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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. Characterising Alzheimer's Disease With EEG-Based Energy Landscape Analysis.

Author: Dominik Klepl, Fei He 0002, Min Wu 0008, Matteo De Marco, Daniel J. Blackburn, and Ptolemaios G. Sarrigiannis
Published: 2022
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4. 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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5. 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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6. 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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7. 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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8. 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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9. 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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10. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease

Author: Catherine J. Mummery, Anne Börjesson-Hanson, Daniel J. Blackburn, Everard G. B. Vijverberg, Peter Paul De Deyn, Simon Ducharme, Michael Jonsson, Anja Schneider, Juha O. Rinne, Albert C. Ludolph, Ralf Bodenschatz, Holly Kordasiewicz, Eric E. Swayze, Bethany Fitzsimmons, Laurence Mignon, Katrina M. Moore, Chris Yun, Tiffany Baumann, Dan Li, Daniel A. Norris, Rebecca Crean, Danielle L. Graham, Ellen Huang, Elena Ratti, C. Frank Bennett, Candice Junge, Roger M. Lane, Neurology, Amsterdam Neuroscience - Neurodegeneration, and Molecular Neuroscience and Ageing Research (MOLAR)
Subjects: General Medicine, ddc:610, General Biochemistry, Genetics and Molecular Biology
Abstract: Tau plays a key role in Alzheimer’s disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989.
Published: 2023
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11. Characterising Alzheimer's Disease with EEG-based Energy Landscape Analysis.

Author: Dominik Klepl, Fei He 0002, Min Wu 0008, Daniel J. Blackburn, Matteo De Marco, and Ptolemaios G. Sarrigiannis
Published: 2021

12. Peptide Selenocysteine Substitutions Reveal Direct Substrate–Enzyme Interactions at Auxiliary Clusters in Radical S-Adenosyl-<scp>l</scp>-methionine Maturases

Author: Katherine W. Rush, Karsten A. S. Eastman, William M. Kincannon, Ninian J. Blackburn, and Vahe Bandarian
Subjects: Colloid and Surface Chemistry, General Chemistry, Biochemistry, Catalysis
Published: 2023
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13. 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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14. Evolving role of immunotherapy in small cell lung cancer

Author: Elizabeth D, Barrows, Matthew J, Blackburn, and Stephen V, Liu
Subjects: Cancer Research, Lung Neoplasms, Humans, Immunologic Factors, Immunotherapy, Small Cell Lung Carcinoma, Etoposide
Abstract: Small cell lung cancer (SCLC) is a highly lethal subtype of lung cancer with a particularly poor prognosis. For decades, the best available systemic therapy was platinum plus etoposide chemotherapy, which offered frequent but transient responses. Survival gains were finally realized with the addition of immune checkpoint inhibitors to first-line chemotherapy. The phase III IMpower 133 trial showed that the addition of atezolizumab to chemotherapy improved survival. The subsequent CASPIAN trial demonstrated a similar benefit with durvalumab. These results quickly established chemo-immunotherapy as the preferred initial treatment for advanced SCLC, but outcomes remain poor for most patients. Here, we review the current and evolving role of immunotherapy in SCLC and outline emerging strategies poised to further elevate the standard of care.
Published: 2022
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15. 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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16. Hobrecht and His Singers Robert Nosow

Author: Bonnie J Blackburn
Subjects: Music
Published: 2022
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17. Exploration de l’évolution de la consommation d’antibiotiques d’un centre hospitalier universitaire mère-enfant selon la classification AWaRe de l’Organisation mondiale de la santé

