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21 results on '"J., Blackburn"'

1. Testing central auditory processing abilities in older adults with and without dementia using the consonant-vowel dichotic listening task

Author

Jenna Littlejohn, Daniel J. Blackburn, and Annalena Venneri

Subjects
dementia, mild cognitive impairment, dichotic listening, auditory laterality, memory assessment service, Medicine
Abstract

BackgroundHearing loss and dementia are linked, although the roles of peripheral and central auditory dysfunction are not well defined. Many behavioral measures of hearing are confounded by the overlapping cognitive functions required to perform the tests.ObjectiveTo collect pilot data to identify how central auditory function, measured using a dichotic listening test that indexes both auditory and cognitive components under different attentional conditions, differs among people with mild cognitive impairment (MCI), dementia and controls, and how performance relates to neuropsychological results.MethodFifty-eight participants (17 MCI, 11 dementia and 30 controls) undertook hearing screening, the Bergen consonant-vowel dichotic listening paradigm, and a short battery of neuropsychological tests chosen to index attention and executive control. Dichotic listening was assessed under three attentional conditions (non-forced, forced right ear and forced left) amongst older adults with normal cognitive function, MCI and dementia.ResultsWe report two main findings: (a) The expected right ear advantage under non-forced conditions, was seen in controls and patients with dementia but not in people with MCI, who showed equal numbers of correct responses from both ears (i.e., a lack of asymmetry); (b) Performance under forced attentional conditions was significantly associated with disease progression (i.e., control > MCI > dementia) and performance on the cognitive tasks.ConclusionThe reduction in asymmetry on dichotic listening tasks may be a marker of MCI and reflect underlying compensatory mechanisms. Use of this test could aid stratification of patients with memory disorders. Whether abnormalities could predict dementia onset needs longitudinal investigation in a larger sample.

Published
2023
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2. Adaptive Gated Graph Convolutional Network for Explainable Diagnosis of Alzheimer’s Disease Using EEG Data

Author

Dominik Klepl, Fei He, Min Wu, Daniel J. Blackburn, and Ptolemaios Sarrigiannis

Subjects
Alzheimer's disease, graph neural network, classification, EEG, Medical technology, R855-855.5, Therapeutics. Pharmacology, RM1-950
Abstract

Graph neural network (GNN) models are increasingly being used for the classification of electroencephalography (EEG) data. However, GNN-based diagnosis of neurological disorders, such as Alzheimer’s disease (AD), remains a relatively unexplored area of research. Previous studies have relied on functional connectivity methods to infer brain graph structures and used simple GNN architectures for the diagnosis of AD. In this work, we propose a novel adaptive gated graph convolutional network (AGGCN) that can provide explainable predictions. AGGCN adaptively learns graph structures by combining convolution-based node feature enhancement with a correlation-based measure of power spectral density similarity. Furthermore, the gated graph convolution can dynamically weigh the contribution of various spatial scales. The proposed model achieves high accuracy in both eyes-closed and eyes-open conditions, indicating the stability of learned representations. Finally, we demonstrate that the proposed AGGCN model generates consistent explanations of its predictions that might be relevant for further study of AD-related alterations of brain networks.

Published
2023
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3. EEG-Based Graph Neural Network Classification of Alzheimer’s Disease: An Empirical Evaluation of Functional Connectivity Methods

Author

Dominik Klepl, Fei He, Min Wu, Daniel J. Blackburn, and Ptolemaios Sarrigiannis

Subjects
Alzheimer’s disease, graph neural network, classification, EEG, functional connectivity, Medical technology, R855-855.5, Therapeutics. Pharmacology, RM1-950
Abstract

Alzheimer’s disease (AD) is the leading form of dementia worldwide. AD disrupts neuronal pathways and thus is commonly viewed as a network disorder. Many studies demonstrate the power of functional connectivity (FC) graph-based biomarkers for automated diagnosis of AD using electroencephalography (EEG). However, various FC measures are commonly utilised, as each aims to quantify a unique aspect of brain coupling. Graph neural networks (GNN) provide a powerful framework for learning on graphs. While a growing number of studies use GNN to classify EEG brain graphs, it is unclear which method should be utilised to estimate the brain graph. We use eight FC measures to estimate FC brain graphs from sensor-level EEG signals. GNN models are trained in order to compare the performance of the selected FC measures. Additionally, three baseline models based on literature are trained for comparison. We show that GNN models perform significantly better than the other baseline models. Moreover, using FC measures to estimate brain graphs improves the performance of GNN compared to models trained using a fixed graph based on the spatial distance between the EEG sensors. However, no FC measure performs consistently better than the other measures. The best GNN reaches 0.984 area under sensitivity-specificity curve (AUC) and 92% accuracy, whereas the best baseline model, a convolutional neural network, has 0.924 AUC and 84.7% accuracy.

Published
2022
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4. Integrated molecular and behavioural data reveal deep circadian disruption in response to artificial light at night in male Great tits (Parus major)

Author

Davide M. Dominoni, Maaike de Jong, Kees van Oers, Peter O’Shaughnessy, Gavin J. Blackburn, Els Atema, A. Christa Mateman, Pietro B. D’Amelio, Lisa Trost, Michelle Bellingham, Jessica Clark, Marcel E. Visser, and Barbara Helm

Subjects
Medicine, Science
Abstract

Abstract Globally increasing levels of artificial light at night (ALAN) are associated with shifting rhythms of behaviour in many wild species. However, it is unclear whether changes in behavioural timing are paralleled by consistent shifts in the molecular clock and its associated physiological pathways. Inconsistent shifts between behavioural and molecular rhythms, and between different tissues and physiological systems, disrupt the circadian system, which coordinates all major body functions. We therefore compared behavioural, transcriptional and metabolomic responses of captive great tits (Parus major) to three ALAN intensities or to dark nights, recording activity and sampling brain, liver, spleen and blood at mid-day and midnight. ALAN advanced wake-up time, and this shift was paralleled by advanced expression of the clock gene BMAL1 in all tissues, suggesting close links between behaviour and clock gene expression across tissues. However, further analysis of gene expression and metabolites revealed that clock shifts were inconsistent across physiological systems. Untargeted metabolomic profiling showed that only 9.7% of the 755 analysed metabolites followed the behavioural shift. This high level of desynchronization indicates that ALAN disrupted the circadian system on a deep, easily overlooked level. Thus, circadian disruption could be a key mediator of health impacts of ALAN on wild animals.

Published
2022
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5. Advancing on the promises of techno-ecological nature-based solutions: A framework for green technology in water supply and treatment

Author

Emma A. J. Blackburn, Monica B. Emelko, Sarah Dickson-Anderson, and Micheal Stone

Subjects
biofiltration, drinking water, green infrastructure, greenness, natural capital, source water protection, Environmental engineering, TA170-171, Urbanization. City and country, HT361-384
Abstract

Nature-based solutions (NBS) are increasingly proposed for effectively and adaptively addressing societal challenges such as water security and natural disasters. However, NBS that are exclusively reliant on natural processes are not fit-for-purpose for the provision of safe drinking water – some range of built technology is required. There is a wide spectrum of techno-ecological NBS – ‘green technologies’ – that are fit-for-purpose in the treatment and distribution of safe drinking water. A framework was developed to enable an accurate and transparent description of the ‘green’ attributes of technology – including green infrastructure – in the water industry. The framework differentiates technology ‘greenness’ by relatively examining key attributes that may cause environmental impacts across the technology's life cycle through the lens of the environmental setting in which it is applied. In the water industry, green technology can be described by four main attributes: natural-resource basis, energy consumption, waste production, and footprint. These attributes are closely linked and must be considered relative to the biophysical and human environments in which they are applied and the other technologies to which they are being compared. The use of the framework can facilitate techno-ecological decision-making that strives to address diverse stakeholder priorities – including the influence of sociocultural factors on the green technology preferences of individuals, groups, or communities. HIGHLIGHTS NBS exclusively reliant on natural processes are not fit-for-purpose for the provision of safe drinking water.; Green technology falls on a spectrum.; The four main attributes of green technology are natural-resource basis, energy consumption, waste production, and footprint.; Operational control is often reduced as technology ‘greenness’ increases.; Biofiltration is an underutilized, green drinking water treatment technology.;

Published
2021
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6. The Impact of Social Isolation Due to COVID-19 on Symptom Progression in People With Dementia: Findings of the SOLITUDE Study

Author

Riccardo Manca, Matteo De Marco, Amanda Colston, Vanessa Raymont, Jay Amin, Rhys Davies, Pramod Kumar, Gregor Russell, Daniel J. Blackburn, and Annalena Venneri

Subjects
dementia, COVID-19, social isolation, neuropsychiatric symptoms, cognitive decline, Psychiatry, RC435-571
Abstract

BackgroundPeople with dementia (PWD) are vulnerable to abrupt changes to daily routines. The lockdown enforced on the 23rd of March 2020 in the UK to contain the expansion of the COVID-19 pandemic limited opportunities for PWD to access healthcare services and socialise. The SOLITUDE study explored the potential long-term effects of lockdown on PWD’s symptoms and carers’ burden.MethodsForty-five carers and 36 PWD completed a telephone-based assessment at recruitment (T0) and after 3 (T1) and 6 months (T2). PWD completed measures validated for telephonic evaluations of cognition and depression. Carers completed questionnaires on their burden and on PWD’s health and answered a customised interview on symptom changes observed in the initial months of lockdown. Longitudinal changes were investigated for all outcome variables with repeated-measures models. Additional post hoc multiple regression analyses were carried out to investigate whether several objective factors (i.e., demographics and time under social restrictions) and carer-reported symptom changes observed following lockdown before T0 were associated with all outcomes at T0.ResultsNo significant changes were observed in any outcomes over the 6 months of observations. However, post hoc analyses showed that the length of social isolation before T0 was negatively correlated with episodic and semantic memory performance at T0. Carers reporting worsening of neuropsychiatric symptoms and faster disease progression in PWD also reported higher burden. Moreover, carer-reported worsening of cognitive symptoms was associated with poorer semantic memory at T0.ConclusionPWD’s symptoms and carers’ burden remained stable over 6 months of observation. However, the amount of time spent under social restrictions before T0 appears to have had a significant detrimental impact on cognitive performance of patients. In fact, carer-reported cognitive decline during social isolation was consistent with the finding of poorer semantic memory, a domain sensitive to progression in Alzheimer’s disease. Therefore, the initial stricter period of social isolation had greater detrimental impact on patients and their carers, followed then by a plateau. Future interventions may be designed to maintain an optimal level of social and cognitive engagement for PWD in challenging times, to prevent abrupt worsening of symptoms and associated detrimental consequences on patients’ carers.

