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3,062 results on '"Fazakerley, A."'

1. Prior infection with unrelated neurotropic virus exacerbates influenza disease and impairs lung T cell responses

Author

Foo, Isabelle Jia-Hui, Chua, Brendon Y., Clemens, E. Bridie, Chang, So Young, Jia, Xiaoxiao, McQuilten, Hayley A., Yap, Ashley Huey Yiing, Cabug, Aira F., Ashayeripanah, Mitra, McWilliam, Hamish E. G., Villadangos, Jose A., Evrard, Maximilien, Mackay, Laura K., Wakim, Linda M., Fazakerley, John K., Kedzierska, Katherine, and Kedzierski, Lukasz

Published
2024
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2. Limited oxygen in standard cell culture alters metabolism and function of differentiated cells

Author

Tan, Joycelyn, Virtue, Sam, Norris, Dougall M, Conway, Olivia J, Yang, Ming, Bidault, Guillaume, Gribben, Christopher, Lugtu, Fatima, Kamzolas, Ioannis, Krycer, James R, Mills, Richard J, Liang, Lu, Pereira, Conceição, Dale, Martin, Shun-Shion, Amber S, Baird, Harry JM, Horscroft, James A, Sowton, Alice P, Ma, Marcella, Carobbio, Stefania, Petsalaki, Evangelia, Murray, Andrew J, Gershlick, David C, Nathan, James A, Hudson, James E, Vallier, Ludovic, Fisher-Wellman, Kelsey H, Frezza, Christian, Vidal-Puig, Antonio, and Fazakerley, Daniel J

Published
2024
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3. Author Correction: Limited oxygen in standard cell culture alters metabolism and function of differentiated cells

Author

Tan, Joycelyn, Virtue, Sam, Norris, Dougall M, Conway, Olivia J, Yang, Ming, Bidault, Guillaume, Gribben, Christopher, Lugtu, Fatima, Kamzolas, Ioannis, Krycer, James R, Mills, Richard J, Liang, Lu, Pereira, Conceição, Dale, Martin, Shun-Shion, Amber S, Baird, Harry JM, Horscroft, James A, Sowton, Alice P, Ma, Marcella, Carobbio, Stefania, Petsalaki, Evangelia, Murray, Andrew J, Gershlick, David C, Nathan, James A, Hudson, James E, Vallier, Ludovic, Fisher-Wellman, Kelsey H, Frezza, Christian, Vidal-Puig, Antonio, and Fazakerley, Daniel J

Published
2024
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4. Picalm, a novel regulator of GLUT4-trafficking in adipose tissue

Author

Jasmin Gaugel, Neele Haacke, Ratika Sehgal, Markus Jähnert, Wenke Jonas, Anne Hoffmann, Matthias Blüher, Adhideb Ghosh, Falko Noé, Christian Wolfrum, Joycelyn Tan, Annette Schürmann, Daniel J. Fazakerley, and Heike Vogel

Subjects
Picalm, GLUT4-translocation, White adipose tissue, Type 2 diabetes, Obesity, miRNA, Internal medicine, RC31-1245
Abstract

