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Results

Hospitals and the patient experience: architecture, art, music and treatment. 20 Sep 2006

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.

Amount: £2,980
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Structure, function and drug interactions in voltage-gated sodium channels. 17 Oct 2005

Sodium channels are responsible for mediating ion permeability in nerve and cardiac cells; different isoforms are responsible for either producing a voltage potential essential to neurotransmission or creating the initial upstroke of the action potential seen in electrocardiograms. A number of neurological and cardiovascular diseases involving sodium channel mutations have been identified, and these channels are good potential targets for rational drug design. In preliminary work we have isolated, purified, and structurally- and functionally- characterised sodium channels from electric eels, which have a high sequence identity with the human sodium channels, and which can be prepared in sufficient quantities for 2D crystallisations. Furthermore we have developed a circular dichroism spectroscopic assay that enables us to distinguish between the various functional states, inactivated, open, closed, etc., of the channels. This project will use 2D crystallography and electron microscopy to provide 3D structural information on this pharmacologically-important membrane protein. The use of drugs and toxins to stabilise, or 'trap', channel molecules in conformations associated with specific functional states (as monitored by Cd spectroscopy) should provide information that improves the homogeneity of the population, thereby improving the crystal order, and should aid in the understanding of the structural basis of these different states.

Amount: £289,207
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

'Relief Operations in Europe in the immediate aftermath of WWII' workshop to be held at Birbeck College, London on 16th June 2006. 22 May 2006

Workshop: Relief operations in Europe in the immediate aftermath of WWII, Birkbeck College, London, 16 June 2006 Although in the aftermath of war relief operations were carried out by a multitude of different organisations (civilian, military, medical) on a fantastic scale and at huge cost, the subject of relief work has not so far received significant attention. While medical histories of the immediate post-war period have until recently been insulated from broader historiographical concerns and trends, general histories have persistently ignored public health and medical questions. This workshop aims to advance our understanding of the post-war period by moving the subject of medical relief work to the centre of mainstream historical enquiries of post-war Europe. This workshop will bring into focus the problem fo relief work in the immediate aftermath of war. It will document the extent to which relief work was seen as a first step in the longer-term rehabilitation of war-torn Europe. It will also assess the ways in which relief work was from the start shaped by a number of at times conflicting premises, which helped to identify, define and justify different categories of people and populations in need of assistance. Overall, the workshop will shed light on the complexities of post-war relief efforts.

Amount: £1,980
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Housing environments and health in early modern London, 1550-1750. 14 Jun 2006

The project's key goal is a better understanding of the extent to which environmental factors (including housing) and the social characteristics of individual, family and locality determined the disease and mortality profile of the pre-industrial city. It focuses on three contrasting areas of London in the period 1550-1750, exploring the ways in which a recently-created dataset, representing a unique reconstruction of local populations in their physical setting, can be further extended and interrogated to illuminate and map health and mortality patterns within those populations, and to develop more general conclusions. Specific objectives of the project include: - a detailed analysis of patterns of mortality by house and household in city-centre Cheapside, incorporating data on household wealth, family size and composition, housing quality and amenity, and residential density; - a similar analysis for extramural Aldgate, by local neighbourhoods rather than house by house, but incorporating detailed information on cause of death; - a correlation between large-scale family reconstitution and mortality patterns for suburban Clerkenwell, linking this with population growth and the development of housing and new settlement; - the development of a model of the interaction of the variables noted above in the production of local mortality patterns and outcomes.

