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Results

Archival Research into the Theatrical Component of Early Modern Spanish Medical Practice. 29 May 2015

Archival research in four different locations in Spain, one week each. In each case, the goal is to find information in legal and other documents regarding any theatrical component in any medical practice, including the sale of medicine. These components can range from simple street-hawking, to setting up shop in a public place, to oration and speech-making in a public place, including song-and-dance as a means to attract and convince patients. 1) Archivo Hist rico Nacional: The Consejos section is housed here, which contains legal documents related to the licensing and disputes involving medical practitioners in Madrid. 2) Archivo General de Simancas: This archive contains legal documents related to the licensing and disputes involving medical practitioners, especially salary disputes, that are not contained in the Archivo Hist rico Nacional. 3) Archivo de la Real Chanciller a de Valladolid: This archive contains the documentation of many lawsuits involving medical pract itioners. 4) Archivo del Reino de Valencia: This archive a source of documentation on what Mar a Luz L pez Terrada calls extra-academic medical practices , evidence of which may not be covered by documents in other archives, or has been lost, or destroyed elsewhere.

Amount: £2,943
Funder: The Wellcome Trust
Recipient: University of St Andrews

Use of medieval recipes by a sixteenth-century reader. 14 Apr 2014

This grant application requests funding to support a one-week archival visit to Oxford. I wish to make a detailed study of a single fifteenth-century manuscript, Oxford, Bodleian Library, MS Rawlinson c. 299. This manuscript contains a collection of medieval medical recipes written in English. The hand-written collection comprises about 150 recipes in total, including some charms and a uroscopy. A unique point of interest is that the manuscript had a known owner and location in the sixteenth-cen tury. My investigation will consider this later owner's use of this medieval medical material by charting the exact nature of his annotations and interractions in the manuscript.

Amount: £653
Funder: The Wellcome Trust
Recipient: University of St Andrews

SFX: A UK/European user consortium for a serial femtosecond crystallography beamline at the European X-ray Free Electron Laser. 10 Oct 2013

Third generation synchrotron sources have revolutionised our understanding of the macromolecular machinery of the cell - over 33,000 structures have been elucidated in the last five years, providing atomic detail of macromolecular complexes, membrane proteins and viruses. Fourth generation light sources, such as hard X-ray Free Electron Lasers (XFELs) will allow us to greatly improve one of the bottlenecks of Structural Biology by removing the need for large crystals, which is achieved by outrun ning radiation damage. XFELs also enable sub-picosecond time-resolved analyses and may ultimately provide atomic information for single particles such as viruses and large complexes. The UK is currently not committed to or involved in the construction of a fourth generation light source, including the European XFEL, under construction in Hamburg. This proposal aims to enfranchise the UK structural biology community, amongst the leading in Europe, in this potentially game-changing technology. W e propose to provide training and infrastructure and to directly contribute to the construction and operation of SFX, a user facility for serial femtosecond crystallography at XFEL. An UK Hub at Diamond will allow sample preparation and triage to optimise the use of SFX by UK scientists and maximise the impact of XFEL.

Amount: £3,250,206
Funder: The Wellcome Trust
Recipient: University of St Andrews

The interaction of paramyxoviruses with the interferon system. 10 Jul 2013

The interferon (IFN) system is a major component of vertebrate innate anti-viral immunity. It is so powerful that most (if not all) viruses have evolved IFN antagonists1. Whilst there has been an explosion in our knowledge of this subject in the last 10-15 years(1), there are still many unanswered questions about how viruses interact with the system. Our aim is tobuild up a comprehensive understanding of this interaction by focusing on paramyxoviruses; our studies will determine how paramyxovirus infections trigger IFN production, whether overstimulation of the system (and other innate responses) exacerbates disease processes, how IFNcontrols paramyxovirus infections and influences virus host range, pathogenicity and

Amount: £1,247,873
Funder: The Wellcome Trust
Recipient: University of St Andrews

Transport and polymerisation of bacterial polysaccharides: from cytoplasm to the outside world. 26 Nov 2012