Objective: Picalm (phosphatidylinositol-binding clathrin assembly protein), a ubiquitously expressed clathrin-adapter protein, is a well-known susceptibility gene for Alzheimer's disease, but its role in white adipose tissue (WAT) function has not yet been studied. Transcriptome analysis revealed differential expression of Picalm in WAT of diabetes-prone and diabetes-resistant mice, hence we aimed to investigate the potential link between Picalm expression and glucose homeostasis, obesity-related metabolic phenotypes, and its specific role in insulin-regulated GLUT4 trafficking in adipocytes. Methods: Picalm expression and epigenetic regulation by microRNAs (miRNAs) and DNA methylation were analyzed in WAT of diabetes-resistant (DR) and diabetes-prone (DP) female New Zealand Obese (NZO) mice and in male NZO after time-restricted feeding (TRF) and alternate-day fasting (ADF). PICALM expression in human WAT was evaluated in a cross-sectional cohort and assessed before and after weight loss induced by bariatric surgery. siRNA-mediated knockdown of Picalm in 3T3-L1-cells was performed to elucidate functional outcomes on GLUT4-translocation as well as insulin signaling and adipogenesis. Results: Picalm expression in WAT was significantly lower in DR compared to DP female mice, as well as in insulin-sensitive vs. resistant NZO males, and was also reduced in NZO males following TRF and ADF. Four miRNAs (let-7c, miR-30c, miR-335, miR-344) were identified as potential mediators of diabetes susceptibility-related differences in Picalm expression, while 11 miRNAs (including miR-23a, miR-29b, and miR-101a) were implicated in TRF and ADF effects. Human PICALM expression in adipose tissue was lower in individuals without obesity vs. with obesity and associated with weight-loss outcomes post-bariatric surgery. siRNA-mediated knockdown of Picalm in mature 3T3-L1-adipocytes resulted in amplified insulin-stimulated translocation of the endogenous glucose transporter GLUT4 to the plasma membrane and increased phosphorylation of Akt and Tbc1d4. Moreover, depleting Picalm before and during 3T3-L1 differentiation significantly suppressed adipogenesis, suggesting that Picalm may have distinct roles in the biology of pre- and mature adipocytes. Conclusions: Picalm is a novel regulator of GLUT4-translocation in WAT, with its expression modulated by both genetic predisposition to diabetes and dietary interventions. These findings suggest a potential role for Picalm in improving glucose homeostasis and highlight its relevance as a therapeutic target for metabolic disorders.

Published
2024
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5. Thin current sheet behind the dipolarization front

Author

Nakamura, Baumjohann, M., T. K., Panov, Schmid, Varsani, Apatenkov, S., Sergeev, V. A., Birn, J., Nagai, T., Gabrielse, C., Andre, M., Burch, J. L., Carr, C., Dandouras, I. S, Escoubet, C. P., Fazakerley, N., Giles, B. L., Contel, O. Le, Russell, C. T., and Torbert, R. B.

Subjects
Astrophysics - Earth and Planetary Astrophysics, Physics - Space Physics
Abstract

We report a unique conjugate observation of fast flows and associated current sheet disturbances in the near-Earth magnetotail by MMS (Magnetospheric Multiscale) and Cluster preceding a positive bay onset of a small substorm at ~14:10 UT, Sep. 8, 2018. MMS and Cluster were located both at X ~-14 RE. A dipolarization front (DF) of a localized fast flow was detected by Cluster and MMS, separated in the dawn-dusk direction by ~4 RE, almost simultaneously. Adiabatic electron acceleration signatures revealed from comparison of the energy spectra confirm that both spacecraft encounter the same DF. We analyzed the change in the current sheet structure based on multi-scale multi-point data analysis. The current sheet thickened during the passage of DF, yet, temporally thinned subsequently associated with another flow enhancement centered more on the dawnward side of the initial flow. MMS and Cluster observed intense perpendicular and parallel current in the off-equatorial region mainly during this interval of the current sheet thinning. Maximum field-aligned currents both at MMS and Cluster are directed tailward. Detailed analysis of MMS data showed that the intense field-aligned currents consisted of multiple small-scale intense current layers accompanied by enhanced Hall-currents in the dawn-dusk flow-shear region. We suggest that the current sheet thinning is related to the flow bouncing process and/or to the expansion/activation of reconnection. Based on these mesoscale and small-scale multipoint observations, 3D evolution of the flow and current-sheet disturbances was inferred preceding the development of a substorm current wedge.

Published
2022
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6. Prior infection with unrelated neurotropic virus exacerbates influenza disease and impairs lung T cell responses

Author

Isabelle Jia-Hui Foo, Brendon Y. Chua, E. Bridie Clemens, So Young Chang, Xiaoxiao Jia, Hayley A. McQuilten, Ashley Huey Yiing Yap, Aira F. Cabug, Mitra Ashayeripanah, Hamish E. G. McWilliam, Jose A. Villadangos, Maximilien Evrard, Laura K. Mackay, Linda M. Wakim, John K. Fazakerley, Katherine Kedzierska, and Lukasz Kedzierski

