiment culturally inflected and regulated? What is and has been the role of images themselves in mediating the corporeal territories of war from the wealth of visual documentati on contained in WWI medical archives, to the visual rhetoric of sacrifice in the illustrated press, or in more self-consciously realistic cinematic propaganda like The Battle of the Somme? The case studies I will be working with will shed light on other topical issues including the relationship between art and surgery, and the relationship between war, representation and censorship particularly the selective representation of casualties. I want, most of all, to question and complicate the horror of disfigurement and death by contextualising the image and idea of the wounded, dying and dead body in First World War Britain. This will involve detailed archival research as well as a critical engagement with theories of embodiment, faciality and visual culture.
Type IV secretion machines are composed of at least 12 proteins termed VirB1-11 and VirD4. In the previous grant period, we have solved the structures of six of the VirB proteins or fragments thereof (VirB5, 7, 8, 9, 10, and 11). We have initiated a programme aiming at providing the structures of complexes of VirB proteins with each other. One of these complex structures has been solved. A massive cloning effort has led to the identification and purification of 3 more complexes. For the next gra nt period, we will focus on protein complexes. We will continue our cloning co-expression effort in view of identifying additional binary, ternary, and quaternary complexes. We will image existing and future complexes using cryo-electron microscopy, NMR, and x-ray crystallography. We will also attempt to purify the entire type IV secretion machine with the long-term aim to produce high-resolution cryo-EM maps into which individual single or complex structures can be docked. Our ultimate aim is t o provide a view of the type IV secretion machine to understand how it works.
Crystallographic mapping of the serpinopathies. 06 Dec 2005
Serpins (predominantly serine proteinase inhibitors) control critical proteolytic cascades in animals, plants, prokaryotes and viruses via a remarkable conformational transition. As with most sophisticated mechanisms, however, this is vulnerable to dysfunction. Pathogenic mutations result in the formation of serpin polymers, retained in the cell of synthesis. In these polymers the reactive loop of one molecule inserts as an extra ß-strand into a ß-sheet of the next. Polymerisation underlies a wide range of clinical diseases grouped together as the serpinopathies. I shall use crystallography and cryo-electron microscopy to define the pathways of polymerisation and to develop strategies to attenuate the ensuing disease. In particular I propose to i) determine the crystal structures of normal and abnormal conformers of neuroserpin associated with the dementia FENIB, ii) determine the structure of a serpin dimer: the basic unit of the toxic polymer, iii) define the structure of the serpin polymer using cryo-electron microscopy, and iv) determine the crystal structures of serpins bound to small molecules capable of blocking polymerisation.These approaches will provide information on how polymers form and how intermediates may be stabilised to ameliorate disease.
The goal of this proposal is to gain a mechanistic understanding of how cytoplasmic dynein and kinesin are spatially targeted and activated to power movements within eukaryotic cells. In Aim1, I will determine how cytoplasmic dynein, the large and complex motor that moves toward the minus-end of microtubules, is initially targeted to the plus-end. My recent in vitro reconstitution of dynein transport to the plus-end by the kinesin Kip2 makes a detailed dissection possible. Using single-molecule fluorescence microscopy, I will determine how dynein targeting is temporally controlled during the cell cycle, and the mechanism by which dynein's minus-end-directed motility is activated. The structural basis for dynein targeting will be revealed by combining electron microscopy with protein engineering. In Aim2, I will use a synthetic biology approach to probe how dynein and kinesins attach to membrane-bound compartments. I will test the hypothesis that Rab GTPases and generation of phospholip ids on the membrane surface are key determinants for transport. Finally, I will elucidate the architecture of a vesicle in the act of transport using electron tomography. This combination of techniques will shed new light on the regulation of motor proteins, which I will develop into a molecular movie.
UnLoCKE: Understanding Learning of Counterintuitive Concepts through Knowledge Interference Control in Science and Mathematics Education 01 Oct 2014
Molecular and cellular mechanisms of protein aggregation and toxicity in models of neurodegeneration. 03 Dec 2014