Author: H. Roy, Denis Lebel, C. Chabut, Jean-François Bussières, P. Ovetchkine, A. Bleuse, and J. Blackburn
Subjects: Pharmacology, Political science, Pharmaceutical Science, Humanities
Abstract: Resume Contexte Differentes mesures de l’utilisation des antimicrobiens assurent leur bon usage, dans le cadre d’un programme d’antibiogouvernance (aussi appele programme de gerance des antimicrobiens). Objectif L’objectif principal de cette etude etait de decrire la consommation d’antibiotiques au sein d’un etablissement universitaire mere-enfant en utilisant la classification AWaRe sur une periode 15 ans. Methode L’etude descriptive et retrospective a inclus toutes les donnees de consommations d’antibiotiques des patients admis dans un centre hospitalier universitaire mere-enfant du 1er avril 2005 au 31 mars 2021. Des 180 denominations communes d’antibiotiques proposees par l’Organisation mondiale de la sante (OMS), 54 etaient utilisees. Le nombre de jours de traitement (JT) par 1000 jours-presence (JP) a ete calcule par annee, par patientele (chirurgie, pediatrie, oncologie, soins intensifs, soins intensifs neonataux, pouponniere, psychiatrie, readaptation et obstetrique-gynecologie) et de facon globale. Les donnees ont ete classees selon les trois groupes AWaRe de l’OMS. Resultats Un total de 10 489 JT/1000JP a ete collecte sur 15 ans, soit 53,9 % du groupe « Access », 45,2 % du groupe « Watch » et 0,9 % du groupe « Reserve ». Sur 15 ans, on note une faible reduction du recours aux antibiotiques. Le rapport des valeurs de consommation en JT/1000JP de 2020-2021 sur celles de 2005-2006 etait de 0,84 globalement (4743/5653), 0,79 pour le groupe « Access » (286/361), 0,89 pour le groupe « Watch » (270/302) et 0,88 pour le groupe « Reserve » (2,1/2,4). Conclusion La classification AWaRe a ete utilisee afin de decrire la consommation d’antibiotiques au sein d’un centre mere-enfant. La consommation du centre hospitalier etudie se compare avantageusement aux donnees internationales et s’approche des cibles de l’OMS. Cette position peut etre liee a la presence d’un programme structure d’antibiogouvernance mis en place depuis plusieurs annees au sein de notre etablissement. D’autres travaux sont necessaires afin de cibler plus finement les antibiotiques devant profiter d’un meilleur encadrement.
Published: 2022
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18. 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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19. Pre-Steady-State Reactivity of Peptidylglycine Monooxygenase Implicates Ascorbate in Substrate Triggering of the Active Conformer

Author: Evan F. Welch, Katherine W. Rush, Renee J. Arias, and Ninian J. Blackburn
Subjects: Oxygen, Multienzyme Complexes, Electron Spin Resonance Spectroscopy, Ascorbic Acid, Biochemistry, Copper, Mixed Function Oxygenases
Abstract: Peptidylglycine monooxygenase (PHM) is essential for the posttranslational amidation of neuroendocrine peptides. An important aspect of the PHM mechanism is the complete coupling of oxygen reduction to substrate hydroxylation, which implies no oxygen reactivity of the fully reduced enzyme in the absence of peptidyl substrates. As part of studies aimed at investigating this feature of the PHM mechanism, we explored pre-steady-state kinetics using chemical quench (CQ) and rapid freeze-quench (RFQ) studies of the fully reduced ascorbate-free PHM enzyme. First, we confirmed the absence of Cu(I)-enzyme oxidation by O
Published: 2023

20. Deficits in mitochondrial function and glucose metabolism seen in sporadic and familial Alzheimer’s disease derived Astrocytes are ameliorated by increasing hexokinase 1 expression