Subjects
Science
Abstract

Abstract Immunity to infectious diseases is predominantly studied by measuring immune responses towards a single pathogen, although co-infections are common. In-depth mechanisms on how co-infections impact anti-viral immunity are lacking, but are highly relevant to treatment and prevention. We established a mouse model of co-infection with unrelated viruses, influenza A (IAV) and Semliki Forest virus (SFV), causing disease in different organ systems. SFV infection eight days before IAV infection results in prolonged IAV replication, elevated cytokine/chemokine levels and exacerbated lung pathology. This is associated with impaired lung IAV-specific CD8+ T cell responses, stemming from suboptimal CD8+ T cell activation and proliferation in draining lymph nodes, and dendritic cell paralysis. Prior SFV infection leads to increased blood brain barrier permeability and presence of IAV RNA in brain, associated with increased trafficking of IAV-specific CD8+ T cells and establishment of long-term tissue-resident memory. Relative to lung IAV-specific CD8+ T cells, brain memory IAV-specific CD8+ T cells have increased TCR repertoire diversity within immunodominant DbNP366 +CD8+ and DbPA224 +CD8+ responses, featuring suboptimal TCR clonotypes. Overall, our study demonstrates that infection with an unrelated neurotropic virus perturbs IAV-specific immune responses and exacerbates IAV disease. Our work provides key insights into therapy and vaccine regimens directed against unrelated pathogens.

Published
2024
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7. The Stability of the Electron Strahl against the Oblique Fast-magnetosonic/Whistler Instability in the Inner Heliosphere

Author

Jeong, Seong-Yeop, Abraham, Joel B., Verscharen, Daniel, Berčič, Laura, Stansby, David, Nicolaou, Georgios, Owen, Christopher J., Wicks, Robert T., Fazakerley, Andrew N., Rueda, Jeffersson A. Agudelo, and Bakrania, Mayur

Subjects
Astrophysics - Solar and Stellar Astrophysics, Physics - Plasma Physics, Physics - Space Physics
Abstract

We analyze the micro-kinetic stability of the electron strahl in the solar wind depending on heliocentric distance. The oblique fast-magnetosonic/whistler (FM/W) instability has emerged in the literature as a key candidate mechanism for the effective scattering of the electron strahl into the electron halo population. Using data from Parker Solar Probe (PSP) and Helios, we compare the measured strahl properties with the analytical thresholds for the oblique FM/W instability in the low- and high-$\beta_{\parallel c}$ regimes, where $\beta_{\parallel c}$ is the ratio of the core parallel thermal pressure to the magnetic pressure. Our PSP and Helios data show that the electron strahl is on average stable against the oblique FM/W instability in the inner heliosphere. Our analysis suggests that the instability, if at all, can only be excited sporadically and on short timescales. We discuss the caveats of our analysis and potential alternative explanations for the observed scattering of the electron strahl in the solar wind. Furthermore, we recommend the numerical evaluation of the stability of individual distributions in the future to account for any uncertainties in the validity of the analytical expressions for the instability thresholds., Comment: Accepted in ApJL

Published
2022
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8. The Kinetic Expansion of Solar-Wind Electrons: Transport Theory and Predictions for the very Inner Heliosphere

Author

Jeong, Seong-Yeop, Verscharen, Daniel, Vocks, Christian, Abraham, Joel B., Owen, Christopher J., Wicks, Robert T., Fazakerley, Andrew N., Stansby, David, Berčič, Laura, Nicolaou, Georgios, Rueda, Jeffersson A. Agudelo, and Bakrania, Mayur