Amount: £197,539
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Structural analysis of non-native protein binding to chaperonin complexes. 29 Jun 2006

The research project is aimed at understanding the mechanism of assisted protein folding by chaperonins. The GroEL-GroES molecular chaperone system is required in almost all cells for the correct folding of a subset of essential cellular proteins. It is known that non-native proteins bind to the cavity surface of GroEL and then become encapsulated in a folding chamber by a process that leads to their release from the initial binding sites. There is little known about conformational changes of the substrate protein during its interaction with GroEL. The approach of cryo EM and image processing provides unique information on the structures of chaperonin-substrate complexes, since it is one of the only structural biology methods that can provide 3-dimensional structures from heterogeneous populations. Structures of complexes with substrates such as METK, the tetrameric enzyme S-adenosyl methionine synthetase, that stringently requires GroE for its folding, will provide new insights into the details of chaperonin-substrate interaction, including the 3D density distribution of a natural substrate and its interaction sites on GroEL. The single particle analysis and separation methods are well established in the Birkbeck laboratory, and the project will provide high level training in cryo EM and image processing for the applicant.

Amount: £271,475
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

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.

Amount: £507,549
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Cryo-electron microscopy equipment for structure determination of macromolecular and cellular assemblies. 27 Apr 2006

Our aim is to perform the structure/function analysis of macromolecular machines, including molecular chaperones, transcription regulators, membrane channels, bacterial secretion systems, viral replication systems and cytoskeletal motors. We already have well-established research programmes using single particle analysis and helical reconstruction. We are requesting astate-of-the-art cryo-electron microscope so that we can remain at the forefront of this field of structural biology and also extend our work to include tomography of large assemblies and cellular structures. The overall goal is to relate macromolecular structure to biological function in the cell.The challenge is to integrate our structural results with studies of higher order functional assemblies in the context of the cell. With a substantial increase in cryo-EM expertise and activity at Birkbeck (two new EM groups and increased participation of crystallography groups since the award of a JIF infrastructure grant in 2000), we now wish to acquire equipment for electron tomography, automation and high-resolution single particle cryo EM. This equipment will enable us to take advantage of developments in automation, improve resolution and throughput and expand our capabilities in cell biology.

Amount: £989,125
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

The role of the prefrontal cortex in the development of uniquely human social cognition. 30 May 2007

Among the specific brain areas involved in the adult social brain, functional activity in prefrontal cortex (PFC), particularly the medial prefrontal cortices (MPFC), is of special importance for uniquely human social cognition. However, we know very little about the role that the PFC plays in the development of human social cognition. The proposed project will test between two hypotheses: (1) maturational view: that PFC regions mature later in development (after the first year) and enables the child to apply sophisticated processing to social stimuli; (2) specialisation view: that PFC is active, but poorly specialised, early in development, and gradually, with development, becomes more specialised in dealing with the social world. Therefore, the goal of the proposed project is to systematically investigate prefrontal activity across ages in response to a variety of socially relevant cues that have been found to activate specific areas in adult PFC (mutual gaze, joint attention) using neuroimaging techniques that allow precise spatial localization (i.e., functional magnetic resonance imaging in children and near-infrared spectroscopy in infants). This will enable us to map the involvement of the prefrontal cortex across early developmental stages to better understand the functional specialisation of the social brain.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

beta2-microglobulin amyloid: Native-like assembly or conformational conversion? 01 Nov 2006

How proteins aggregate into amyloid fibrils is a key question in structural biology. Although the amino acid sequence dictates the structure of native proteins, it is now clearthat polypeptide chains can adopt an alternative conformation based upon the cross-beta structure of amyloid. Despite enormous interest in this field, the structure of amyloid fibrils, particularly those from biomedically-relevant proteins, remains unknown. Here we propose to determine the 3D structure and subunit arrangement of amyloid fibrils formed from the 99-residue protein,beta-2- microglobulin (â2m), combining cryo-electron microscopy (Saibil, Birkbeck) andprotein chemical analysis (Radford, Leeds). Building on remarkable 3D density maps recently obtained of â2m fibrils formed in vitro, we propose to determine structural restraints using cross-linking and fluorescence experiments to enable model building, and to further test and refine these models using mutagenesis. In parallel, we will improve the cryo-EM maps by collectinglarger data sets, allowing finer subdivision of the image data into more uniform subsets, and will use site-specific nanogold labelling to guide docking of the chain into the electron density maps. The overall aim is to answer the fundamental question of how the same polypeptide chain can fold into two structures: a functional monomer and an aggregated polymer.

