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Results

Preserving the history of human and medical genetics. 28 Mar 2006

The key goal of this research project can be summarised as being to ensure preservation of the 20th century history of human and medical genetics by: 1. Identifying and conserving key written records, including personal scientific records of workers, records of societies and institutions, and images. 2. Developing and cataloguing a collection of key monographs and other books on human and medical genetics. 3. Consolidation of an international network of interested historians and scientists across Europe, the Genetics and Medicine Historical Network, through international workshops, an electronic newsletter and a website (genmedhist.net). 4.  To make the history of this field more accessible to the wider public, through our website and our links with Science Centres in Cardiff and across the UK. The project can be regarded as the first step towards forming a virtual British human genetics archive; this will become a research resource that should stimulate historians and others to explore specific historical aspects of this important field of science and medicine. The network should itself result in collaborations that will initiate such research.

Amount: £91,366
Funder: The Wellcome Trust
Recipient: Cardiff University

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

An in vitro study of the cellular and network basis of the cortical and subcortical pacemakers of key brain rhythms. 13 Dec 2005

Rhythmic EEG activity is generated by the concerted action of neuronal networks in both cortical and subcortical areas. One area which is crucial in promoting EEG rhythms is the thalamus. However, how the cortex and thalamus interact to form coherent oscillations is largely unknown. This is mainly because in vivo preparations do not provide a controlled enough environment for dissecting different mechanistic components whereas in vitro preparations do not normally contain sufficiently intact circuitry for realistically examining thalamocortical oscillations. I will bridge this gap by combining traditional in vitro approaches with multisite electrophysiological recording in a mouse thalamocortical slice which preserves portions of the somatosensorycortex and thalamus as well as viable thalamocortical and corticothalamic fibres between the two. The thalamocortical slice will combine the flexibilityof the in vitro environment with the option of examining realistic network oscillations. I will focus my attention on three types of thalamocortical oscillations: slow (<1 Hz) waves, alpha/theta oscillations and cyclic paroxysms. For each of these, my primary goals are (i) to conduct a thorough study of their spatiotemporal properties and (ii) to obtain a detailed insightinto how different neurones and networks in the cortex and thalamus interact to form coherent oscillations.

Amount: £436,989
Funder: The Wellcome Trust
Recipient: Cardiff University

Commercialisation of the bio-therapeutic resolution agent HYPER-DS-sll-6R 10 Feb 2006

The increased incidence of antibiotic resistant bacterial strains such as MRSA and VRSAover the past few years has identified the necessity for development of alternative therapeutic strategies. Professor Nicholas Topley and Dr Simon Jones at the University of Wales have been awarded translational funding to further develop a therapeutic to supplement the body's existing defence system to help clear various types of bacterial infection.

Amount: £801,762
Funder: The Wellcome Trust
Recipient: Cardiff University

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

Visual motion sensitivity during eye movement: Investigating the interaction between retinal and extra-retinal noise. 06 Feb 2007

Detecting and discriminating motion are primary tasks for the visual system. Success relies on the precision of neural estimates of visual motion. Precision is limited by variability in stimulation (external noise) and fluctuation in neuronal firing (internal noise). Traditional motion psychophysics concentrates on internal noise, emphasising the contribution made by image-motion sensors. This is largely because traditional psychophysical experiments prevent eye (and head) movement. Yet in norma l viewing we continually track objects by moving our eyes, which potentially increases noise in two additional ways: 1) externally, via the image motion generated by motor activity; 2) internally, via the extra-retinal motion signals estimating eye velocity. Extra-retinal motion signals originate in the motor system (motor commands, proprioception) and are used to transform image-motion information from an eye-centred to a head-centred coordinate frame. Extra-retinal signals converge on key moti on-processing centres in the cortex. The goal of the current proposal is to determine when combinations of motion-sensor and extra-retinal noise limit motion sensitivity during normal viewing behaviour. The work aims to establish fundamental principles in active motion psychophysics.

Amount: £135,799
Funder: The Wellcome Trust
Recipient: Cardiff University

The TNF superfamily in neuronal development. 08 Oct 2008

We will use a multidisciplinary approach to investigate the functions and mechanism of action of the TNFSF in the developing mouse nervous system. We will use well-characterized primary neuron culture systems to investigate whether the TNFSF cytokines we have already shown to promote or inhibit axon growth also affect dendrite growth and whether they are capable of influencing growth cone direction as either diffusible or cell surface ligands. We will use compartment cultures to determine wheth er localized receptor activation by individual cytokines has purely localized or generalized effects on neurite growth. We will use pharmacological inhibitors, expression of mutated signalling proteins and biochemical methods to delineate the signalling mechanisms by which these cytokines affect neurite growth and will use microarrays to identify NF-kB regulated genes required for promoting and/or inhibiting neurite growth. We will investigate appropriate phenotypic changes in neural processes and tissue innervation in transgenic mice to ascertain the physiological and developmental relevance of our in vitro observations. We will also investigate the roles of selected cytokines in neuronal survival and neuroblast development based on pilot data. Finally, will explore the roles of additional TNFSF cytokines selected on the basis of our comprehensive developmental profiling of TNFSF receptors.