Published
2022
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7. Serial Recall Order and Semantic Features of Category Fluency Words to Study Semantic Memory in Normal Ageing

Author

Matteo De Marco, Daniel J. Blackburn, and Annalena Venneri

Subjects
semantic memory, efficiency, centrality, hippocampus, Alzheimer’s disease, pre-clinical, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: Category Fluency Test (CFT) is a common measure of semantic memory (SM). Test performance, however, is also influenced by other cognitive functions. We here propose a scoring procedure that quantifies the correlation between the serial recall order (SRO) of words retrieved during the CFT and a number of linguistic features, to obtain purer SM measures. To put this methodology to the test, we addressed a proof-of-concept hypothesis whereby, in alignment with the literature, older adults would show better SM.Methods: Ninety participants (45 aged 18–21 years; 45 aged 70–81 years) with normal neurological and cognitive functioning completed a 1-min CFT. SRO was scored as an ordinal variable incrementing by one unit for each valid entry. Each word was also scored for 16 additional linguistic features. Participant-specific normalised correlation coefficients were calculated between SRO and each feature and were analysed with group comparisons and graph theory.Results: Younger adults showed more negative correlations between SRO and “valence” (a feature of words pleasantness). This was driven by the first five words generated. When analysed with graph theory, SRO had significantly higher degree and lower betweenness centrality among older adults.Conclusion: In older adults, SM relies significantly less on pleasantness of entries typically retrieved without semantic control. Moreover, graph-theory metrics indicated better optimised links between SRO and linguistic features in this group. These findings are aligned with the principle whereby SM processes tend to solidify with ageing. Although additional work is needed in support of an SRO-based item-level scoring procedure of CFT performance, these initial findings suggest that this methodology could be of help in characterising SM in a purer form.

Published
2021
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8. The Potential of Topoisomerase Inhibitor-Based Antibody–Drug Conjugates

Author

Seungmin Han, Kwang Suk Lim, Brody J. Blackburn, Jina Yun, Charles W. Putnam, David A. Bull, and Young-Wook Won

Subjects
topoisomerase inhibitor, topoisomerase 1, antibody–drug conjugates, targeted drug delivery, anti-cancer drug, Pharmacy and materia medica, RS1-441
Abstract

DNA topoisomerases are essential enzymes that stabilize DNA supercoiling and resolve entanglements. Topoisomerase inhibitors have been widely used as anti-cancer drugs for the past 20 years. Due to their selectivity as topoisomerase I (TOP1) inhibitors that trap TOP1 cleavage complexes, camptothecin and its derivatives are promising anti-cancer drugs. To increase accumulation of TOP1 inhibitors in cancer cells through the targeting of tumors, TOP1 inhibitor antibody–drug conjugates (TOP1-ADC) have been developed and marketed. Some TOP1-ADCs have shown enhanced therapeutic efficacy compared to prototypical anti-cancer ADCs, such as T-DM1. Here, we review various types of camptothecin-based TOP1 inhibitors and recent developments in TOP1-ADCs. We then propose key points for the design and construction of TOP1-ADCs. Finally, we discuss promising combinatorial strategies, including newly developed approaches to maximizing the therapeutic potential of TOP1-ADCs.

Published
2022
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9. Feasibility of reporting results of large randomised controlled trials to participants: experience from the Fluoxetine Or Control Under Supervision (FOCUS) trial