Extracellular polysaccharides play a variety of roles in bacteria, most relevant to the Trust is their role in the pathogenesis of bacteria. The sugar polymers can help evade the immune system, protect against the immune response or even modulate the immune system. I wish to study the process by which sugar molecules are transported across the cytoplasmic membrane, polymerized and attached to the proteins. There are of course conceptual similarities to protein glycosylation in eukaryotes. The fi rst step of the process is coupling of sugar to a lipid carrier. There are two broad classes of integral membrane proteins that carry out this process, one of which has a similarity to human proteins. We have expressed both these integral membrane protein and propose to study both its structure and mechanism. The next step is flipping across the cytoplasm, carried out by the flippase protein. From a biochemical viewpoint this is a fascinating reaction and distinct from the ATP driven process of MsbA etc. The units are then polymerized into chain of a defined length by the polymerase, another integral membrane protein. The length of the polymer is tightly regulated and we have data to suggest a possible molecular mechanism for this. The polymer can be attached to a protein or exported or transferred to another receptor. Our focus will be on the attachment of the polymer to protein substrates. We have cloned and expressed two such transferases and have crystals of one which diffract to a round 5A.

Amount: £2,085,352
Funder: The Wellcome Trust
Recipient: University of St Andrews

Open access award 2015/16. 21 Sep 2015

Not available

Amount: £23,044
Funder: The Wellcome Trust
Recipient: University of St Andrews

Investigating Trypanosoma brucei's unusual inositol metabolism. 05 Oct 2010

In this proposal we will use multi-disciplinary approaches to investigate myo-inositol phospholipid biosynthesis and catabolism in Trypanosoma brucei. Emphasis will be on extending our understanding of myo-inositol metabolic pathways both in bloodstream and procyclic form T.brucei, allowing us to genetically and chemically validated the biosynthetic steps as potential drug targets. This project aims to answer four key questions: Are T.brucei auxotrophic for myo-inositol? Is de novo synthesised myo-inositol central to other cellular processes? Does the catabolism of inositol phosphoceramide in the procylic form, determine carbon source usage? Are T.brucei vulnerable to inhibition of de novo myo-inositol synthesis? Consequently our key goals are to: understand the uptake and subsequent usage of the separate pools of myo-inositol validate enzymes involved in myo-inositol uptake and metabolism as drug targets understand the role of inosit ol-phospholipid catabolism. develop and carry out high-throughput assays for enzymes involved in myo-inositol metabolism. obtain kinetic, substrate specificity and structural information about the enzymes involved in inositol metabolism, thus allowing construction of structure-activity relationships to facilitate the design of potent parasite-specific inhibitors.

Amount: £511,161
Funder: The Wellcome Trust
Recipient: University of St Andrews

Lipid biosynthesis and its influence on the glycosylphosphatidylinositol pathway in protozoan parasistes. 19 Sep 2007

Advances in the understanding of general cell-surface architecture of trypanosomatid parasites, particularly human pathogens like Trypanosoma brucei, Trypanosoma cruzi and Leishmania has come about by the identification and structural characterisation of the most abundant cell-surface molecules. The majority of these are glycosylphosphatidylinositol (GPI) anchored glycoproteins and/or GPI-related molecules. Significant differences between the GPI biosynthetic pathways of protozoa and humans has lead to the suggestion that it might be a viable therapeutic target. In T. brucei, the causative agent of African Sleeping Sickness, this has been validated by the lethal disruption of the GPI biosynthetic pathway in the bloodstream form of the parasite by knocking out the TbGPI10 gene. Thus, it follows that the formation of the acceptor and donors required for GPI biosynthesis must also be essential. These incude the biosynthesis pathways of phosphatidylinositol (PI) acceptor, phosphatidylethanolamine (PE) and dolichol-phosphate-mannose (Dol-P-Man) donors. In yeast, several null and conditional (temperature sensitive) mutants of the genes involved in these lipid biosynthetic pathways have been created. These have been invaluable in studying lipid biosynthesis and several of these have been shown to affect GPI biosynthesis. Current knowledge of the biology and biochemistry of these biosynthetic enzymes in trypanosomatids is inadequate in many respects, but advances in molecular and biochemical techniques and the advances in the T. brucei genome project has made available exiting new possibilities for investigations of these biosynthetic enzymes and pathways. Thus, the primary theme of this proposal is to study the enzymology, mechanisms, structure, protein-protein interaction and influence that these biosynthetic enzymes have on the the GPI pathway. Unique pathways and/or enzymes involved in lipid biosynthesis in trypanosomatids may be identified, highlighting potential exploitable differences between mammalian and parasite lipid biosynthesis and providing novel therapeutic targets. Finally, part of the project is to capitalise on pre-existing inhibitors of general lipid biosynthesis having anti-protozoan activity and ascertain whether these inhibitors can be modified so that they can permeate the cell-membrane of living trypanosomes. The proposed project will continue my research interests in GPI biosynthesis, but from a wider perspective, using a multi-disciplinary approach to study parasite lipid biosynthesis and its direct effect on the essential GPI pathway.