Author: Simon M Bell, Hollie Wareing, Alexander Hamshaw, Suman De, Elizabeth New, Pamela J Shaw, Matteo De Marco, Annalena Venneri, Daniel J Blackburn, Laura Ferraiuolo, and Heather Mortiboys
Abstract: BackgroundAstrocytes have multiple roles including providing neurons with metabolic substrates and maintaining neurotransmitter synaptic homeostasis. Astrocyte glucose metabolism plays a key role in learning and memory with astrocytic glycogen a key substrate supporting memory encoding. The neuronal support provided by astrocytes has a high metabolic demand. Deficits in astrocytic mitochondrial metabolic functioning and glycolysis could impair neuronal function. Changes to cellular metabolism are seen early in Alzheimer’s disease (AD). Understanding cellular metabolism changes in AD astrocytes could be exploited as a new biomarker or synergistic therapeutic agent when combined with anti-amyloid treatments in AD.MethodsIn this project, we characterised mitochondrial and glycolytic function in astrocytes derived from patients with sporadic (n=6) and familial (PSEN1, n=3) forms of AD. Astrocytes were derived using direct reprogramming methods. Astrocyte metabolic outputs: ATP, and extracellular lactate levels were measured using luminescent and fluorescent protocols. Mitochondrial respiration and glycolytic function were measured using a Seahorse XF Analyzer. Hexokinase deficits identified where corrected by transfecting astrocytes with an adenovirus viral vector containing the hexokinase 1 gene.ResultsThere was a reduction of total cellular ATP of 20% (p=0.05 in sAD astrocytes) and of 48% (pConclusionAD astrocytes have abnormalities in functional capacity of mitochondria and the process of glycolysis. These functional deficits can be improved by correcting hexokinase expression deficits with adenoviral vectors. This suggests that hexokinase 1 deficiency could potentially be exploited as a new therapeutic target for AD.
Published: 2023
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21. New structures reveal flexible dynamics between the subdomains of peptidylglycine monooxygenase. Implications for an open to closed mechanism

Author: Renee J. Arias, Evan F. Welch, and Ninian J. Blackburn
Subjects: Molecular Biology, Biochemistry
Published: 2023
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22. Investigating corneal properties through temporal decorrelation in OCT images (Conference Presentation)

Author: Brecken J. Blackburn, Matthew McPheeters, Michael Jenkins, William J. Dupps, and Andrew M. Rollins
Published: 2023
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23. 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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24. Biological filtration is resilient to wildfire ash-associated organic carbon threats to drinking water treatment

Author: Emma A. J. Blackburn, Sarah E. Dickson-Anderson, William B. Anderson, and Monica B. Emelko
Subjects: Chemistry (miscellaneous), Environmental Chemistry, Chemical Engineering (miscellaneous), Water Science and Technology
Abstract: Elevated/altered levels of dissolved organic matter (DOM) in water can be challenging to treat after wildfire. Biologically-mediated treatment removes some DOM; its ability to remove elevated/altered post-fire dissolved organic carbon (DOC) resulting from wildfire ash was therefore investigated. The treatment of low, medium, and high wildfire ash-amended source waters by bench-scale biofilters was evaluated in duplicate. Turbidity and DOC were typically well-removed during periods of stable operation (effluent turbidity ≤ 0.3 NTU in 93% of samples, average DOC removal ~20% in all biofilters during periods of non- impaired DOC removal). Daily DOC removal across all biofilters was generally consistent, suggesting that the wildfire ash and associated water extractable organic matter did not reduce the DOC biodegradation capacity of the biofilters. DOM fractionation indicated that this was because the low molecular weight neutral (which are known to be readily biodegradable) and biopolymer fractions of DOM were reduced; however, humics were largely recalcitrant. Thus, biological filtration may be resilient to wildfire ash-associated DOM threats to drinking water treatment. However, operational resilience may be compromised if the balance between readily removed and recalcitrant fractions of DOM change, as was observed when baseline source water quality fluctuated for brief periods during the investigation.
Published: 2023
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25. Kernel-based Nonlinear Manifold Learning for EEG Functional Connectivity Analysis with Application to Alzheimer's Disease

Author: R. Gunawardena, P. G. Sarrigiannis, D. J. Blackburn, and F. He
Published: 2022
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26. 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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27. P15 Equitable care: identifying racial disparities in epidural analgesia

Author: J. Blackburn, L. Williams, E. Plunkett, J. Geoghegan, and V. Hodgetts Morton
Subjects: Anesthesiology and Pain Medicine, Obstetrics and Gynecology
Published: 2023
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28. Image enhancement method for digital mammography.