Author

Martin Dennis, D Cohen, A Thompson, M Smith, A Naqvi, Graham Ellis, A Khan, L Hunt, X Huang, J Andrews, J Foot, J Smith, S Wong, A Stevens, D Bailey, S Johnston, S Jones, R Robinson, A Johnson, S Williams, T Smith, A Ahmed, S Bloom, L Sekaran, D Singh, F Smith, R Greenwood, A Singh, R Brown, J White, S Smith, S Arif, S Ross, S Trippier, S Levy, B Patel, M Khan, A Thomas, S Brown, V Jones, D Wood, S Maguire, U Khan, P Nair, A Smith, G Hann, R Williams, M Cooper, S Jackson, M Hassan, P Kumar, A Metcalf, R Patel, A Wright, S Khan, A Bell, C Williams, M Robinson, K Jones, S Alam, R Shah, J Simpson, K Ali, K Miller, K Kennedy, S Ahmed, J Francis, L Thomas, M Scott, S Nelson, S Clayton, L Zhang, B Charles, P Lopez, A Fleming, C Lambert, A Shah, J Wong, David Burgess, L Wilson, A Siddiqui, S Kumar, A Hassan, D Cooke, M Williams, P Cooper, S Graham, S Morrison, M Holland, C Green, C Edwards, K Subramanian, K Patel, J Mitchell, J Stewart, S Keenan, C Duggan, S McKenna, R Murphy, M Ward, S Walker, S Lewis, R Jones, L Wright, M Edwards, N Sattar, J Mcgee, R Butler, M Wilkinson, S Das, C Kelly, R Cowan, C Brown, K Moore, L Denny, M Harrison, S Patel, R Rodriguez, J Allen, M Kalita, Gillian Mead, A Bowring, A Edwards, J Scott, J Drew, D Ward, L Dixon, K Burton, E Brown, E Epstein, R Miller, F Reid, A Jones, P Murphy, A Ali, N Ahmad, S Noor, C Leonard, A Nair, M Naeem, M Johnson, E Douglas, J Thompson, R Evans, C Jenkins, J Wilson, R Anderson, H Wilson, H Stone, J Ward, L Greenhalgh, P Walker, A Hill, K Stagg, S Naqvi, R Scott, M Hughes, P Jones, M Simpson, K Elliott, M Davy, S Young, Karen Innes, Pippa Tyrrell, A David, Steff Lewis, A Bwalya, C Buckley, S Kelly, C Thomas, I Kane, M Hussain, S Shah, J Roberts, D Morales, C McInnes, N Khan, N Weir, L Hill, J McLaughlin, K Kavanagh, R Clarke, P Thompson, J Price, J Ball, L Benton, E Walton, E Walker, L Burgess, K McCormick, L Wade, C Anderson, S Stevenson, R Blackburn, L Brown, B Clarke, T Khan, S Dhar, L Harrison, S Bell, D Buchanan, A Deary, J Drever, R Fraser, C Graham, K Innes, C McGill, D Perry, A Barugh, G Blair, Y Chun, E Maschauer, J Forbes, M Hackett, G Hankey, A House, E Lundström, Peter Sandercock, Judith Williamson, John Forbes, Graeme Hankey, Maree Hackett, Veronica Murray, Ray French, David Stott, Jonathan Emberson, P Sandercock, M MacLeod, F Sullivan, P Langhorne, H Rodgers, N Hunter, R Parakramawansha, A Fazal, P Taylor, W Rutherford, R Buchan, A MacRaild, R Paulton, S Burgess, D McGowan, J Skwarski, F Proudfoot, J Perry, J Bamford, C Bedford, D Waugh, E Veraque, M Kambafwile, L Makawa, P Smalley, M Randall, L Idrovo, T Thirugnana-Chandran, R Vowden, J Jackson, A Bhalla, C Tam, A Rudd, C Gibbs, J Birns, L Lee Carbon, E Cattermole, A Cape, L hurley, K Marks, S Kullane, N Smyth, E Giallombardo, C Eglinton, D Dellafera, P Reidy, M Pitt, L Sykes, A Frith, V Croome, J Duffy, M Hancevic, L Kerwood, C Narh, C Merritt, J Willson, T Jackson, H Bowler, C Kamara, J Howe, K Stocks, G Dunn, K Endean, F Claydon, S Duty, C Doyle, K Harkness, E Richards, M Meegada, A Maatouk, L Barron, K Dakin, R Lindert, A Majid, P Rana, C Brighouse-Johnson, J Greig, M Kyu, S Prasad, B Mclean, I Alam, Z Ahmed, C Roffe, S Brammer, A Barry, C Beardmore, K Finney, H Maguire, P Hollinshead, J Grocott, I Natarajan, J Chembala, R Sanyal, S Lijko, N Abano, A Remegoso, P Ferdinand, S Stevens, C Stephen, P Whitmore, A Butler, C Causley, R Varquez, G Muddegowda, R Carpio, J Hiden, H Denic, J Sword, F Hall, J Cageao, R Curwen, M James, P Mudd, C Roughan, H Kingwell, A Hemsley, C Lohan, S Davenport, T Chapter, M Hough, D Strain, K Gupwell, A Goff, E Cusack, S Todd, R Partridge, G Jennings, K Thorpe, J Stephenson, K Littlewood, M Barber, F Brodie, S Marshall, D Esson, I Coburn, F Ross, V Withers, E Bowie, H Barcroft, L Miller, P Willcoxson, M Keeling, M Donninson, D Daniel, J Coyle, M Elliott, P Wanklyn, J Wightman, E Iveson, A Porteous, N Dyer, M Haritakis, J Bell, C Emms, P Wood, P Cottrell, L Doughty, L Carr, C Anazodo, M O Neill, J Westmoreland, R Mir, C Donne, E Bamford, P Clark Brown, A Stanners, I Ghouri, A Needle, M Eastwood, M Carpenter, P Datta, R Davey, F Razik, G Bateman, J Archer, V Balasubramanian, L Jackson, R Bowers, J Ellam, K Norton, P Guyler, S Tysoe, P Harman, A Kundu, T Dowling, S Chandler, O Omodunbi, T Loganathan, S Kunhunny, D Sinha, M Sheppard, S Kelavkar, K Ng, A Ropun, L Kamuriwo, R Orath Prabakaran, E France, S Rashmi, D Mangion, C Constantin, S Markova, A Hardwick, J Borley, L De Michele Hock, T Lawrence, J Fletcher, K Netherton, R Spencer, H Palmer, M Soliman, S Leach, J Sharma, C Taylor, I Wahishi, A Fields, S Butler, J Hindle, E Watson, C Hewitt, C Cullen, D Hamill, Z Mellor, T Fluskey, V Hankin, A Keeling, R Durairaj, D Shackcloth, R Tangney, T Hlaing, V Sutton, J Ewing, C Patterson, H Ramadan, R Bellfield, U Hamid, M Hooley, R Ghulam, L Masters, W Gaba, O Quinn, M Tate, N Mohammed, S Sethuraman, L Alwis, K Bharaj, R Pattni, F Justin, M Chauhan, L Eldridge, S Mintias, J Palmones, C Holmes, L Guthrie, N Devitt, J Leonard, M Osborn, L Ball, A Steele, E Dodd, A Holloway, P Baker, I Penwarden, S Caine, S Clarke, L Dow, R Wynn-Williams, J Kennedy, A DeVeciana, P Mathieson, I Reckless, R Teal, U Schulz, G Ford, P Mccann, G Cluckie, G Howell, J Ayer, B Moynihan, R Ghatala, G Cloud, N Al-Samarrai, F Watson, T Adedoyin, N Chopra, L Choy, N Clarke, A Dainty, A Blight, J Selvarajah, W Smith, F Moreton, A Welch, D Kalladka, B Cheripelli, A Lush, S El Tawil, N Day, K Montgomery, H Hamilton, D Ritchie, S Ramachandra, K McLeish, B Badiani, M Abdul-Saheb, A Chamberlain, M Mpelembue, R Bathula, M Lang, J Devine, L Southworth, N Epie, E Owoyele, F Guo, A Oshodi, V Sudkeo, K Thavanesan, D Tiwari, C Ovington, E Rogers, R Bower, B Longland, O David, A Hogan, S Loganathan, C Cox, S Orr, M Keltos, K Rashed, B Williams-Yesson, J Board, S De Bruijn, C Vickers, S Board, J Allison, E Keeling, T Duckett, D Donaldson, C Barron, L Balian, T England, A Hedstrom, E Bedford, M Harper, E Melikyan, W Abbott, M Goldsworthy, M Srinivasan, I Mukherjee, U Ghani, A Yeomans, F Hurford, R Chapman, S Shahzad, N Motherwell, L Tonks, R Young, D Dutta, P Brown, F Davis, J Turfrey, M Obaid, B Cartwright, B Topia, J Spurway, C Hughes, S OConnell, K Collins, R Bakawala, K Chatterjee, T Webster, S Haider, P Rushworth, F Macleod, C Perkins, A Nallasivan, E Burns, S Leason, T Carter, S Seagrave, E Sami, S Parkinson, L Armstrong, S Mawer, G Darnbrook, C Booth, B Hairsine, S Williamson, F Farquhar, B Esisi, T Cassidy, B McClelland, G Mankin, M Bokhari, D Sproates, S Hurdowar, N Sukhdeep, S Razak, N Upton, A Hashmi, K Osman, K Fotherby, A Willberry, D Morgan, G Sahota, K Jennings-Preece, D Butler, K Kauldhar, F Harrington, A Mate, J Skewes, K Adie, K Bond, G Courtauld, C Schofield, L Lucas, A James, S Ellis, B Maund, L Allsop, C Brodie, E Driver, K Harris, M Drake, E Thomas, M Burn, A Hamilton, S Mahalingam, A Benford, D Hilton, A Misra, L Hazell, K Ofori, M Mathew, S Dayal, I Burn, D Bruce, R Burnip, R Hayman, P Earnshaw, P Gamble, S Dima, M Dhakal, G Rogers, L Stephenson, R Nendick, Y Pai, K Nyo, V Cvoro, M Couser, A Tachtatzis, K Ullah, R Cain, N Chapman, S Pound, S McAuley, D Hargroves, B Ransom, K Mears, K Griffiths, L Cowie, T Hammond, T Webb, I Balogun, H Rudenko, A Thomson, D Ceccarelli, A Gillian, E Beranova, A Verrion, N Chattha, N Schumacher, A Bahk, D Sims, R Tongue, M Willmot, C Sutton, E Littleton, J Khaira, S Maiden, J Cunningham, Y Chin, M Bates, K Ahlquist, J Breeds, T Sargent, L Latter, A Pitt Ford, T Levett, N Gainsborough, A Dunne, E Barbon, S Hervey, S Ragab, T Sandell, C Dickson, S Power, J Dube, N Evans, B Wadams, S Elitova, B Aubrey, T Garcia, J Mcilmoyle, C Dickinson, C Jeffs, J Howard, C Armer, J Frudd, A Potter, S Donaldson, D Collas, S Sundayi, L Denham, D Oza, M Bhandari, S Ispoglou, K Sharobeem, A Hayes, J Howard-Brown, S Shanu, S Billingham, G Howard, E Wood, V Pressly, P Crawford, H Burton, A Walters, J Marigold, R Said, C Allen, S Evans, S Egerton, J Hakkak, R Lampard, S Tsang, R Creeden, I Gartrell, F Price, J Pryor, A Hedges, L Moseley, L Mercer, E Warburton, D Handley, S Finlay, N Hannon, A Espanol, H Markus, D Chandrasena, J Sesay, D Hayden, H Hayhoe, J Macdonald, M Bolton, C Farron, E Amis, D Day, A Culbert, L Whitehead, S Crisp, J OConnell, E Osborne, R Beard, P Corrigan, L Mokoena, M Myint, R Krishnamurthy, A Azim, S Whitworth, A Nicolson, M Krasinska-Chavez, J Imam, S Chaplin, J Curtis, L Wood, A Byrne, C McGhee, A Smart, F Donaldson, J Blackburn, C Copeland, P Fitzsimmons, G Fletcher, A Manoj, P Cox, L Trainor, H Allsop, U Sukys, S Valentine, D Jarrett, K Dodsworth, M Wands, C Watkinson, W Golding, J Tandy, K Yip, C James, Y Davies, A Suttling, K Nagaratnam, N Mannava, N Haque, N Shields, K Preston, G Mason, K Short, G Uitenbosch, G Lumsdale, H Emsley, S Sultan, B Walmsley, D Doyle, A McLoughlin, L Hough, B Gregary, S Raj, A Maney, S Blane, G Gamble, A Hague, B Duran, R Whiting, M Harvey, J Homan, L Foote, L Graham, C Lane, L Kemp, J Rowe, H Durman, L Brotherton, N Hunt, A Whitcher, C Pawley, P Sutton, S Mcdonald, D Pak, A Wiltshire, J Balami, C Self, J Jagger, G Healey, M Crofts, A Chakrabarti, C Hmu, J Keshet-Price, G Ravenhill, C Grimmer, T Soe, I Potter, P Tam, M Langley, M Christie, J Irvine, A Joyson, F Annison, D Christie, C Meneses, V Taylor, J Furnace, H Gow, J Reid, Y Abousleiman, S Goshawk, J Purcell, T Beadling, S Collins, S Sangaralingham, E Munuswamy Vaiyapuri, M Landicho, Y Begum, S Mutton, J Lowe, I Wiggam, S Tauro, S Cuddy, B Wells, A Mohd Nor, N Persad, M Weinling, S Weatherby, D Lashley, A Pace, A Mucha, J Baker, M Marner, J Westcott, N Wilmshurst, D Chadha, M Fairweather, D Walstow, R Fong, M Krishnan, H Thompson Jones, C Lynda, C Clements, T Anjum, S Sharon, D Lynne, S Tucker, D Colwill, E Vasileiadis, A Parry, C Mason, M Holden, K Petrides, T Nishiyama, H Mehta, S Mumani, C Almadenboyle, S Carson, M Stirling, E Tenbruck, D Broughton, A Annamalai, D Tryambake, A Skotnicka, A Sigsworth, S Whitehouse, J Pagan, A Pusalkar, H Beadle, K Chan, P Dangri, A Asokanathan, A Rana, S Gohil, K Crabtree, A Cook, M Massyn, P Aruldoss, S Dabbagh, T Black, C Clarke, R Fennelly, L Nardone, V DiMartino, A Anthony, D Mead, M Tribbeck, B Affley, C Sunderland, E Young, L Goldenberg, P Wilkinson, L Abbott, R Nari, S Lock, A Shakhon, R Pereira, M DSouza, S Dunn, N Cron, A Mckenna, R Sivakumar, S Cook, J Ngeh, R Saksena, J Ketley-O'Donel, R Needle, E Chinery, L Howaniec, C Watchurst, R Erande, M Brezitski, N Passeron, E Elliott, N Oji, D Austin, A Banaras, C Hogan, T Corbett, M Kidd, G Hull, S Punekar, J Nevinson, H Penney, W Wareing, N Hayes, K Bunworth, L Connell, K Mahawish, G Drummond, N Sengupta, M Metiu, C Gonzalez, J Margalef, S Funnell, G Peters, I Chadbourn, H Proeschel, P Ashcroft, S Sharpe, P Cook, D Jenkinson, D Kelly, H Bray, G Gunathilagan, S Tilbey, S Abubakar, A Rajapakse, A Nasar, J Janbieh, L Otter, I Wynter, S Haigh, R Boulton, J Burgoyne, A Boulton, J Vassallo, A Hasan, L Orrell, S Qamar, D Leonard, E Hewitt, M Haque, J Awolesi, E Bradshaw, A Kent, A Hynes, E Nurse, S Raza, U Pallikona, B Edwards, G Morgan, H Tench, R Loosley, K Dennett, T Trugeon-Smith, D Robson, R Rayessa, A Abdul-Hamid, V Lowthorpe, K Mitchelson, E Clarkson, H Rhian, R Kirthivasan, J Topliffe, R Keskeys, F McNeela, E Bohannan, L Cooper, G Zachariah, F Cairns, T James, L Fergey, S Smolen, A Lyle, E Cannon, S Omer, S Mavinamane, S Meenakshisundaram, L Ranga, J Bate, M Hargreaves, S Dealing, S Amlani, G Gulli, M Hawkes-Blackburn, L Francis, S Holland, A Peacocke, J Amero, M Burova, O Speirs, S Brotheridge, S Al Hussayni, H Lyon, C Hare, J Featherstone, M Goorah, J Walford, D Rusk, D Sutton, F Patel, S Duberley, K Hayes, E Ahmed El Nour, S Dyer, E Temlett, J Paterson, S Honour, C Box, R Furness, E Orugun, H Crowther, R Glover, C Brewer, S Thornthwaite, M Sein, K Haque, L Bailey, E Gibson, L Brookes, K Rotchell, K Waltho, C Lindley, P Harlekar, C Culmsee, L Booth, J Ritchie, N Mackenzie, J Barker, M Haley, D Cotterill, L Lane, D Simmons, R Warinton, G Saunders, H Dymond, S Kidd, C Little, Y Neves-Silva, B Nevajda, M Villaruel, U Umasankar, A Man, N Gadi, N Christmas, R Ladner, R Rangasamy, G Butt, W Alvares, M Power, S Hagan, K Dynan, D Wilson, S Crothers, B Wroath, G Douris, D Vahidassr, B Gallen, C McGoldrick, M Bhattad, J Putteril, R Gallifent, E Makanju, M Lepore, C McRedmond, L Arundell, A Goulding, K Kawafi, P Jacob, L Turner, N Saravanan, L Johnson, D Morse, R Namushi, S Humphrey, M Salehin, S Tinsley, T Jones, L Garcia-Alen, L Kalathil, N Gautam, J Horton, J Meir, E Margerum, A Ritchings, K Amor, V Nadarajan, J Laurence, S Fung Lo, S Melander, P Nicholas, E Woodford, G McKenzie, V Le, J Crause, P OMahony, C Orefo, C McDonald, E Osikominu, G Appiatse, A Wardale, M Augustin, R Luder, M Bhargava, G Bhome, V Johnson, D Chesser, H Bridger, E Murali, A Burns, J Graham, M Duffy, E Pitcher, J Gaylard, J Newman, S Punnoose, S Oakley, V Murray, C Bent, R Walker, K Purohit, A Rees, S Besley, O Chohan, L Argandona, L Cuenoud, H Hassan, E Erumere, A OCallaghan, O Redjep, G Auld, P Gompertz, A Song, R Hungwe, H Kabash, T Tarkas, G Livingstone, F Butler, S Bradfield, L Gordon, J Schmit, A Wijewardane, C Medcalf, T Edmunds, R Wills, and C Peixoto