Subjects
Physics - Space Physics
Abstract

We propose a transport theory for the kinetic evolution of solar-wind electrons in the heliosphere. We derive a gyro-averaged kinetic transport equation that accounts for the spherical expansion of the solar wind and the geometry of the Parker-spiral magnetic field. To solve our three-dimensional kinetic equation, we develop a mathematical approach that combines the Crank--Nicolson scheme in velocity space and a finite-difference Euler scheme in configuration space. We initialize our model with isotropic electron distribution functions and calculate the kinetic expansion at heliocentric distances from 5 to 20 solar radii. In our kinetic model, the electrons evolve mainly through the combination of the ballistic particle streaming, the magnetic mirror force, and the electric field. By applying fits to our numerical results, we quantify the parameters of the electron strahl and core part of the electron velocity distributions. The strahl fit parameters show that the density of the electron strahl is around 7% of the total electron density at a distance of 20 solar radii, the strahl bulk velocity and strahl temperature parallel to the background magnetic field stay approximately constant beyond a distance of 15 solar radii, and $\beta_{\parallel s}$ (i.e., the ratio between strahl parallel thermal pressure to the magnetic pressure) is approximately constant with heliocentric distance at a value of about 0.02. We compare our results with data measured by Parker Solar Probe. Furthermore, we provide theoretical evidence that the electron strahl is not scattered by the oblique fast-magnetosonic/whistler instability in the near-Sun environment., Comment: Accepted in ApJ

Published
2021
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11. A journey of exploration to the polar regions of a star: probing the solar poles and the heliosphere from high helio-latitude

Author

Harra, Louise, Andretta, Vincenzo, Appourchaux, Thierry, Baudin, Frédéric, Bellot-Rubio, Luis, Birch, Aaron C., Boumier, Patrick, Cameron, Robert H., Carlsson, Matts, Corbard, Thierry, Davies, Jackie, Fazakerley, Andrew, Fineschi, Silvano, Finsterle, Wolfgang, Gizon, Laurent, Harrison, Richard, Hassler, Donald M., Leibacher, John, Liewer, Paulett, MacDonald, Malcolm, Maksimovic, Milan, Murphy, Neil, Naletto, Giampiero, Nigro, Giuseppina, Owen, Christopher, Martínez-Pillet, Valentín, Rochus, Pierre, Romoli, Marco, Sekii, Takashi, Spadaro, Daniele, Veronig, Astrid, and Schmutz, Werner

Subjects
Astrophysics - Solar and Stellar Astrophysics
Abstract

A mission to view the solar poles from high helio-latitudes (above 60$^\circ$) will build on the experience of Solar Orbiter as well as a long heritage of successful solar missions and instrumentation (e.g. SOHO \cite{SOHO}, STEREO \cite{stereo}, Hinode \cite{Hinode}, SDO \cite{SDO}), but will focus for the first time on the solar poles, enabling scientific investigations that cannot be done by any other mission. One of the major mysteries of the Sun is the solar cycle. The activity cycle of the Sun drives the structure and behaviour of the heliosphere and is, of course, the driver of space weather. In addition, solar activity and variability provides fluctuating input into the Earth climate models, and these same physical processes are applicable to stellar systems hosting exoplanets. One of the main obstructions to understanding the solar cycle, and hence all solar activity, is our current lack of understanding of the polar regions. In this White Paper, submitted to the European Space Agency in response to the Voyage 2050 call, we describe a mission concept that aims to address this fundamental issue. In parallel, we recognise that viewing the Sun from above the polar regions enables further scientific advantages, beyond those related to the solar cycle, such as unique and powerful studies of coronal mass ejection processes, from a global perspective, and studies of coronal structure and activity in polar regions. Not only will these provide important scientific advances for fundamental stellar physics research, they will feed into our understanding of impacts on the Earth and other planets' space environment., Comment: 29 pages, 9 figures, White paper for ESA Voyage 2050

Published
2021
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12. Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q.

Author

Ayer, Anita, Fazakerley, Daniel J, Suarna, Cacang, Maghzal, Ghassan J, Sheipouri, Diba, Lee, Kevin J, Bradley, Michelle C, Fernández-Del-Rio, Lucía, Tumanov, Sergey, Kong, Stephanie My, van der Veen, Jelske N, Yang, Andrian, Ho, Joshua WK, Clarke, Steven G, James, David E, Dawes, Ian W, Vance, Dennis E, Clarke, Catherine F, Jacobs, René L, and Stocker, Roland