Author: Nikolai V. Slavine, Stephen Seiler, Timothy J. Blackburn, and Robert E. Lenkinski
Published: 2018
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29. Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein–Protein Interaction

Author: Benoit Carbain, Keisha Hearn, Ildiko Maria Buck, Burcu Anil, Sarah J. Cully, Gianni Chessari, Jane A. Endicott, John Lunec, Neil T. Thompson, Juan Castro, Roger J. Griffin, Rhian S. Holvey, Karen Haggerty, Charlotte H. Revill, Ruth H. Bawn, Stephen R. Wedge, Christiane Riedinger, Christopher N. Johnson, Bernard T. Golding, Lynsey Fazal, Ian R. Hardcastle, Mladen Vinkovic, Claire E. Jennings, Jong Sook Ahn, Bian Zhang, Pamela A. Williams, Celine Cano, Suzannah J. Harnor, Ben Cons, Stephen J. Hobson, E. Anscombe, Jeffrey D. St. Denis, Steven Howard, David R. Newell, Emiliano Tamanini, Nicola E. Wilsher, Miller Duncan Charles, Huw D. Thomas, Timothy J. Blackburn, Martin E.M. Noble, Judith Reeks, Yan Zhao, and Luke Bevan
Subjects: Male, Metabolite, Mice, Nude, Antineoplastic Agents, Bone Neoplasms, Isoindoles, Pharmacology, Crystallography, X-Ray, 01 natural sciences, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Drug Stability, In vivo, Cell Line, Tumor, Drug Discovery, Animals, Humans, Structure–activity relationship, neoplasms, Cell Proliferation, 030304 developmental biology, Mice, Inbred BALB C, Osteosarcoma, 0303 health sciences, Molecular Structure, biology, Chemistry, Proto-Oncogene Proteins c-mdm2, Ligand (biochemistry), Xenograft Model Antitumor Assays, Cytostasis, Small molecule, In vitro, 0104 chemical sciences, Macaca fascicularis, 010404 medicinal & biomolecular chemistry, Microsomes, Liver, biology.protein, Molecular Medicine, Mdm2, Female, Protein Multimerization, Tumor Suppressor Protein p53, Protein Binding
Abstract: Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.
Published: 2021
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30. 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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31. 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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32. 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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33. Do Pilot and Demonstration Projects Work? Evidence from a Green Building Program

Author: Juan Moreno-Cruz, Daniel C. Matisoff, Christopher J. Blackburn, Mallory E. Flowers, and Department of Strategic Management and Entrepreneurship
Subjects: Process management, Public Administration, Sociology and Political Science, 05 social sciences, 050301 education, Social learning, General Business, Management and Accounting, Work (electrical), 0502 economics and business, Green building, Business, Peer effects, 050207 economics, 0503 education, Externality
Abstract: Pilot and demonstration (P&D) projects are commonly deployed to catalyze early adoption of technology but are poorly understood in terms of mechanism and impact. We conceptually distinguish unique functions of pilots and demonstrations, then examine whether they accelerate adoption in the case of green building technology. To identify effects on adoption, we develop a difference-in-difference-in-differences strategy, exploiting variation in timing, location, and technologies of green building P&Ds. Results indicate local quarterly green building adoption rates double following completion of a P&D project. Further analyses examine mechanisms driving this effect. The results suggest green building demonstration projects create learning externalities, proliferating technology diffusion in local markets and through building owner networks. Together, these results suggest that investments in P&D projects by public and private actors can lower costs for subsequent adoption.
Published: 2020
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34. RNA-Seq Profiling of Neutrophil-Derived Microvesicles in Alzheimer's Disease Patients Identifies a miRNA Signature That May Impact Blood-Brain Barrier Integrity