Subjects
Medicine
Abstract

Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

Published
2020
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10. A Review of Structural and Biomechanical Changes in the Cornea in Aging, Disease, and Photochemical Crosslinking

Author

Brecken J. Blackburn, Michael W. Jenkins, Andrew M. Rollins, and William J. Dupps

Subjects
cornea biomechanical properties, cornea, aging, crosslinking, crosslinking (CXL) corneal collagen, keratoconus, Biotechnology, TP248.13-248.65
Abstract

The study of corneal biomechanics is motivated by the tight relationship between biomechanical properties and visual function within the ocular system. For instance, variation in collagen fibril alignment and non-enzymatic crosslinks rank high among structural factors which give rise to the cornea's particular shape and ability to properly focus light. Gradation in these and other factors engender biomechanical changes which can be quantified by a wide variety of techniques. This review summarizes what is known about both the changes in corneal structure and associated changes in corneal biomechanical properties in aging, keratoconic, and photochemically crosslinked corneas. In addition, methods for measuring corneal biomechanics are discussed and the topics are related to both clinical studies and biomechanical modeling simulations.

Published
2019
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11. Reactivity of vanadium oxytrichloride with β-diketones and diesters as precursors for vanadium nitride and carbide

Author

Ben J. Blackburn, Jared H. Crane, Caroline E. Knapp, Michael J. Powell, Peter Marchand, David Pugh, Joseph C. Bear, Ivan P. Parkin, and Claire J. Carmalt

Subjects
Materials of engineering and construction. Mechanics of materials, TA401-492
Abstract

Vanadium(V) oxytrichloride was reacted with 2,4-pentanedione, diethyl malonate, and diethyl succinate under inert conditions, forming compounds: dichloro(oxo)(2,4-pentanedione) vanadium(V) [1], dichloro(oxo)(diethyl malonate) vanadium(IV) [2] and dichloro(oxo)(diethyl succinate) vanadium(IV) [3]. Compounds 1–3 are coordinated to the vanadium centre through the two carbonyl oxygen atoms of the bidentate ligand. It was determined by X-ray crystallography that the structures of the resulting complexes were significantly different, resulting in a monomeric complex (1), a tetrameric ring (2) and a 1D coordination polymer (3). Following the synthesis and isolation of 1–3, they were tested as precursors for vanadium nitride and vanadium carbide by annealing under nitrogen and argon respectively at 1200 °C for 24 h. The resulting materials were characterised by: XRD, EDS, XPS and TEM. Keywords: Vanadium oxychloride, Precursors, Ester adducts, Vanadium carbide, Vanadium nitride, Hard materials

Published
2016
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12. Mitochondrial Dysfunction in Alzheimer’s Disease: A Biomarker of the Future?

Author

Simon M. Bell, Katy Barnes, Matteo De Marco, Pamela J. Shaw, Laura Ferraiuolo, Daniel J. Blackburn, Annalena Venneri, and Heather Mortiboys

Subjects
mitochondria, Alzheimer’s disease, biomarker, Biology (General), QH301-705.5
Abstract

Alzheimer’s disease (AD) is the most common cause of dementia worldwide and is characterised pathologically by the accumulation of amyloid beta and tau protein aggregates. Currently, there are no approved disease modifying therapies for clearance of either of these proteins from the brain of people with AD. As well as abnormalities in protein aggregation, other pathological changes are seen in this condition. The function of mitochondria in both the nervous system and rest of the body is altered early in this disease, and both amyloid and tau have detrimental effects on mitochondrial function. In this review article, we describe how the function and structure of mitochondria change in AD. This review summarises current imaging techniques that use surrogate markers of mitochondrial function in both research and clinical practice, but also how mitochondrial functions such as ATP production, calcium homeostasis, mitophagy and reactive oxygen species production are affected in AD mitochondria. The evidence reviewed suggests that the measurement of mitochondrial function may be developed into a future biomarker for early AD. Further work with larger cohorts of patients is needed before mitochondrial functional biomarkers are ready for clinical use.