Amount: £336,551
Funder: The Wellcome Trust
Recipient: University of St Andrews

Molecular biology of bunyavirus host cell interactions. 24 Apr 2006

The Bunyaviridae is a family of mainly arthropod transmitted viruses that contain a tripartite single-stranded RNA genome. Some members of the family are of medical importance causing encephalitis or haemorrhagic fever in man. My laboratory has used Bunyamwera virus, the prototype of the family, as the representative on which to perform molecular biological studies such as functional analyses of recombinant expressed viral proteins, and the development of a reverse genetic system to recover infe ctious virus entirely from cDNAs. This proposal exploits the materials and reagents we have developed to continue and expand our work analysing the replication processes of bunyaviruses at the molecular level, with the overall goal of understanding how the virus interacts with host cells of mammalian and insect origin. Our underlying hypothesis is that differences in virus:cell protein:protein interactions between these cell types determine the outcome of infection. Specifically, using a combina tion of molecular, biochemical and cell biological approaches we will address the following interrelated areas: (i) interactions of viral proteins with cellular proteins during bunyavirus replication; (ii) real-time microscopic analysis of bunyavirus infection using fluorescently tagged viruses; and (iii) functional analysis of the bunyavirus NSs protein in mammalian and insect cells.

Amount: £1,224,645
Funder: The Wellcome Trust
Recipient: University of St Andrews

The SAINTS: Saint Andrews iGEM neuralizes threatening staphylococus. 29 Mar 2010

We will build an E. coli that can detect and kill S. aureus. The project will consist of three steps (Fig 2): detection, destruction, and enhancement. First, we will build E. coli to signal detection of AlP by producing green fluorescent protein (GFP). We will use the BioBrick BBa_1746220 created by Cambridge in 2007 to detect group I AlP in E. coli; Cambridge did not succeed in verifying this BioBrick (igem.org), thus we will first "debug" it to create a working copy. In particular, we note that BBa_l746220 does not include SarA, a general transcription factor believed to act in concert with AgrA to activate promoters P2 and P3 (Novick 2003). We will explore addition of SarA to the BioBrick, as well as other refinements, such as including the entire P2 to P3 promoter regions (Novick 2003). We will pair this with GFP (BioBrick BBa_K203103) to cause fluorescence upon detection of AlP. We will then create our S. aureus destroying E. coli by replacing the GFP with the "Kamikaze" BioBrick BBa_K284022 created by UNICAMP-Brazil in 2009: BBa_K284022 creates lysosyme, thus killing the cell and any nearby bacteria, and has been verified to work (iGem. org). Finally, we will enhance the sensitivity of both these constructs by inserting an E. coli quorum sensing loop in between the AlP detector and the output (e.g. verified BioBrick BBa_l15030, UT Austin 2005): this serves to amplify the signal from AlP to produce greater output (GFP or lysosyme) per cell and recruit other nearby E. coli.