Author: Irina Vázquez-Villaseñor, Cynthia I. Smith, Yung J. R. Thang, Paul R. Heath, Stephen B. Wharton, Daniel J. Blackburn, Victoria C. Ridger, and Julie E. Simpson
Subjects: Neutrophils, Organic Chemistry, Endothelial Cells, General Medicine, Catalysis, Computer Science Applications, Inorganic Chemistry, MicroRNAs, Alzheimer Disease, Blood-Brain Barrier, Humans, RNA-Seq, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract: (1) Background: Systemic infection is associated with increased neuroinflammation and accelerated cognitive decline in AD patients. Activated neutrophils produce neutrophil-derived microvesicles (NMV), which are internalised by human brain microvascular endothelial cells and increase their permeability in vitro, suggesting that NMV play a role in blood–brain barrier (BBB) integrity during infection. The current study investigated whether microRNA content of NMV from AD patients is significantly different compared to healthy controls and could impact cerebrovascular integrity. (2) Methods: Neutrophils isolated from peripheral blood samples of five AD and five healthy control donors without systemic infection were stimulated to produce NMV. MicroRNAs isolated from NMV were analysed by RNA-Seq, and online bioinformatic tools were used to identify significantly differentially expressed microRNAs in the NMV. Target and pathway analyses were performed to predict the impact of the candidate microRNAs on vascular integrity. (3) Results: There was no significant difference in either the number of neutrophils (p = 0.309) or the number of NMV (p = 0.3434) isolated from AD donors compared to control. However, 158 microRNAs were significantly dysregulated in AD NMV compared to controls, some of which were associated with BBB dysfunction, including miR-210, miR-20b-5p and miR-126-5p. Pathway analysis revealed numerous significantly affected pathways involved in regulating vascular integrity, including the TGFβ and PDGFB pathways, as well as Hippo, IL-2 and DNA damage signalling. (4) Conclusions: NMV from AD patients contain miRNAs that may alter the integrity of the BBB and represent a novel neutrophil-mediated mechanism for BBB dysfunction in AD and the accelerated cognitive decline seen as a result of a systemic infection.
Published: 2022

35. Clinical activity of PD-1 inhibition in the treatment of locally advanced or metastatic basal cell carcinoma

Author: Gino Kim In, Aparna Nallagangula, Jacob Seung Choi, Lisa Tachiki, Matthew J Blackburn, Stephen Capone, Kathryn B Bollin, Daniel Y. Reuben, Keisuke Shirai, Sandy Zhang-Nunes, Omar Ragab, Alicia Terando, Jenny C. Hu, Han Lee, Shailender Bhatia, Sunandana Chandra, Jose Lutzky, and Geoffrey Thomas Gibney
Subjects: Pharmacology, Cancer Research, Skin Neoplasms, Oncology, Carcinoma, Basal Cell, Immunology, Programmed Cell Death 1 Receptor, Molecular Medicine, Immunology and Allergy, Humans, Hedgehog Proteins, Retrospective Studies
Abstract: BackgroundBasal cell carcinoma (BCC) is the most common malignancy worldwide, yet the management of patients with advanced or metastatic disease is challenging, with limited treatment options. Recently, programmed death receptor 1 (PD-1) inhibition has demonstrated activity in BCC after prior Hedgehog inhibitor treatment.MethodsWe conducted a multicenter, retrospective analysis of BCC patients treated with PD-1 inhibitor therapy. We examined the efficacy and safety of PD-1 therapy, as well as clinical and pathological variables in association with outcomes. Progression-free survival (PFS), overall survival (OS) and duration of response (DOR) were calculated using Kaplan-Meier methodology. Toxicity was graded per Common Terminology Criteria for Adverse Events V.5.0.ResultsA total of 29 patients with BCC who were treated with PD-1 inhibition were included for analysis, including 20 (69.0%) with locally advanced and 9 (31.0%) with metastatic disease. The objective response rate was 31.0%, with five partial responses (17.2%), and four complete responses (13.8%). Nine patients had stable disease (31.0%), with a disease control rate of 62.1%. The median DOR was not reached. Median PFS was 12.2 months (95% CI 0.0 to 27.4). Median OS was 32.4 months (95% CI 18.1 to 46.7). Two patients (6.9%) developed grade 3 or higher toxicity, while four patients (13.8%) discontinued PD-1 inhibition because of toxicity. Higher platelets (p=0.022) and any grade toxicity (p=0.024) were significantly associated with disease control rate.ConclusionsThe clinical efficacy of PD-1 inhibition among patients with advanced or metastatic BCC in this real-world cohort were comparable to published trial data. Further investigation of PD-1 inhibition is needed to define its optimal role for patients with this disease.
Published: 2022