Published
2021
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13. Global scaling of the heat transport in fusion plasmas

Author

Sara Moradi, Johan Anderson, Michele Romanelli, Hyun-Tae Kim, JET contributors, X. Litaudon, S. Abduallev, M. Abhangi, P. Abreu, M. Afzal, K. M. Aggarwal, T. Ahlgren, J. H. Ahn, L. Aho-Mantila, N. Aiba, M. Airila, R. Albanese, V. Aldred, D. Alegre, E. Alessi, P. Aleynikov, A. Alfier, A. Alkseev, M. Allinson, B. Alper, E. Alves, G. Ambrosino, R. Ambrosino, L. Amicucci, V. Amosov, E. Andersson Sundén, M. Angelone, M. Anghel, C. Angioni, L. Appel, C. Appelbee, P. Arena, M. Ariola, H. Arnichand, S. Arshad, A. Ash, N. Ashikawa, V. Aslanyan, O. Asunta, F. Auriemma, Y. Austin, L. Avotina, M. D. Axton, C. Ayres, M. Bacharis, A. Baciero, D. Baião, S. Bailey, A. Baker, I. Balboa, M. Balden, N. Balshaw, R. Bament, J. W. Banks, Y. F. Baranov, M. A. Barnard, D. Barnes, M. Barnes, R. Barnsley, A. Baron Wiechec, L. Barrera Orte, M. Baruzzo, V. Basiuk, M. Bassan, R. Bastow, A. Batista, P. Batistoni, R. Baughan, B. Bauvir, L. Baylor, B. Bazylev, J. Beal, P. S. Beaumont, M. Beckers, B. Beckett, A. Becoulet, N. Bekris, M. Beldishevski, K. Bell, F. Belli, M. Bellinger, É. Belonohy, N. Ben Ayed, N. A. Benterman, H. Bergsȧker, J. Bernardo, M. Bernert, M. Berry, L. Bertalot, C. Besliu, M. Beurskens, B. Bieg, J. Bielecki, T. Biewer, M. Bigi, P. Bìlkovà, F. Binda, A. Bisoffi, J. P. S. Bizarro, C. Björkas, J. Blackburn, K. Blackman, T. R. Blackman, P. Blanchard, P. Blatchford, V. Bobkov, A. Boboc, G. Bodnàr, O. Bogar, I. Bolshakova, T. Bolzonella, N. Bonanomi, F. Bonelli, J. Boom, J. Booth, D. Borba, D. Borodin, I. Borodkina, A. Botrugno, C. Bottereau, P. Boulting, C. Bourdelle, M. Bowden, C. Bower, C. Bowman, T. Boyce, C. Boyd, H. J. Boyer, J. M. A. Bradshaw, V. Braic, R. Bravanec, B. Breizman, S. Bremond, P. D. Brennan, S. Breton, A. Brett, S. Brezinsek, M. D. J. Bright, M. Brix, W. Broeckx, M. Brombin, A. Brosawski, D. P. D. Brown, M. Brown, E. Bruno, J. Bucalossi, J. Buch, J. Buchanan, M. A. Buckley, R. Budny, H. Bufferand, M. Bulman, N. Bulmer, P. Bunting, P. Buratti, A. Burckhart, A. Buscarino, A. Busse, N. K. Butler, I. Bykov, J. Byrne, P. Cahyna, G. Calabrò, I. Calvo, Y. Camenen, P. Camp, D. C. Campling, J. Cane, B. Cannas, A. J. Capel, P. J. Card, A. Cardinali, P. Carman, M. Carr, D. Carralero, L. Carraro, B. B. Carvalho, I. Carvalho, P. Carvalho, F. J. Casson, C. Castaldo, N. Catarino, J. Caumont, F. Causa, R. Cavazzana, K. Cave-Ayland, M. Cavinato, M. Cecconello, S. Ceccuzzi, E. Cecil, A. Cenedese, R. Cesario, C. D. Challis, M. Chandler, D. Chandra, C. S. Chang, A. Chankin, I. T. Chapman, S. C. Chapman, M. Chernyshova, G. Chitarin, G. Ciraolo, D. Ciric, J. Citrin, F. Clairet, E. Clark, M. Clark, R. Clarkson, D. Clatworthy, C. Clements, M. Cleverly, J. P. Coad, P. A. Coates, A. Cobalt, V. Coccorese, V. Cocilovo, S. Coda, R. Coelho, J. W. Coenen, I. Coffey, L. Colas, S. Collins, D. Conka, S. Conroy, N. Conway, D. Coombs, D. Cooper, S. R. Cooper, C. Corradino, Y. Corre, G. Corrigan, S. Cortes, D. Coster, A. S. Couchman, M. P. Cox, T. Craciunescu, S. Cramp, R. Craven, F. Crisanti, G. Croci, D. Croft, K. Crombé, R. Crowe, N. Cruz, G. Cseh, A. Cufar, A. Cullen, M. Curuia, A. Czarnecka, H. Dabirikhah, P. Dalgliesh, S. Dalley, J. Dankowski, D. Darrow, O. Davies, W. Davis, C. Day, I. E. Day, M. De Bock, A. de Castro, E. de la Cal, E. de la Luna, G. De Masi, J. L. de Pablos, G. De Temmerman, G. De Tommasi, P. de Vries, K. Deakin, J. Deane, F. Degli Agostini, R. Dejarnac, E. Delabie, N. den Harder, R. O. Dendy, J. Denis, P. Denner, S. Devaux, P. Devynck, F. Di Maio, A. Di Siena, C. Di Troia, P. Dinca, R. Dinca, B. Ding, T. Dittmar, H. Doerk, R. P. Doerner, T. Donné, S. E. Dorling, S. Dormido-Canto, S. Doswon, D. Douai, P. T. Doyle, A. Drenik, P. Drewelow, P. Drews, Ph. Duckworth, R. Dumont, P. Dumortier, D. Dunai, M. Dunne, I. Duran, F. Durodié, P. Dutta, B. P. Duval, R. Dux, K. Dylst, N. Dzysiuk, P. V. Edappala, J. Edmond, A. M. Edwards, J. Edwards, Th. Eich, A. Ekedahl, R. El-Jorf, C. G. Elsmore, M. Enachescu, G. Ericsson, F. Eriksson, J. Eriksson, L. G. Eriksson, B. Esposito, S. Esquembri, H. G. Esser, D. Esteve, B. Evans, G. E. Evans, G. Evison, G. D. Ewart, D. Fagan, M. Faitsch, D. Falie, A. Fanni, A. Fasoli, J. M. Faustin, N. Fawlk, L. Fazendeiro, N. Fedorczak, R. C. Felton, K. Fenton, A. Fernades, H. Fernandes, J. Ferreira, J. A. Fessey, O. Février, O. Ficker, A. Field, S. Fietz, A. Figueiredo, J. Figueiredo, A. Fil, P. Finburg, M. Firdaouss, U. Fischer, L. Fittill, M. Fitzgerald, D. Flammini, J. Flanagan, C. Fleming, K. Flinders, N. Fonnesu, J. M. Fontdecaba, A. Formisano, L. Forsythe, L. Fortuna, E. Fortuna-Zalesna, M. Fortune, S. Foster, T. Franke, T. Franklin, M. Frasca, L. Frassinetti, M. Freisinger, R. Fresa, D. Frigione, V. Fuchs, D. Fuller, S. Futatani, J. Fyvie, K. Gàl, D. Galassi, K. Galazka, J. Galdon-Quiroga, J. Gallagher, D. Gallart, R. Galvão, X. Gao, Y. Gao, J. Garcia, A. Garcia-Carrasco, M. Garca-Munoz, J.-L. Gardarein, L. Garzotti, P. Gaudio, E. Gauthier, D. F. Gear, S. J. Gee, B. Geiger, M. Gelfusa, S. Gerasimov, G. Gervasini, M. Gethins, Z. Ghani, M. Ghate, M. Gherendi, J. C. Giacalone, L. Giacomelli, C. S. Gibson, T. Giegerich, C. Gil, L. Gil, S. Gilligan, D. Gin, E. Giovannozzi, J. B. Girardo, C. Giroud, G. Giruzzi, S. Glöggler, J. Godwin, J. Goff, P. Gohil, V. Goloborod'ko, R. Gomes, B. Goncalves, M. Goniche, M. Goodliffe, A. Goodyear, G. Gorini, M. Gosk, R. Goulding, A. Goussarov, R. Gowland, B. Graham, M. E. Graham, J. P. Graves, N. Grazier, P. Grazier, N. R. Green, H. Greuner, B. Grierson, F. S. Griph, C. Grisolia, D. Grist, M. Groth, R. Grove, C. N. Grundy, J. Grzonka, D. Guard, C. Guérard, C. Guillemaut, R. Guirlet, C. Gurl, H. H. Utoh, L. J. Hackett, S. Hacquin, A. Hagar, R. Hager, A. Hakola, M. Halitovs, S. J. Hall, S. P. Hallworth Cook, C. Hamlyn-Harris, K. Hammond, C. Harrington, J. Harrison, D. Harting, F. Hasenbeck, Y. Hatano, D. R. Hatch, T. D. V. Haupt, J. Hawes, N. C. Hawkes, J. Hawkins, P. Hawkins, P. W. Haydon, N. Hayter, S. Hazel, P. J. L. Heesterman, K. Heinola, C. Hellesen, T. Hellsten, W. Helou, O. N. Hemming, T. C. Hender, M. Henderson, S. S. Henderson, R. Henriques, D. Hepple, G. Hermon, P. Hertout, C. Hidalgo, E. G. Highcock, M. Hill, J. Hillairet, J. Hillesheim, D. Hillis, K. Hizanidis, A. Hjalmarsson, J. Hobirk, E. Hodille, C. H. A. Hogben, G. M. D. Hogeweij, A. Hollingsworth, S. Hollis, D. A. Homfray, J. Horàcek, G. Hornung, A. R. Horton, L. D. Horton, L. Horvath, S. P. Hotchin, M. R. Hough, P. J. Howarth, A. Hubbard, A. Huber, V. Huber, T. M. Huddleston, M. Hughes, G. T. A. Huijsmans, C. L. Hunter, P. Huynh, A. M. Hynes, D. Iglesias, N. Imazawa, F. Imbeaux, M. Imrìŝek, M. Incelli, P. Innocente, M. Irishkin, I. Ivanova-Stanik, S. Jachmich, A. S. Jacobsen, P. Jacquet, J. Jansons, A. Jardin, A. Järvinen, F. Jaulmes, S. Jednoróq, I. Jenkins, C. Jeong, I. Jepu, E. Joffrin, R. Johnson, T. Johnson, Jane Johnston, L. Joita, G. Jones, T. T. C. Jones, K. K. Hoshino, A. Kallenbach, K. Kamiya, J. Kaniewski, A. Kantor, A. Kappatou, J. Karhunen, D. Karkinsky, I. Karnowska, M. Kaufman, G. Kaveney, Y. Kazakov, V. Kazantzidis, D. L. Keeling, T. Keenan, J. Keep, M. Kempenaars, C. Kennedy, D. Kenny, J. Kent, O. N. Kent, E. Khilkevich, H. T. Kim, H. S. Kim, A. Kinch, C. King, D. King, R. F. King, D. J. Kinna, V. Kiptily, A. Kirk, K. Kirov, A. Kirschner, G. Kizane, C. Klepper, A. Klix, P. Knight, S. J. Knipe, S. Knott, T. Kobuchi, F. Köchl, G. Kocsis, I. Kodeli, L. Kogan, D. Kogut, S. Koivuranta, Y. Kominis, M. Köppen, B. Kos, T. Koskela, H. R. Koslowski, M. Koubiti, M. Kovari, E. Kowalska-Strzeciwilk, A. Krasilnikov, V. Krasilnikov, N. Krawczyk, M. Kresina, K. Krieger, A. Krivska, U. Kruezi, I. Ksiazek, A. Kukushkin, A. Kundu, T. Kurki-Suonio, S. Kwak, R. Kwiatkowski, O. J. Kwon, L. Laguardia, A. Lahtinen, A. Laing, N. Lam, H. T. Lambertz, C. Lane, P. T. Lang, S. Lanthaler, J. Lapins, A. Lasa, J. R. Last, E. Laszynska, R. Lawless, A. Lawson, K. D. Lawson, A. Lazaros, E. Lazzaro, J. Leddy, S. Lee, X. Lefebvre, H. J. Leggate, J. Lehmann, M. Lehnen, D. Leichtle, P. Leichuer, F. Leipold, I. Lengar, M. Lennholm, E. Lerche, A. Lescinskis, S. Lesnoj, E. Letellier, M. Leyland, W. Leysen, L. Li, Y. Liang, J. Likonen, J. Linke, Ch. Linsmeier, B. Lipschultz, G. Liu, Y. Liu, V. P. Lo