Subjects
Coenzyme Q, Insulin resistance, Mitochondria, PEMT, Reactive oxygen species, S-adenosylhomocysteine, S-adenosylmethionine, Animals, Genetic Testing, Mice, Mitochondrial Diseases, Oxidation-Reduction, Phosphatidylethanolamine N-Methyltransferase, Phospholipids, Ubiquinone, Genetics, Nutrition, 5.1 Pharmaceuticals, Metabolic and endocrine, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Pharmacology and Pharmaceutical Sciences
Abstract

Mitochondrial energy production and function rely on optimal concentrations of the essential redox-active lipid, coenzyme Q (CoQ). CoQ deficiency results in mitochondrial dysfunction associated with increased mitochondrial oxidative stress and a range of pathologies. What drives CoQ deficiency in many of these pathologies is unknown, just as there currently is no effective therapeutic strategy to overcome CoQ deficiency in humans. To date, large-scale studies aimed at systematically interrogating endogenous systems that control CoQ biosynthesis and their potential utility to treat disease have not been carried out. Therefore, we developed a quantitative high-throughput method to determine CoQ concentrations in yeast cells. Applying this method to the Yeast Deletion Collection as a genome-wide screen, 30 genes not known previously to regulate cellular concentrations of CoQ were discovered. In combination with untargeted lipidomics and metabolomics, phosphatidylethanolamine N-methyltransferase (PEMT) deficiency was confirmed as a positive regulator of CoQ synthesis, the first identified to date. Mechanistically, PEMT deficiency alters mitochondrial concentrations of one-carbon metabolites, characterized by an increase in the S-adenosylmethionine to S-adenosylhomocysteine (SAM-to-SAH) ratio that reflects mitochondrial methylation capacity, drives CoQ synthesis, and is associated with a decrease in mitochondrial oxidative stress. The newly described regulatory pathway appears evolutionary conserved, as ablation of PEMT using antisense oligonucleotides increases mitochondrial CoQ in mouse-derived adipocytes that translates to improved glucose utilization by these cells, and protection of mice from high-fat diet-induced insulin resistance. Our studies reveal a previously unrecognized relationship between two spatially distinct lipid pathways with potential implications for the treatment of CoQ deficiencies, mitochondrial oxidative stress/dysfunction, and associated diseases.

Published
2021

14. Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake

Author

Williamson, Alice, Norris, Dougall M., Yin, Xianyong, Broadaway, K. Alaine, Moxley, Anne H., Vadlamudi, Swarooparani, Wilson, Emma P., Jackson, Anne U., Ahuja, Vasudha, Andersen, Mette K., Arzumanyan, Zorayr, Bonnycastle, Lori L., Bornstein, Stefan R., Bretschneider, Maxi P., Buchanan, Thomas A., Chang, Yi-Cheng, Chuang, Lee-Ming, Chung, Ren-Hua, Clausen, Tine D., Damm, Peter, Delgado, Graciela E., de Mello, Vanessa D., Dupuis, Josée, Dwivedi, Om P., Erdos, Michael R., Silva, Lilian Fernandes, Frayling, Timothy M., Gieger, Christian, Goodarzi, Mark O., Guo, Xiuqing, Gustafsson, Stefan, Hakaste, Liisa, Hammar, Ulf, Hatem, Gad, Herrmann, Sandra, Højlund, Kurt, Horn, Katrin, Hsueh, Willa A., Hung, Yi-Jen, Hwu, Chii-Min, Jonsson, Anna, Kårhus, Line L., Kleber, Marcus E., Kovacs, Peter, Lakka, Timo A., Lauzon, Marie, Lee, I-Te, Lindgren, Cecilia M., Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Luan, Jian’an, Aly, Dina Mansour, Mathiesen, Elisabeth, Moissl, Angela P., Morris, Andrew P., Narisu, Narisu, Perakakis, Nikolaos, Peters, Annette, Prasad, Rashmi B., Rodionov, Roman N., Roll, Kathryn, Rundsten, Carsten F., Sarnowski, Chloé, Savonen, Kai, Scholz, Markus, Sharma, Sapna, Stinson, Sara E., Suleman, Sufyan, Tan, Jingyi, Taylor, Kent D., Uusitupa, Matti, Vistisen, Dorte, Witte, Daniel R., Walther, Romy, Wu, Peitao, Xiang, Anny H., Zethelius, Björn, Ahlqvist, Emma, Bergman, Richard N., Chen, Yii-Der Ida, Collins, Francis S., Fall, Tove, Florez, Jose C., Fritsche, Andreas, Grallert, Harald, Groop, Leif, Hansen, Torben, Koistinen, Heikki A., Komulainen, Pirjo, Laakso, Markku, Lind, Lars, Loeffler, Markus, März, Winfried, Meigs, James B., Raffel, Leslie J., Rauramaa, Rainer, Rotter, Jerome I., Schwarz, Peter E. H., Stumvoll, Michael, Sundström, Johan, Tönjes, Anke, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Wagner, Robert, Barroso, Inês, Walker, Mark, Grarup, Niels, Boehnke, Michael, Wareham, Nicholas J., Mohlke, Karen L., Wheeler, Eleanor, O’Rahilly, Stephen, Fazakerley, Daniel J., and Langenberg, Claudia