36. The impact of social isolation due to the COVID-19 pandemic on patients with dementia and caregivers

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: caregiver burden, behavioral symptoms, COVID-19, Psychiatry and Mental health, Caregivers, Social Isolation, cognitive dysfunction, social Isolation, Communicable Disease Control, Humans, Dementia, Pandemics, Biological Psychiatry, health care economics and organizations, dementia
Abstract: Objective:Social distancing to limit COVID-19 transmission has led to extensive lifestyle changes, including for people with dementia (PWD). The aim of this study, therefore, was to assess the impact of lockdown on the mental health of PWD and their carers.Methods:Forty-five carers of PWD completed a telephone interview during the baseline assessment of the SOLITUDE study to gather information on life conditions and changes in symptoms of PWD during lockdown. Associations between changes in symptoms of PWD and carers’ concerns and mental health were investigated.Results:About 44% of carers experienced anxiety and irritability and reported changes in behavioural and cognitive symptoms in PWD. These changes were associated with worse carers’ mental health and concerns about faster disease progression (χ2 = 13.542, p < 0.001).Conclusion:COVID-19-related social isolation has had a negative impact on patients’ and carers’ mental health. Potential long-term neurocognitive consequences require further investigation.
Published: 2022

37. Phase decorrelation-OCT for monitoring the depth-dependent effect of accelerated corneal crosslinking

Author: Brecken J. Blackburn, Matthew T. McPheeters, Michael W. Jenkins, William J. Dupps, and Andrew M. Rollins
Published: 2022
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38. Functional neuroimaging of the corneal nerves longitudinally and in vivo

Author: Matthew T. McPheeters, Brecken J. Blackburn, William J. Dupps, Andrew M. Rollins, and Michael W. Jenkins
Published: 2022
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39. The Peripatetic Career of a Converted Jew

Author: BONNIE J. BLACKBURN
Published: 2022
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40. Segmentation of beating embryonic heart structures from 4-D OCT images using deep learning

Author: Shan Ling, Brecken J. Blackburn, Michael W. Jenkins, Michiko Watanabe, Stephanie M. Ford, Maryse Lapierre-Landry, and Andrew M. Rollins
Subjects: Article, Atomic and Molecular Physics, and Optics, Biotechnology
Abstract: Optical coherence tomography (OCT) has been used to investigate heart development because of its capability to image both structure and function of beating embryonic hearts. Cardiac structure segmentation is a prerequisite for the quantification of embryonic heart motion and function using OCT. Since manual segmentation is time-consuming and labor-intensive, an automatic method is needed to facilitate high-throughput studies. The purpose of this study is to develop an image-processing pipeline to facilitate the segmentation of beating embryonic heart structures from a 4-D OCT dataset. Sequential OCT images were obtained at multiple planes of a beating quail embryonic heart and reassembled to a 4-D dataset using image-based retrospective gating. Multiple image volumes at different time points were selected as key-volumes, and their cardiac structures including myocardium, cardiac jelly, and lumen, were manually labeled. Registration-based data augmentation was used to synthesize additional labeled image volumes by learning transformations between key-volumes and other unlabeled volumes. The synthesized labeled images were then used to train a fully convolutional network (U-Net) for heart structure segmentation. The proposed deep learning-based pipeline achieved high segmentation accuracy with only two labeled image volumes and reduced the time cost of segmenting one 4-D OCT dataset from a week to two hours. Using this method, one could carry out cohort studies that quantify complex cardiac motion and function in developing hearts.
Published: 2023
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41. Phase-Decorrelation Optical Coherence Tomography Measurement of Cold-Induced Nuclear Cataract