Amount: £1,366,318
Funder: The Wellcome Trust
Recipient: Cardiff University

Characterisation of phospholipid-esterified eicosanoids generated by lipoxygenases. 11 Feb 2009

The proposed studies will address the hypothesis that PE-H(p)ETEs are transducers of LOX bioactivity in immune cells, through characterising the biology and fate of these lipids in platelets and monocytes/macrophages. Aim 1. Determine kinetics and mechanism of formation of PE-HETEs by purified recombinant LOX isoforms in vitro. The factors that regulate oxidation of PE versus arachidonate in intact cells are unknown. This aim will characterise PE oxidation mechanisms and kinetics using reco mbinant 12- and 15-LOXs in vitro. Aim 2. Characterise changes in the biological behaviour of PE by LOX oxidation. Introduction of a polar (O(O)H) group will change PE conformation, altering membrane physicochemical properties, including membrane thickness/phase. The ability of PE-H(p)ETEs to modulate membrane behaviour will be characterised by X-ray diffraction, using isolated cell membrane and purified lipid. Also, LOX regulation of PE dynamics in live cells will be determined using mass spectrometry and live cell imaging. Aim 3. Characterise PE-H(p)ETE metabolism and reactions of oxidised PE with cellular proteins via formation of covalent adducts or non-covalent interactions. Oxidized PE may interact with membrane proteins through a number of mechanisms. In this aim, decomposition of the hydroperoxy group of esterified HpETE including formation of protein adducts will be characterised.

Amount: £234,374
Funder: The Wellcome Trust
Recipient: Cardiff University

Functional analysis of nuclear proteins in the Drosophila male germ-line. 25 Feb 2009

Understanding cell type specific regulation of gene expression is critical for understanding differentiation in multi-cellular organisms. The male germ-line is a unipotent cell type, committed only to making sperm. During spermatogenesis dramatic changes in gene expression occur, to facilitate the differentiation of highly specialised cells. We have previously identified a group of testis specific transcriptional regulators important for this spermatogenesis specific gene expression in Drosop hila. We will test the TEV protease system for cleavage of target proteins in the Drosophila male germ-line with known factors, and develop a P-element replacement exon tagging approach to allow specific ablation of potentially many target proteins in a controlled manner. We will test this approach by initiating the analysis of testis-specific functions of conserved potential transcriptional regulators that act in both the male germ-line and in other cell types, concentrating on a small set of proteins for which we already have localisation data and functional predictions.

Amount: £90,898
Funder: The Wellcome Trust
Recipient: Cardiff University

"7th International Congress on Traditional Asian Medicine" to be held in Thimbu, Bhutan on 7-11 September 2009 21 Jul 2009

This panel in the Seventh International Congress on Traditional Asian Medicine (http://www.iastam.org/conferences.htm) will consider medicine and healing in the pre-Buddhist tradition of Tibet, known as Bon. The main medical text of this tradition is known as the Bumzhi (the four hundred thousand healing arts), which according to Bon history dates back more than 1 000 years to the Central Asian kingdom of Zhang Zhung. In the 1930s the Bon lama and scholar Khyungtrul Jigmai Namkai Dorje (1897-1955) wrote a comprehensive four-volume commentary on the 'Bum bzhi, the Khyung sprul sman dpe, which is based on both Buddhist and Bonpo sources. In recent years there has been a resurgence of the Bon medical tradition which is currently been taught in a number of medical schools in Tibet and Nepal using both the 'Bum bzhi and the Khyung sprul sman dpe. The panel consists of 11 participants all presenting on different aspect of this ancient medical tradition. Several of the papers will focus specifically on Khyungtrul's medical work.

Amount: £1,762
Funder: The Wellcome Trust
Recipient: Cardiff University

Identification of mechanisms underpinning regulatory T cell involvement in disease. 02 Feb 2009

Studies of T cell mediated tolerance indicate that a subpopulation of T cells, named regulatory T cells (Tregs) serve as a major negative influence on the immune system. These cells, characterised by expression of CD4 and the transcription factor, Foxp3, keep both innate and adaptive immune responses in check and suppress responses to both self- and non-self antigens. A clear objective of Treg research is to determine how they can be manipulated therapeutically to treat a wide range of immune-ba sed diseases. In my laboratory we have found, using mouse models and studies of patients with cancer, that tumours represent a defined location of Treg enrichment. This finding highlights the utility of studying tumours for the purpose of identifying conditions and mechanisms that facilitate Treg involvement in disease. The key goal of this project is to use tumours to identify mechanisms that promote or inhibit the involvement of Tregs in a given immune response. This informat ion will subsequently be utilised in the design of strategies to block or enhance the activity of the cells for immunotherapeutic purposes.