Amount: £203,186
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Structural Studies of the Haemophilus influenzae Hia Autotransported Adhesin and of its membrane insertion partner, D15, an Omp85 homolog. 19 Oct 2006

Haemophilus influenzae is a common cause of respiratory tract disease, including otitis media, sinusitis, bronchitis, and pneumonia. Less commonly, this organism causes serious systemic disease, such as meningitis, endocarditis, and septicemia. The initial step in the pathogenesis of H. influenzae disease involves colonization of the upper respiratory mucosa. A high-molecular-weight outer-membrane protein called Hia, present in nontypable (nonencapsulated) H. influenzae, promotes attachment to the human respiratory epithelium. The Hia protein is a non-pilus adhesin and belongs to the family of autotransporter proteins. Hia is synthesized as a 114 kDa precursor protein that consists of three domains: a 49 residue N-terminal signal sequence, an internal passenger domain (residues 50-1022), and a C-terminal beta-domain (residue 1023-1098). Adherence activity is localized to the passenger domain. The protein inserts in the bacterial membrane as a trimer and remains attached in a trimeric form. Insertion of Hia in the membrane is thought to be facilitated by the integral membrane protein D15, an Omp85 homolog. This grant proposal aims at solving the structures of full-length and/or large fragments of Hia and at initiating crystallographic work on D15. These structures will provide the structural basis of Hia autotranport and insertion in and through the membrane.

Amount: £243,225
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Structural biology of bacterial type IV secretion systems. 24 Apr 2007

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.

Amount: £1,655,214
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Value in People Award. 17 Oct 2007

Not available

Amount: £200,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Kinesin motor proteins in malaria. 10 Jul 2008

Kinesins are microtubule-based, ATP-dependent molecular motors that have many essential roles in eukaryotes including in cell division, cell motility and intracellular transport. Elimination of kinesin function often proves fatal because essential cell processes are compromised. The malaria genome encodes ten putative kinesin motors, about which little is known, and the proposed research will aim to characterise them biochemically, structurally and within the parasite. Key goals: Assessment of kinesin expression in parasites by RT-PCR Clone and express Plasmodium kinesins, particularly their motor domains which contain microtubule and ATP-binding sites. Begin with four kinesins with homologues in humans. Biochemical characterisation of microtubule-stimulated ATPase activity, providing insight into likely functions Visualisation of the kinesin motor-microtubule interaction by cryo-electron microscopy and 3D reconstruction Generate pseudo-atomic models of the motor-microt ubule interaction using homology models and dock these into the EM-derived molecular envelope Expression of GFP-tagged motors in vivo to determine their location and assess their possible roles in vivo Use of electron tomography to visualise the morphology of parasite microtubules and correlate this with kinesin localisation Combine in vitro and in vivo assays to set up drug screens to look for kinesin-specific inhibitors

Amount: £349,388
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

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.

Amount: £77,100
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Structural basis of the cell stress response. 27 Feb 2007

The purpose of the proposed sabbatical project is to take advantage of recent developments in cryo electron tomography and vitrified cell sectioning, in order to examine the structure of yeast cells during and after heat stress. Itwill enable me to combine our previous mechanistic work on individual molecular chaperones with studies of aggregate formation and clearance in vivo. A network of heat shock proteins has been implicated in the prevention and reversal of protein aggregation, but the details of aggregate structure and interaction with chaperones are poorly understood. With the facilities andexpertise now available at EMBL, I will be able to observe the three-dimensional arrangement of large macromolecular assemblies and organelles in yeast cells during the stress response. I will follow the courseof aggregation and examine the involvement of the cytoskeleton, ER, Golgi and lysosomes in processing aggregates through the proteasomal and autophagy pathways. As an extension of my existing collaboration with Prof B Bukau at the ZMBH, Heidelberg, I will be able to compare the processing of aggregates in wild-type cells with that in chaperone deletion mutants, with over expression of aggregation-prone polypeptides, and/or in prion strains, depending on the outcome of initial work.