Author: Brecken J. Blackburn, Matthew T. McPheeters, Michael W. Jenkins, William J. Dupps, and Andrew M. Rollins
Subjects: Ophthalmology, Biomedical Engineering
Published: 2023
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42. 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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43. Intravenous gene transfer throughout the brain of infant Old World primates using AAV

Author: Miguel R. Chuapoco, Nicholas C. Flytzanis, Nick Goeden, J. Christopher Octeau, Kristina M. Roxas, Ken Y. Chan, Jon Scherrer, Janet Winchester, Roy J. Blackburn, Lillian J. Campos, Cynthia M. Arokiaraj, Timothy F. Miles, Min J. Jang, Julia Vendemiatti, Benjamin E. Deverman, James Pickel, Andrew S. Fox, and Viviana Gradinaru
Abstract: Adeno-associated viruses (AAVs) can enable robust and safe gene delivery to the mammalian central nervous system (CNS). While the scientific community has developed numerous neurotropic AAV variants for systemic gene-transfer to the rodent brain, there are few AAVs that efficiently access the CNS of higher order primates. We describe here AAV.CAP-Mac, an engineered AAV variant that enables systemic, brain-wide gene delivery in infants of two Old World primate species—the rhesus macaque (Macaca mulatta) and the green monkey (Chlorocebus sabaeus). We identified CAP-Mac using a multi-species selection strategy, initially screening our library in the adult common marmoset (Callithrix jacchus) and narrowing our pool of test-variants for another round of selection in infant macaques. In individual characterization, CAP-Mac robustly transduces human neurons in vitro and Old World primate neurons in vivo, where it targets all lobes of cortex, the cerebellum, and multiple subcortical regions of disease relevance. We use CAP-Mac for Brainbow-like multicolor labeling of macaque neurons throughout the brain, enabling morphological reconstruction of both medium spiny neurons and cortical pyramidal cells. Because of its broad distribution throughout the brain and high neuronal efficiency in infant Old World primates compared to AAV9, CAP-Mac shows promise for researchers and clinicians alike to unlock novel, noninvasive access to the brain for efficient gene transfer.
Published: 2022
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44. Patient and clinician experience of providing remote memory assessment services

Author: Afifa Aftab, Emad Sidhom, Anna Forrest, Nicola Judge, Benjamin R. Underwood, Kirsty Harkness, and Daniel J. Blackburn
Subjects: Psychiatry and Mental health, Geriatrics and Gerontology
Published: 2021
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45. Characterising spoken interactions of healthy ageing adults with CognoSpeak, a web‐based cognitive assessment tool

Author: Elena Brewer, Bahman Mirheidari, Ronan O'Malley, Markus Reuber, Heidi Christensen, and Daniel J. Blackburn
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published: 2021
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46. Study protocol: SOcial LImitations Turn Up DEmentia (SOLITUDE)—Impact of COVID‐19 social isolation on patients’ cognition and mental health and on carers’ wellbeing

Author: Riccardo Manca, Matteo De Marco, Daniel J Blackburn, Gregor Russell, Kimberly Evans, Sarah Kirkland, Jay Amin, Lynn Davies, Claire Firth, Vanessa Raymont, Amanda Colston, Zoe Collett, Pramod Kumar, Sarra Balckman, Shani McCoy, Rhys Davies, Selina Robertson, Erik van Diepen, and Annalena Venneri
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published: 2021
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47. 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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48. 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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49. pH-Induced Binding of the Axial Ligand in an Engineered CuA Site Favors the πu State