Schiavo, T. Loarer, A. Loarte, R. C. Lobel, B. Lomanowski, P. J. Lomas, J. Lönnroth, J. M. López, J. López-Razola, R. Lorenzini, U. Losada, J. J. Lovell, A. B. Loving, C. Lowry, T. Luce, R. M. A. Lucock, A. Lukin, C. Luna, M. Lungaroni, C. P. Lungu, M. Lungu, A. Lunniss, I. Lupelli, A. Lyssoivan, N. Macdonald, P. Macheta, K. Maczewa, B. Magesh, P. Maget, C. Maggi, H. Maier, J. Mailloux, T. Makkonen, R. Makwana, A. Malaquias, A. Malizia, P. Manas, A. Manning, M. E. Manso, P. Mantica, M. Mantsinen, A. Manzanares, Ph. Maquet, Y. Marandet, N. Marcenko, C. Marchetto, O. Marchuk, M. Marinelli, M. Marinucci, T. Markovic, D. Marocco, L. Marot, C. A. Marren, R. Marshal, A. Martin, Y. Martin, A. Martín de Aguilera, F. J. Martínez, J. R. Martín-Solís, Y. Martynova, S. Maruyama, A. Masiello, M. Maslov, S. Matejcik, M. Mattei, G. F. Matthews, F. Maviglia, M. Mayer, M. L. Mayoral, T. May-Smith, D. Mazon, C. Mazzotta, R. McAdams, P. J. McCarthy, K. G. McClements, O. McCormack, P. A. McCullen, D. McDonald, S. McIntosh, R. McKean, J. McKehon, R. C. Meadows, A. Meakins, F. Medina, M. Medland, S. Medley, S. Meigh, A. G. Meigs, G. Meisl, S. Meitner, L. Meneses, S. Menmuir, K. Mergia, I. R. Merrigan, Ph. Mertens, S. Meshchaninov, A. Messiaen, H. Meyer, S. Mianowski, R. Michling, D. Middleton-Gear, J. Miettunen, F. Militello, E. Militello-Asp, G. Miloshevsky, F. Mink, S. Minucci, Y. Miyoshi, J. Mlynàr, D. Molina, I. Monakhov, M. Moneti, R. Mooney, S. Moradi, S. Mordijck, L. Moreira, R. Moreno, F. Moro, A. W. Morris, J. Morris, L. Moser, S. Mosher, D. Moulton, A. Murari, A. Muraro, S. Murphy, N. N. Asakura, Y. S. Na, F. Nabais, R. Naish, T. Nakano, E. Nardon, V. Naulin, M. F. F. Nave, I. Nedzelski, G. Nemtsev, F. Nespoli, A. Neto, R. Neu, V. S. Neverov, M. Newman, K. J. Nicholls, T. Nicolas, A. H. Nielsen, P. Nielsen, E. Nilsson, D. Nishijima, C. Noble, M. Nocente, D. Nodwell, K. Nordlund, H. Nordman, R. Nouailletas, I. Nunes, M. Oberkofler, T. Odupitan, M. T. Ogawa, T. O'Gorman, M. Okabayashi, R. Olney, O. Omolayo, M. O'Mullane, J. Ongena, F. Orsitto, J. Orszagh, B. I. Oswuigwe, R. Otin, A. Owen, R. Paccagnella, N. Pace, D. Pacella, L. W. Packer, A. Page, E. Pajuste, S. Palazzo, S. Pamela, S. Panja, P. Papp, R. Paprok, V. Parail, M. Park, F. Parra Diaz, M. Parsons, R. Pasqualotto, A. Patel, S. Pathak, D. Paton, H. Patten, A. Pau, E. Pawelec, C. Paz Soldan, A. Peackoc, I. J. Pearson, S.-P. Pehkonen, E. Peluso, C. Penot, A. Pereira, R. Pereira, P. P. Pereira Puglia, C. Perez von Thun, S. Peruzzo, S. Peschanyi, M. Peterka, P. Petersson, G. Petravich, A. Petre, N. Petrella, V. Petrzilka, Y. Peysson, D. Pfefferlé, V. Philipps, M. Pillon, G. Pintsuk, P. Piovesan, A. Pires dos Reis, L. Piron, A. Pironti, F. Pisano, R. Pitts, F. Pizzo, V. Plyusnin, N. Pomaro, O. G. Pompilian, P. J. Pool, S. Popovichev, M. T. Porfiri, C. Porosnicu, M. Porton, G. Possnert, S. Potzel, T. Powell, J. Pozzi, V. Prajapati, R. Prakash, G. Prestopino, D. Price, M. Price, R. Price, P. Prior, R. Proudfoot, G. Pucella, P. Puglia, M. E. Puiatti, D. Pulley, K. Purahoo, Th. Pütterich, E. Rachlew, M. Rack, R. Ragona, M. S. J. Rainford, A. Rakha, G. Ramogida, S. Ranjan, C. J. Rapson, J. J. Rasmussen, K. Rathod, G. Rattà, S. Ratynskaia, G. Ravera, C. Rayner, M. Rebai, D. Reece, A. Reed, D. Réfy, B. Regan, J. Regana, M. Reich, N. Reid, F. Reimold, M. Reinhart, M. Reinke, D. Reiser, D. Rendell, C. Reux, S. D. A. Reyes Cortes, S. Reynolds, V. Riccardo, N. Richardson, K. Riddle, D. Rigamonti, F. G. Rimini, J. Risner, M. Riva, C. Roach, R. J. Robins, S. A. Robinson, T. Robinson, D. W. Robson, R. Roccella, R. Rodionov, P. Rodrigues, J. Rodriguez, V. Rohde, F. Romanelli, M. Romanelli, S. Romanelli, J. Romazanov, S. Rowe, M. Rubel, G. Rubinacci, G. Rubino, L. Ruchko, M. Ruiz, C. Ruset, J. Rzadkiewicz, S. Saarelma, R. Sabot, E. Safi, P. Sagar, G. Saibene, F. Saint-Laurent, M. Salewski, A. Salmi, R. Salmon, F. Salzedas, D. Samaddar, U. Samm, D. Sandiford, P. Santa, M. I. K. Santala, B. Santos, A. Santucci, F. Sartori, R. Sartori, O. Sauter, R. Scannell, T. Schlummer, K. Schmid, V. Schmidt, S. Schmuck, M. Schneider, K. Schöpf, D. Schwörer, S. D. Scott, G. Sergienko, M. Sertoli, A. Shabbir, S. E. Sharapov, A. Shaw, R. Shaw, H. Sheikh, A. Shepherd, A. Shevelev, A. Shumack, G. Sias, M. Sibbald, B. Sieglin, S. Silburn, A. Silva, C. Silva, P. A. Simmons, J. Simpson, J. Simpson-Hutchinson, A. Sinha, S. K. Sipilä, A. C. C. Sips, P. Sirén, A. Sirinelli, H. Sjöstrand, M. Skiba, R. Skilton, K. Slabkowska, B. Slade, N. Smith, P. G. Smith, R. Smith, T. J. Smith, M. Smithies, L. Snoj, S. Soare, E. R. Solano, A. Somers, C. Sommariva, P. Sonato, A. Sopplesa, J. Sousa, C. Sozzi, S. Spagnolo, T. Spelzini, F. Spineanu, G. Stables, I. Stamatelatos, M. F. Stamp, P. Staniec, G. Stankunas, C. Stan-Sion, M. J. Stead, E. Stefanikova, I. Stepanov, A. V. Stephen, M. Stephen, A. Stevens, B. D. Stevens, J. Strachan, P. Strand, H. R. Strauss, P. Ström, G. Stubbs, W. Studholme, F. Subba, H. P. Summers, J. Svensson, L. Swiderski, T. Szabolics, M. Szawlowski, G. Szepesi, T. T. Suzuki, B. Tàl, T. Tala, A. R. Talbot, S. Talebzadeh, C. Taliercio, P. Tamain, C. Tame, W. Tang, M. Tardocchi, L. Taroni, D. Taylor, K. A. Taylor, D. Tegnered, G. Telesca, N. Teplova, D. Terranova, D. Testa, E. Tholerus, J. Thomas, J. D. Thomas, P. Thomas, A. Thompson, C.-A. Thompson, V. K. Thompson, L. Thorne, A. Thornton, A. S. Thrysoe, P. A. Tigwell, N. Tipton, I. Tiseanu, H. Tojo, M. Tokitani, P. Tolias, M. Tomes, P. Tonner, M. Towndrow, P. Trimble, M. Tripsky, M. Tsalas, P. Tsavalas, D. Tskhakaya jun, I. Turner, M. M. Turner, M. Turnyanskiy, G. Tvalashvili, S. G. J. Tyrrell, A. Uccello, Z. Ul-Abidin, J. Uljanovs, D. Ulyatt, H. Urano, I. Uytdenhouwen, A. P. Vadgama, D. Valcarcel, M. Valentinuzzi, M. Valisa, P. Vallejos Olivares, M. Valovic, M. Van De Mortel, D. Van Eester, W. Van Renterghem, G. J. van Rooij, J. Varje, S. Varoutis, S. Vartanian, K. Vasava, T. Vasilopoulou, J. Vega, G. Verdoolaege, R. Verhoeven, C. Verona, G. Verona Rinati, E. Veshchev, N. Vianello, J. Vicente, E. Viezzer, S. Villari, F. Villone, P. Vincenzi, I. Vinyar, B. Viola, A. Vitins, Z. Vizvary, M. Vlad, I. Voitsekhovitch, P. Vondràcek, N. Vora, T. Vu, W. W. Pires de Sa, B. Wakeling, C. W. F. Waldon, N. Walkden, M. Walker, R. Walker, M. Walsh, E. Wang, N. Wang, S. Warder, R. J. Warren, J. Waterhouse, N. W. Watkins, C. Watts, T. Wauters, A. Weckmann, J. Weiland, H. Weisen, M. Weiszflog, C. Wellstood, A. T. West, M. R. Wheatley, S. Whetham, A. M. Whitehead, B. D. Whitehead, A. M. Widdowson, S. Wiesen, J. Wilkinson, J. Williams, M. Williams, A. R. Wilson, D. J. Wilson, H. R. Wilson, J. Wilson, M. Wischmeier, G. Withenshaw, A. Withycombe, D. M. Witts, D. Wood, R. Wood, C. Woodley, S. Wray, J. Wright, J. C. Wright, J. Wu, S. Wukitch, A. Wynn, T. Xu, D. Yadikin, W. Yanling, L. Yao, V. Yavorskij, M. G. Yoo, C. Young, D. Young, I. D. Young, R. Young, J. Zacks, R. Zagorski, F. S. Zaitsev, R. Zanino, A. Zarins, K. D. Zastrow, M. Zerbini, W. Zhang, Y. Zhou, E. Zilli, V. Zoita, S. Zoletnik, and I. Zychor