Amount: £829,539
Funder: The Wellcome Trust
Recipient: Cardiff University

Biomedical vacation scholarship. 29 May 2009

Not available

Amount: £3,040
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

The genetic testing of children: how to decide?. 18 Apr 2007

The Genetic Testing of Children: How To Decide? The issues raised by the predictive genetic testing of children and testing to identify healthy carriers of genetic disorders have been debated since ~1990 and were discussed at a meeting in London in 1996, sponsored by BMA Medical Ethics, GIG and Euroscreen (a research network) and supported by the Wellcome Trust. Rather than set up another debate grounded in the relevant principles, we wish to bring together families and professionals who have some experience of these issues in practice. In particular we wish to involve some non-specialist health professionals (i.e. those not working primarily in clinical genetics or genetic counselling) as well as some families and some genetics professionals. We wish to focus discussion on a small number of constructed but realistic scenarios, so that the experience of participants can contribute to the discussion without being caught up in details specific to just one or two groups. While carrier testing continues to raise a number of issues, e.g. in relation to newborn screening for sickle cell disease, perhaps the most significant area of change since the last meeting on this topic in 1996 has been in relation to predictive genetic testing where the test results may (or may not) lead to improved medical management for a child at risk of a serious inherited disorder. When does interest in a child's genetic status become clinically useful? - In what clinical contexts? With what family circumstances? And for which diseases? A meeting would need to hear the voices of (1) non-genetics health professionals (especially haematologists, paediatricians, cardiologists) as well as clinical geneticists and genetic counsellors, (2) families and support groups, (3) ethicists, social scientists and psychologists.

Amount: £3,900
Funder: The Wellcome Trust
Recipient: Cardiff University

Student elective prize for Jemima Tagal. 18 Apr 2007

Factors affecting treatment compliance in patients with spinal tuberculosis - demographics, clinical features and treatment regimens Patient compliance with treatment is a major factor in determining a successful outcome, especially in patients with tuberculosis (TB). Non-compliance results in treatment failure, disease relapse, and drug resistance. Malaysia has adopted the WHO Directly Observed Treatment, Short Course (DOTS) programme in an effort to reduce the national TB incidence. Despite this, local compliance with treatment remains a problem. Spinal TB is quite common in Malaysia, and has an extremely high morbidity. The local demographical, clinical and treatment regimen factors that may affect compliance with anti-TB treatment in Malaysia has not been analysed in patients with spinal TB. Aims of project: Consider the local demographics of patients with tuberculosis of the spine Compare the demographical and clinical features, and treatment regimens of compliant and non-compliant patients with tuberculosis of the spine The ultimate aim of this study is to identify patients at higher risk of defaulting anti-TB treatment to serve as a basis for planning health promotive interventions.

Amount: £1,000
Funder: The Wellcome Trust
Recipient: Cardiff University

Open Access Awards. 16 Sep 2008

Not available

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

Open Access Awards. 16 Sep 2008

Not available

Amount: £30,000
Funder: The Wellcome Trust
Recipient: Cardiff University

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

Neural network function in a mouse model of Alzheimer's disease. 15 Jul 2008

A recent revision to the amyloid cascade hypothesis has highlighted the important role played by intermediate AB oligomers in early-stage synaptic and cognitive dysfunction in Alzheimer's Disease 1. This revised hypothesis predicts that the very earliest stages of amyloid-induced cognitive dysfunction are a result of a breakdown in synaptic plasticity processes and the subsequent disruption to neural network activity that encodes and retrieves information 2. However, there has been little or no research carried out to examine how amyloid production influences network activity in murine models of amyloid pathology. The main aim of this proposal is to build upon our preliminary work that shows amyloid production disrupts network activity within the hippocampus and between the hippocampus and key regions contributing to memory. Furthermore we will examine how exercise-induced plasticity in the hippocampus (most notably in the dentate gyrus) influences network properties in APP over expressing mice.

Amount: £139,636
Funder: The Wellcome Trust
Recipient: Cardiff University

The Loop - Living Well 07 Jun 2018

To help 50 people improve their mental and physical wellbeing by undertaking various activities.

Amount: £2,000
Funder: Suffolk Community Foundation
Recipient: Volunteering Matters