Published
2023
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15. Mosquito transgenerational antiviral immunity is mediated by vertical transfer of virus DNA sequences and RNAi

Author

Julio Rodriguez-Andres, Jason Axford, Ary Hoffmann, and John Fazakerley

Subjects
Entomology, Virology, Science
Abstract

Summary: Mosquitoes are important vectors for transmission of many viruses of public and veterinary health concern. These viruses most commonly have an RNA genome and infect mosquitoes for life. The principal mosquito antiviral response is the RNAi system which destroys virus RNA. Here, we confirm an earlier study that Aedes aegypti mosquitoes infected with positive-stranded RNA arboviruses can transmit specific immunity to their offspring. We show that this trans-generational immunity requires replication of virus RNA and reverse transcription of vRNA to vDNA in the infected parents and intergenerational transfer of vDNA. This vDNA is both genome-integrated and episomal. The episomal vDNA sequences are flanked by retrotransposon long-terminal repeats, predominantly Copia-like. Integrated vDNA sequences are propagated along several generations but specific immunity is effective only for a few generations and correlates with the presence of vRNA and episomal vDNA. This understanding raises new possibilities for the control of important mosquito-borne virus diseases.

Published
2024
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16. A Quasi-Linear Diffusion Model for Resonant Wave-Particle Instability in Homogeneous Plasma

Author

Jeong, Seong-Yeop, Verscharen, Daniel, Wicks, Robert T., and Fazakerley, Andrew N.

Subjects
Physics - Space Physics, Physics - Plasma Physics
Abstract

In this paper, we develop a model to describe the generalized wave-particle instability in a quasi-neutral plasma. We analyze the quasi-linear diffusion equation for particles by expressing an arbitrary unstable and resonant wave mode as a Gaussian wave packet, allowing for an arbitrary direction of propagation with respect to the background magnetic field. We show that the localized energy density of the Gaussian wave packet determines the velocity-space range in which the dominant wave-particle instability and counter-acting damping contributions are effective. Moreover, we derive a relation describing the diffusive trajectories of resonant particles in velocity space under the action of such an interplay between the wave-particle instability and damping. For the numerical computation of our theoretical model, we develop a mathematical approach based on the Crank-Nicolson scheme to solve the full quasi-linear diffusion equation. Our numerical analysis solves the time evolution of the velocity distribution function under the action of a dominant wave-particle instability and counteracting damping and shows a good agreement with our theoretical description. As an application, we use our model to study the oblique fast-magnetosonic/whistler instability, which is proposed as a scattering mechanism for strahl electrons in the solar wind. In addition, we numerically solve the full Fokker-Planck equation to compute the time evolution of the electron-strahl distribution function under the action of Coulomb collisions with core electrons and protons after the collisionless action of the oblique fast-magnetosonic/whistler instability.