Author: Florencia Emiliani, Damián Alvarez-Paggi, Luciano A. Abriata, Alejandro J. Vila, Kelly N. Chacón, Daniel H. Murgida, Marcos N. Morgada, and Ninian J. Blackburn
Subjects: education.field_of_study, Chemistry, Ph induced, Population, chemistry.chemical_element, Electronic structure, Copper, Inorganic Chemistry, Residue (chemistry), Electron transfer, Crystallography, Deprotonation, Physical and Theoretical Chemistry, Ground state, education
Abstract: CuA centers perform efficient long-range electron transfer. The electronic structure of native CuA sites can be described by a double-potential well with a dominant σu* ground state in fast equilibrium with a less populated πu ground state. Here, we report a CuA mutant in which a lysine was introduced in the axial position. This results in a highly unstable protein with a pH-dependent population of the two ground states. Deep analysis of the high-pH form of this variant shows the stabilization of the πu ground state due to direct binding of the Lys residue to the copper center that we attribute to deprotonation of this residue.
Published: 2019
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50. Catalytic M Center of Copper Monooxygenases Probed by Rational Design. Effects of Selenomethionine and Histidine Substitution on Structure and Reactivity

Author: Katherine B. Alwan, Evan F. Welch, and Ninian J. Blackburn
Subjects: Stereochemistry, Peptidylglycine monooxygenase, Ascorbic Acid, Biochemistry, Article, Mixed Function Oxygenases, Hydroxylation, chemistry.chemical_compound, Copper Transport Proteins, Coordination Complexes, Multienzyme Complexes, Catalytic Domain, Escherichia coli, Histidine, Reactivity (chemistry), Selenomethionine, Ligand, Escherichia coli Proteins, Rational design, Substrate (chemistry), Monooxygenase, Oxygen, Amino Acid Substitution, chemistry, Mutation, Oxidation-Reduction, Copper
Abstract: The M-centers of the mononuclear monooxygenases peptidylglycine monooxygenase (PHM) and dopamine β-monooxygenase (DBM) bind and activate dioxygen on route to substrate hydroxylation. Recently we reported the rational design of a protein-based model wherein the CusF metallochaperone was repurposed via a His to Met mutation to act as a structural and spectroscopic biomimic. The PHM M-site exhibits a number of unusual attributes including a His(2)Met ligand set, a fluxional Cu(I)-S(Met) bond, tight binding of exogenous ligands CO and N(3)(−), and complete coupling of oxygen reduction to substrate hydroxylation even at extremely low turnover rates. In particular, mutation of the Met ligand to His completely eliminates catalytic activity despite the propensity of Cu(I)-His(3) centers to bind and activate dioxygen in other metalloenzyme systems. Here we further develop the CusF-based model to explore methionine variants where Met is replaced by selenomethionine (SeM) and histidine. We examine the effects on coordinate structure and exogenous ligand binding via XAS and EPR and probe the consequences of mutations on redox chemistry via studies on the reduction by ascorbate, and oxidation via molecular oxygen. The M-site model is 3-coordinate in the Cu(I) state and binds CO to form a 4-coordinate carbonyl. In the oxidized forms the coordination changes to tetragonal 5-coordinate with a long axial Met ligand which like the enzymes is undetectable at either the Cu or Se K edges. The EXAFS data at the Se K-edge of the SeM variant provides unique information on the nature of the Cu-methionine bond which is likewise weak and fluxional. Kinetic studies document sluggish reactivity of the Cu(I) complexes with molecular oxygen and rapid rates of reduction of the Cu(II) complexes by ascorbate, indicating a remarkable stability of the Cu(I) state in all three derivatives. The results show little difference between the Met ligand and its SeM and His congeners and suggest that the Met contributes to catalysis in ways that are more complex than simple perturbation of the redox chemistry. Overall the results stimulate critical re-examination of the canonical reaction mechanisms of the mononuclear copper monooxygenases.
Published: 2019
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