Subjects
Physics, QC1-999
Abstract

A global heat flux model based on a fractional derivative of plasma pressure is proposed for the heat transport in fusion plasmas. The degree of the fractional derivative of the heat flux, α, is defined through the power balance analysis of the steady state. The model was used to obtain the experimental values of α for a large database of the Joint European Torus (JET) carbon-wall as well as ITER like-wall plasmas. The fractional degrees of the electron heat flux are found to be α

Published
2020
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14. A comparison of five lipid extraction solvent systems for lipidomic studies of human LDL[S]

Author

Ana Reis, Alisa Rudnitskaya, Gavin J. Blackburn, Norsyahida Mohd Fauzi, Andrew R. Pitt, and Corinne M. Spickett

Subjects
lipidomics, orbitrap, dual polarity, polarity switching, ANOVA simultaneous component analysis, liquid-liquid extraction, Biochemistry, QD415-436
Abstract

Lipidome profile of fluids and tissues is a growing field as the role of lipids as signaling molecules is increasingly understood, relying on an effective and representative extraction of the lipids present. A number of solvent systems suitable for lipid extraction are commonly in use, though no comprehensive investigation of their effectiveness across multiple lipid classes has been carried out. To address this, human LDL from normolipidemic volunteers was used to evaluate five different solvent extraction protocols [Folch, Bligh and Dyer, acidified Bligh and Dyer, methanol (MeOH)-tert-butyl methyl ether (TBME), and hexane-isopropanol] and the extracted lipids were analyzed by LC-MS in a high-resolution instrument equipped with polarity switching. Overall, more than 350 different lipid species from 19 lipid subclasses were identified. Solvent composition had a small effect on the extraction of predominant lipid classes (triacylglycerides, cholesterol esters, and phosphatidylcholines). In contrast, extraction of less abundant lipids (phosphatidylinositols, lyso-lipids, ceramides, and cholesterol sulfates) was greatly influenced by the solvent system used. Overall, the Folch method was most effective for the extraction of a broad range of lipid classes in LDL, although the hexane-isopropanol method was best for apolar lipids and the MeOH-TBME method was suitable for lactosyl ceramides.

Published
2013
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15. Intensive versus Guideline Blood Pressure and Lipid Lowering in Patients with Previous Stroke: Main Results from the Pilot 'Prevention of Decline in Cognition after Stroke Trial' (PODCAST) Randomised Controlled Trial.

Author

Philip M Bath, Polly Scutt, Daniel J Blackburn, Sandeep Ankolekar, Kailash Krishnan, Clive Ballard, Alistair Burns, Jonathan Mant, Peter Passmore, Stuart Pocock, John Reckless, Nikola Sprigg, Rob Stewart, Joanna M Wardlaw, Gary A Ford, and PODCAST Trial Investigators

Subjects
Medicine, Science
Abstract

BACKGROUND:Stroke is associated with the development of cognitive impairment and dementia. We assessed the effect of intensive blood pressure (BP) and/or lipid lowering on cognitive outcomes in patients with recent stroke in a pilot trial. METHODS:In a multicentre, partial-factorial trial, patients with recent stroke, absence of dementia, and systolic BP (SBP) 125-170 mmHg were assigned randomly to at least 6 months of intensive (target SBP

Published
2017
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16. Metabolomic profiling and stable isotope labelling of Trichomonas vaginalis and Tritrichomonas foetus reveal major differences in amino acid metabolism including the production of 2-hydroxyisocaproic acid, cystathionine and S-methylcysteine.

Author

Gareth D Westrop, Lijie Wang, Gavin J Blackburn, Tong Zhang, Liang Zheng, David G Watson, and Graham H Coombs

Subjects
Medicine, Science
Abstract

Trichomonas vaginalis and Tritrichomonas foetus are pathogens that parasitise, respectively, human and bovine urogenital tracts causing disease. Using LC-MS, reference metabolomic profiles were obtained for both species and stable isotope labelling with D-[U-13C6] glucose was used to analyse central carbon metabolism. This facilitated a comparison of the metabolic pathways of T. vaginalis and T. foetus, extending earlier targeted biochemical studies. 43 metabolites, whose identities were confirmed by comparison of their retention times with authentic standards, occurred at more than 3-fold difference in peak intensity between T. vaginalis and T. foetus. 18 metabolites that were removed from or released into the medium during growth also showed more than 3-fold difference between the species. Major differences were observed in cysteine and methionine metabolism in which homocysteine, produced as a bi-product of trans-methylation, is catabolised by methionine γ-lyase in T. vaginalis but converted to cystathionine in T. foetus. Both species synthesise methylthioadenosine by an unusual mechanism, but it is not used as a substrate for methionine recycling. T. vaginalis also produces and exports high levels of S-methylcysteine, whereas only negligible levels were found in T. foetus which maintains significantly higher intracellular levels of cysteine. 13C-labeling confirmed that both cysteine and S-methylcysteine are synthesised by T. vaginalis; S-methylcysteine can be generated by recombinant T. vaginalis cysteine synthase using phosphoserine and methanethiol. T. foetus contained higher levels of ornithine and citrulline than T. vaginalis and exported increased levels of putrescine, suggesting greater flux through the arginine dihydrolase pathway. T. vaginalis produced and exported hydroxy acid derivatives of certain amino acids, particularly 2-hydroxyisocaproic acid derived from leucine, whereas negligible levels of these metabolites occurred in T. foetus.