Amount: £12,600
Funder: The Wellcome Trust
Recipient: University of St Andrews

Biomedical Vacation Scholarship 14 Jun 2010

Not available

Amount: £5,760
Funder: The Wellcome Trust
Recipient: University of St Andrews

Validating choline metabolism as a drug target in the fight against T.brucei 02 Oct 2008

In this proposal we will use multi-disciplinary approaches to investigate choline phospholipid biosynthesis and metabolism in Trypanosoma brucei as a source of potential chemotherapeutic targets. Emphasis will be on understanding choline metabolic pathways, so that we can genetically and chemically validate them as drug targets. This project aims to answer three key questions; 1) T.brucei are auxotrophic for choline, so, how do they obtain choline? 2) Are T.brucei vulnerable to inhibit ion of de novo phosphatidylcholine synthesis? 3) Is catabolism of choline containing species essential to the parasite? Thus our key goals are to: genetically validate the choline branch of the Kennedy pathway (phosphatidylcholine de novo synthesis) as a drug target. understand the uptake and usage of choline containing species by bloodstream T.brucei. develop high-throughput assays for enzymes involved in choline metabolism. obtain kinetic, specificity and structu ral information about the enzymes involved in choline metabolism, that will allow the construction of structure-activity relationships to facilitate the design of more potent parasite-specific inhibitors. ultimately allowing development of potent inhibitors with activity against live trypanosomes compliant with Lipinski s rules, thus suitable for future development as novel anti-trypanosomal drugs.

Amount: £185,040
Funder: The Wellcome Trust
Recipient: University of St Andrews

Biomedical Science Research Complex (BSRC) New World Class Biosciences at the University of St Andrews. 18 Jul 2008

St Andrews University seeks £7.6 M in funding from the Wellcome Trust and will match this investment with over £10.7 M of its own capital. Beyond capital commitment the University will make six new appointments and make permanent three independent research fellows. This is a clear and significant commitment from St Andrews. A new laboratory building will physically link two existing buildings (Purdie/Chemistry and Biomolecular Sciences), creating a world leading and sustainable Biomedical Sciences Research Complex (BSRC). The BSRC will promote pioneering activity at the discipline interfaces of Chemistry, Biology, Physics and Medicine to address key problems in human health. According to the World Health Organisation infectious diseases account for 25% of all human morbidity and mortality. A UK Foresight report identified key global factors that could drive future threats from infectious disease: increasing travel, migration and trade (e.g. spread of infection); increasing risk from zoonoses (SARS, avian influenza and Escherichia coli O157:H7); the rise of drug-resistant organisms (MDRTB, malaria and MRSA) and climate change (distribution of disease). The report concluded that in order to prepare adequately for the future, 'traditional divides - e.g. between virology, bacteriology, mycology and parasitology, or between medicine, veterinary medicine and plant science need to be bridged.' The key objective is to cluster active researchers from different disciplines working in virology, bacteriology, model systems of human biology and parasitology, to allow rapid interchange of expertise, ideas and people so facilitating the use of state-of-

Amount: £5,000,000
Funder: The Wellcome Trust
Recipient: University of St Andrews

Open access award. 21 Sep 2010

Not available

Amount: £30,000
Funder: The Wellcome Trust
Recipient: University of St Andrews

Nitric Oxide signalling and the modulation of mammalian spinal motor networks 05 May 2010

The mammalian spinal cord contains all the neural machinery required to generate locomotor activity, even in the absence of descending and sensory input. Neuromodulation is an important component of this system, allowing locomotor activity to be modulated to suit different states or behaviours. Nitric Oxide (NO) is a potentially critical neuromodulator, about which almost nothing is known in the context of mammalian locomotion. We therefore aim to elucidate the role of NO in the control of mamma lian locomotion. We will initially determine the neuronal sources of NO in the mouse spinal cord using NADPH-d histochemistry and nNOS immunohistochemistry to reveal nitric oxide synthase expression, and DAF-2DA labelling to reveal NO production. Next, using electroneurographic recordings from ventral roots and whole-cell patch-clamp recordings from neurons in spinal cord preparations which can elicit locomotor activity, we will examine the effects of NO-mediated signalling on locomotor networks and determine underlying cellular and synaptic mechanisms. Patch-clamp analyses will concentrate on nitrergic neurons, revealed by DAF-2DA labelling, and motoneurons, the output cells of motor systems. Data obtained will address an important gap in our knowledge of spinal motor networks and provide novel information regarding NO-mediated signalling which should be applicable to other neuronal systems.