Amount: £12,300
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Open Access Awards. 16 Sep 2008

Not available

Amount: £20,000
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Capital Investment in Cell Biology, Cellular Tomography and Structural Biophysics at the Institute for Structural Molecular Biology on the Birkbeck Site. 18 Jul 2008

The Birkbeck site of the joint UCL/Birkbeck Institute for Structural Molecular Biology wishes to expand its activities into cellular tomography and Cell Biology and to increase its effectiveness in protein crystallography, biophysics and chemical biology and microbiology. This will be achieved by a major capital investment. with the following key objectives · New equipment and dedicated space prepared to house it for X-ray crystallography and cell and tissue preparation for cryo-electron tomography in the basement of Birkbeck. · Birkbeck to appoint a new Chair in Cell Biology attracted by the opportunity to collaborate in work using state of the art cellular tomography and a second junior academic post to be jointly funded by Birkbeck and UCL, both of which are to complement structural research in the ISMB. · 350 m2 of state of the art laboratories and 100 m2 of associated offices to replace space on the third floor of the Malet St building that has only undergone piecemeal refurbishment since its construction in the 1950s.

Amount: £380,275
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

In Pursuit of the Nazi Mind: The Deployment and Development of Psychoanalysis in the Allied Struggle against Germany. 12 Jun 2008

'In Pursuit of the Nazi Mind' demonstrates how models of the unconscious and cognate clinical techniques contributed to and were reshaped by the Allied struggle against the Third Reich. Important studies of Nazi psychology, centred on the concept of the superego, were mobilised in military intelligence, post-war planning and policy recommendations. My goal is to contextualise and critically assess medico-psychiatric and psychoanalytical endeavours to grasp the irrational wellsprings of N azism, and to show their significance more widely for the history of psychology in western culture. A panoramic survey will cover the emergence of new Freudian approaches to politics in the 1920s, their apotheosis in the 1940s and disintegration in and beyond the 1960s. Five accompanying core cases, for which extensive documentation exists, are designed to illustrate the varied roles and influences of applied psychoanalysis around the war: 1. Testimony of Hess s doctors, in Britain 1941-45, an d at Nuremberg. 2. Studies of Hitler, commissioned by the US Office of Strategic Services in 1941. 3. Experiments conducted upon Nazi sympathisers through the Allied Control Commission, 1945-6. 4. Psychoanalytic materials furnished to the UNESCO project, Tensions Affecting International Understanding' , 1947-51. 5. Clinical evaluations of imprisoned Nazi murderers psychic lives, 1945-1970.

Amount: £103,358
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

The neural basis of action interpretation in human infants 23 Jun 2009

The aim of the proposed research is to explore the neural bases of action interpretation in human infants. Though much is known about infants abilities to interpret others actions, almost nothing is known about the neural bases of these abilities. I will combine neuroimaging techniques suitable for use with typically-developing infants (EEG and NIRS) and behavioural eye-tracking, in order to understand the relative functional significance of the developing motor system, and non-motor inferenti al mechanisms, for understanding goals and anticipating actions. The research will test hypotheses generated by a model of action understanding which implicates the developing motor system in action anticipation, but not in goal attribution. As the brain undergoes huge development during the first two years of life, it is likely that the social mediation of infant learning has consequences for the development of these neural mechanisms. Having identified the neural correlates involved in goal at tribution and action anticipation, the proposed research will investigate the relationship between variations in action input that infants receive from adults, and the development of these neural mechanisms.

Amount: £495,571
Funder: The Wellcome Trust
Recipient: Birkbeck University of London