Published
2020
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18. Lack of regional pathways impact on surgical delay: Analysis of the Orthopaedic Trauma Hospital Outcomes–Patient Operative Delays (ORTHOPOD) study

Author

Stevenson, Iain, Yoong, Andrel, Rankin, Iain, Dixon, James, Lim, Jun Wei, Sattar, Mariam, McDonald, Stephen, Scott, Sharon, Davies, Helen, Jones, Louise, Nolan, Michelle, McGinty, Rebecca, Stevenson, Helene, Bowe, David, Sim, Francis, Vun, James, Strain, Ritchie, Giannoudis, Vasileios, Talbot, Christopher, Gunn, Christopher, Le, Ha Phuong Do, Bradley, Matthew, Lloyd, William, Hanratty, Brian, Lim, Yizhe, Brookes-Fazakerley, Steven, Varasteh, Amir, Francis, Jonathan, Choudhry, Nameer, Malik, Sheraz, Vats, Amit, Evans, Ashish, Garner, Madeleine, King, Stratton, Zbaeda, Mohamed, Diamond, Owen, Baker, Gavin, Napier, Richard, Guy, Stephen, McCauley, Gordon, King, Samuel, Edwards, Gray, Lin, Benjamin, Davoudi, Kaveh, Haines, Samuel, Raghuvanshi, Manav, Buddhdev, Pranai, Karam, Edward, Nimmyel, Enoch, Ekanem, George, Lateef, Razaq, Jayadeep, JS, Crowther, Ian, Mazur, Karolina, Hafiz, Nauman, Khan, Umair, Chettiar, Krissen, Ibrahim, Amr, Gopal, Prasanth, Tse, Shannon, Lakshmipathy, Raj, Towse, Claudia, Al-Musawi, Hashim, Walmsley, Matthew, Aspinall, Will, Metcalfe, James, Moosa, Aliabbas, Crome, George, Abdelmonem, Mohamed, Lakpriya, Sathya, Hawkins, Amanda, Waugh, Dominic, Kennedy, Matthew, Elsagheir, Mohamed, Kieffer, Will, Oyekan, Adekinte, Collis, Justin, Raad, Marjan, Raut, Pramin, Baker, Markus, Gorvett, Alexander, Gleeson, Hannah, Fahmy, John, Walters, Sam, Tinning, Craig, Chaturvedi, Abhishek, Russell, Heather, Alsawada, Osama, Sinnerton, Robert, Crane, Evan, Warwick, Catherine, Dimascio, Lucia, Ha, Taegyeong Tina, King, Thomas, Engelke, Daniel, Chan, Matthew, Gopireddy, Rajesh, Deo, Sunny, Vasarhelyi, Ferenc, Jhaj, Jasmeet, Dogramatzis, Kostas, McCartney, Sarah, Ardolino, Toni, Fraig, Hossam, Hiller-Smith, Ryan, Haughton, Benjamin, Greenwood, Heather, Stephenson, Nicola, Chong, Yuki, Sleat, Graham, Saedi, Farid, Gouda, Joe, Ravi, Sanjeev Musuvathy, Henari, Shwan, Imam, Sam, Howell, Charles, Theobald, Emma, Wright, Jan, Cormack, Jonathan, Borja, Karlou, Wood, Sandy, Khatri, Amulya, Bretherton, Chris, Tunstall, Charlotte, Lowery, Kathryn, Holmes, Benjamin, Nichols, Jennifer, Bashabayev, Beibit, Wildin, Clare, Sofat, Rajesh, Thiagarajan, Aarthi, Abdelghafour, Karim, Nicholl, James, Abdulhameed, Ahmed, Duke, Kathryn, Maling, Lucy, McCann, Matthew, Masud, Saqib, Marshman, James, Moreau, Joshua, Cheema, Kanwalnaini, Rageeb, Peter Morad, Mirza, Yusuf, Kelly, Andrew, Hassan, Abdul, Christie, Alexander, Davies, Angharad, Tang, Cary, Frostick, Rhiannon, Pemmaraju, Gopalakrishna, Handford, Charles, Chauhan, Govind, Dong, Huan, Choudri, Mohammed