Amount: £317,779
Funder: The Wellcome Trust
Recipient: University of St Andrews

M-LDH as a regulatory subunit in the cytosolic substrate channelling complex. 16 May 2007

Nucleoside diphosphate kinase A (NDPK-A) selectively regulates the alpha1 isoform of the AMP-activated protein kinase (AMPK alpha1), independently of [AMP] and surrounding [ATP], by a process termed substrate channelling . Our preliminary data shows that the muscle form (M-LDH or LDH-A) but not the heart form (H-LDH or LDH-B), of lactate dehydrogenase is physically associated with the rat liver cytosolic substrate channelling complex and NDPK-B, such that M-LDH associates with NDPK-A, AMPK alp ha1 and CK2 and H-LDH associates with NDPK-B. Further, we have evidence that the species of LDH bound to the substrate channelling complex regulates the in vitro enzymatic activity of both AMPK and CK2. Thus, we hypothesise that M-LDH forms an integral part of the cytosolic substrate channelling complex in vivo where it is capable of regulating the substrate channelling mechanism, allowing for efficient sensing of cellular metabolic status and redox potential. Our research aims to further inv estigate these novel findings, characterise the molecular interactions of LDH in the complex and understand the functional relevance of LDH as a regulatory subunit of the substrate channelling complex.

Amount: £26,394
Funder: The Wellcome Trust
Recipient: University of St Andrews

Unravelling structure and mechanism of adenine(22)-tRNA methyltransferase: towards novel antibiotics against MRSA 05 Sep 2017

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital infections worldwide. Once restricted to healthcare facilities, this bacterium has now been found to cause infections in otherwise healthy communities. MRSA isolates have emerged that are resistant to most antibiotics in clinical use. It is imperative that new drugs be developed against MRSA. It is easier to develop specific antibiotics when the bacterial molecules they are meant to target are well understood. Enzymes accelerate chemical reactions in all living beings. If we produce a drug that inhibits an enzyme essential for MRSA growth, that drug will stop infections. If such enzyme is absent in humans, a specific drug can be developed to avoid side effects. The enzyme N1-adenine(22)-tRNA methyltransferase (TrmK) is essential in MRSA and absent in humans, fitting the aforementioned criteria. However, we know little about its structure and function. In this project, we will elucidate the mechanism of action of TrmK using enzyme kinetics and crystallography. Our results will pave the way for follow-up work aiming at rational design of specific inhibitors to be further developed into drugs against MRSA infection. Keywords: kinetics, enzyme mechanism, crystal structure, tRNA methyltransferase, antibiotics

Amount: £99,930
Funder: The Wellcome Trust
Recipient: University of St Andrews

Biomedical Vacation Scholarship. 25 Jun 2012

Not available

Amount: £2,880
Funder: The Wellcome Trust
Recipient: University of St Andrews

Understanding degradation of heparan sulphate with implications for disease. 22 Jun 2011

Glycosaminoglycans are essential components of the extracellular matrix, with roles in inflammation, development and cell signalling. One glycosaminoglycan, heparan sulphate, consists of repeating units of disaccharides, which are modified with acetyl or sulphate moieties. I am interested in how enzymes degrade heparan sulphate. Heparanase is a glycoside hydrolase that cleaves heparan sulphate to produce shorter oligosaccharides. Remodelling of heparan sulphate in the extracellular matrix is imp ortant in cancer invasion; increased heparanase levels correlate with increased metastasis in cancer cell lines and patients. Inhibition of heparanase may, therefore, be an effective approach to slow cancer progression. Nine lysosomal enzymes completely degrade heparan sulphate to regenerate its components. Mutations in these enzymes can affect their stability, preventing them from reaching the lysosome where they function. The reduced enzyme activity limits heparan sulphate degradation, causing accumulation of fragments, and results in a lysosomal storage disorder. One approach for treating these disorders uses molecular chaperones, which are inhibitors that stabilise the enzyme, enabling it to be targeted to the lysosome where it can function. I aim to investigate the mechanistic, structural and functional characteristics of the human enzymes involved in heparan sulphate degradation to enable development of therapeutics for cancer and lysosomal storage disorders.

Amount: £791,530
Funder: The Wellcome Trust
Recipient: University of St Andrews