Published
2017
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17. A Pilot Study Investigating a Novel Non-Linear Measure of Eyes Open versus Eyes Closed EEG Synchronization in People with Alzheimer’s Disease and Healthy Controls

Author

Daniel J. Blackburn, Ptolemaios G. Sarrigiannis, Matteo De Marco, Yifan Zhao, Annalena Venneri, Sarah Lawrence, Zoe C. Unwin, Michelle Blyth, Jenna Angel, Kathleen Baster, Iain D. Wilkinson, Simon M. Bell, Fei He, Hua-Liang Wei, Stephen A. Billings, and Thomas F. D. Farrow

Subjects
Alzheimer’s disease, electroencephalography, clinical marker, ROC curve, nonlinear dynamics, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: The incidence of Alzheimer disease (AD) is increasing with the ageing population. The development of low cost non-invasive diagnostic aids for AD is a research priority. This pilot study investigated whether an approach based on a novel dynamic quantitative parametric EEG method could detect abnormalities in people with AD. Methods: 20 patients with probable AD, 20 matched healthy controls (HC) and 4 patients with probable fronto temporal dementia (FTD) were included. All had detailed neuropsychology along with structural, resting state fMRI and EEG. EEG data were analyzed using the Error Reduction Ratio-causality (ERR-causality) test that can capture both linear and nonlinear interactions between different EEG recording areas. The 95% confidence intervals of EEG levels of bi-centroparietal synchronization were estimated for eyes open (EO) and eyes closed (EC) states. Results: In the EC state, AD patients and HC had very similar levels of bi-centro parietal synchronization; but in the EO resting state, patients with AD had significantly higher levels of synchronization (AD = 0.44; interquartile range (IQR) 0.41 vs. HC = 0.15; IQR 0.17, p < 0.0001). The EO/EC synchronization ratio, a measure of the dynamic changes between the two states, also showed significant differences between these two groups (AD ratio 0.78 versus HC ratio 0.37 p < 0.0001). EO synchronization was also significantly different between AD and FTD (FTD = 0.075; IQR 0.03, p < 0.0001). However, the EO/EC ratio was not informative in the FTD group due to very low levels of synchronization in both states (EO and EC). Conclusion: In this pilot work, resting state quantitative EEG shows significant differences between healthy controls and patients with AD. This approach has the potential to develop into a useful non-invasive and economical diagnostic aid in AD.

Published
2018
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18. Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Author

David John Baker, Daniel J Blackburn, Marcus eKeatinge, Dilraj eSokhi, Paulius eViskaitis, Paul Roy Heath, Laura eFerraiuolo, Janine eKirby, and Pamela Jean Shaw

Subjects
Microarray, motor neuron, neurodegeneration, Superoxide dismutase 1, Cholesterol/steroid, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Astrocytes are key players in the progression of amyotrophic lateral sclerosis (ALS). Previously, gene expression profiling of astrocytes from the pre-symptomatic stage of the SOD1G93A model of ALS has revealed reduced lactate metabolism and altered trophic support. Here, we have performed microarray analysis of symptomatic and late-stage disease astrocytes isolated by laser capture microdissection (LCM) from the lumbar spinal cord of the SOD1G93A mouse to complete the picture of astrocyte behaviour throughout the disease course. Astrocytes at symptomatic and late-stage disease show a distinct up-regulation of transcripts defining a reactive phenotype, such as those involved in the lysosome and phagocytic pathways. Functional analysis of hexosaminidase B enzyme activity in the spinal cord and of astrocyte phagocytic ability has demonstrated a significant increase in lysosomal enzyme activity and phagocytic activity in SOD1G93A vs. littermate controls, validating the findings of the microarray study. In addition to the increased reactivity seen at both stages, astrocytes from late-stage disease showed decreased expression of many transcripts involved in cholesterol homeostasis and decreased cholesterol synthesis has been confirmed in vitro. Staining for the master regulator of cholesterol synthesis, SREBP2, has revealed an increased localisation to the cytoplasm of motor neurons in late-stage SOD1G93A spinal cord, indicating that motor neurons may attempt to synthesise their own cholesterol in response to decreased astrocytic cholesterol provision. Our data reveal that SOD1G93A astrocytes are characterised more by a loss of supportive function than a toxic phenotype during ALS disease progression and future studies should focus upon restorative therapies.

Published
2015
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19. Four-Stage Audit Demonstrating Increased Uptake of HIV Testing in Acute Neurology Admissions Using Staged Practical Interventions.

Author

Dilraj Singh Sokhi, Chantal Oxenham, Rebecca Coates, Mhairi Forbes, Nadi K Gupta, and Daniel J Blackburn

Subjects
Medicine, Science
Abstract

UK National Guidelines (UKNG) advise HIV testing in clinically indicated neurological presentations. We audited the impact of our practical strategies to increase uptake of HIV testing at a regional acute neurology admissions unit.We audited HIV testing in 4 periods over 2 years: before we designed a UKNG-based "HIV testing in Neurology" protocol ("pre-protocol"); after dissemination of the protocol alone ("post-protocol"); post-protocol dissemination combined with both a tailored departmental admissions clerking proforma to prompt for HIV testing & consenting, and regular focussed tutorials to doctors on HIV testing in neurological patients ("post-proforma"); and finally one year after the post-proforma period ("+1 year"). We also looked at the total number of HIV tests sent from the unit during the two-year period. We assessed significance using Fisher's exact test.47.8% of all acute neurology non-stroke admissions were eligible for HIV testing during all the audit periods. Testing rates were as follows: pre-protocol 21.9%; post-protocol 36.6%; post-proforma 83.3%; and at +1 year 65.4% (p

Published
2015
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20. Phosphoenolpyruvate carboxylase identified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism.

Author

Janet Storm, Sonal Sethia, Gavin J Blackburn, Achuthanunni Chokkathukalam, David G Watson, Rainer Breitling, Graham H Coombs, and Sylke Müller

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

Phospoenolpyruvate carboxylase (PEPC) is absent from humans but encoded in the Plasmodium falciparum genome, suggesting that PEPC has a parasite-specific function. To investigate its importance in P. falciparum, we generated a pepc null mutant (D10(Δpepc) ), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10(Δpepc) had a severe growth defect in vitro, which was partially reversed by addition of malate or fumarate, suggesting that pepc may be essential in vivo. Targeted metabolomics using (13)C-U-D-glucose and (13)C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10(Δpepc) and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of (13)C,(15)N-U-glutamine was similar in both parasite lines, although the flux was lower in D10(Δpepc); it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO2 fixing activity of PEPC and suggest that it provides metabolites essential for TCA cycle anaplerosis and the maintenance of cytosolic and mitochondrial redox balance. Moreover, these findings imply that PEPC may be an exploitable target for future drug discovery.

Published
2014
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21. Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer.

Author

Kelly Coffey, Timothy J Blackburn, Susan Cook, Bernard T Golding, Roger J Griffin, Ian R Hardcastle, Lorraine Hewitt, Kety Huberman, Hesta V McNeill, David R Newell, Celine Roche, Claudia A Ryan-Munden, Anna Watson, and Craig N Robson

Subjects
Medicine, Science
Abstract

Tip60 (KAT5) is a histone acetyltransferase (HAT enzyme) involved in multiple cellular processes including transcriptional regulation, DNA damage repair and cell signalling. In prostate cancer, aggressive cases over-express Tip60 which functions as an androgen receptor co-activator via direct acetylation of lysine residues within the KLKK motif of the receptor hinge region. The purpose of this study was to identify and characterise a Tip60 acetylase inhibitor. High-throughput screening revealed an isothiazole that inhibited both Tip60 and p300 HAT activity. This substance (initially identified as 4-methyl-5-bromoisothiazole) and other isothiazoles were synthesised and assayed against Tip60. Although an authentic sample of 4-methyl-5-bromoisothiazole was inactive against Tip60, in an in vitro HAT assay, 1,2-bis(isothiazol-5-yl)disulfane (NU9056) was identified as a relatively potent inhibitor (IC(50) 2 µM). Cellular activity was confirmed by analysis of acetylation of histone and non-histone proteins in a prostate cancer cell line model. NU9056 treatment inhibited cellular proliferation in a panel of prostate cancer cell lines (50% growth inhibition, 8-27 µM) and induced apoptosis via activation of caspase 3 and caspase 9 in a concentration- and time-dependent manner. Also, decreased androgen receptor, prostate specific antigen, p53 and p21 protein levels were demonstrated in response to treatment with NU9056. Furthermore, pre-treatment with NU9056 inhibited both ATM phosphorylation and Tip60 stabilization in response to ionising radiation. Based on the activity of NU9056 and the specificity of the compound towards Tip60 relative to other HAT enzymes, these chemical biology studies have identified Tip60 as a potential therapeutic target for the treatment of prostate cancer.

Published
2012
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