Junaid, Loveday, David, Bawa, Akshdeep, Baldwick, Cheryl, Roberton, Andrew, Burden, Eleanor, Nagi, Sameer, Johnson-Lynn, Sarah, Guiot, Luke, Kostusiak, Milosz, Appleyard, Thomas, Mundy, Gary, Basha, Amr, Abdeen, Bashar, Robertson-Smith, Bill, Hussainy, Haydar Al, Reed, Mike, Jamalfar, Aral, Flintoft, Emily, McGovern, Julia, Alcock, Liam, Koziara, Michal, Ollivere, Benjamin, Zheng, Amy, Atia, Fady, Goff, Thomas, Slade, Henry, Teoh, Kar, Shah, Nikhil, Al-Obaedi, Ossama, Jamal, Bilal, Bell, Stuart, Macey, Alistair, Brown, Cameron, Simpson, Cameron, Alho, Roberto, Wilson, Victoria, Lewis, Charlotte, Blyth, Daniel, Chapman, Laura, Woods, Lisa, Katmeh, Rateb, Pasapula, Chandra, Youssef, Hesham, Tan, Jerry, Famure, Steven, Grazette, Andrew, Lloyd, Adam, Beaven, Alastair, Jackowski, Anna, Piper, Dani, Lotfi, Naeil, Chakravarthy, Jagannath, Elzawahry, Ahmed, Trew, Christopher, Neo, Chryssa, Elamin-Ahmed, Hussam, Ashwood, Neil, Wembridge, Kevin, Eyre-Brook, Alistair, Greaves, Amy, Watts, Anna, Stedman, Tobias, Ker, Andrew, Wong, Li Siang, Fullarton, Mairi, Phelan, Sean, Choudry, Qaisar, Qureshi, Alham, Moulton, Lawrence, Cadwallader, Craig, Jenvey, Cara, Aqeel, Aqeel, Francis, Daniel, Simpson, Robin, Phillips, Jon, Matthews, Edward, Thomas, Ellen, Williams, Mark, Jones, Robin, White, Tim, Ketchen, Debbie, Bell, Katrina, Swain, Keri, Chitre, Amol, Lum, Joann, Syam, Kevin, Dupley, Leanne, O'Brien, Sarah, Ford, David, Chapman, Taya, Zahra, Wajiha, Guryel, Enis, McLean, Elizabeth, Dhaliwal, Kawaljit, Regan, Nora, Berstock, James, Deano, Krisna, Donovan, Richard, Blythe, Andrew, Salmon, Jennifer, Craig, Julie, Hickland, Patrick, Matthews, Scott, Brown, William, Borland, Steven, Aminat, Akinsemoyin, Stamp, Gregory, Zaheen, Humayoon, Jaibaji, Monketh, Egglestone, Anthony, Sampalli, Sridhar Rao, Goodier, Henry, Gibb, Julia, Islam, Saad, Ranaboldo, Tom, Theivendran, Kanthan, Bond, Georgina, Richards, Joanna, Sanghera, Ranjodh, Robinson, Karen, Fong, Angus, Tsang, Bonita, Dalgleish, James, McGregor-Riley, Jonathan, Barkley, Sarah, Eardley, William, Elhassan, Almutasim, Tyas, Ben, Chandler, Henry, McVie, James, Wei, Nicholas, Negus, Oliver, Baldock, Thomas, Ravi, Kuppuswamy, Qazzaz, Layth, Mohamed, Muawia, Sivayoganthan, Sriharan, Poole, William, Slade, George, Beaumont, Hugo, Beaumont, Oliver, Taha, Rowa, Lever, Caroline, Sood, Abhay, Moss, Maximillian, Khatir, Mohammed, Trompeter, Alex, Jeffers, Aisha, Brookes, Charlotte, Dadabhoy, Maria, Bhattacharya, Rajarshi, Singh, Abhinav, Beer, Alexander, Hodgson, Harry, Rahman, Kashed, Barter, Reece, Mackinnon, Thomas, Frasquet-Garcia, Antonio, Aldarragi, Ameer, Warner, Christian, Pantelides, Christopher, Attwood, Joseph, Al-Uzri, Muntadhir, Qaoud, Qaiys Abu, Green, Stephen, Osborne, Alex, Griffiths, Alexandra, Emmerson, Benjamin, Slater, Duncan, Altahoo, Hasan, Scott, Helen, Rowland, David, O'Donnell, Janine, Edwards, Taff, Hafez, Ahmed, Khan, Basharat, Crane, Emily, Axenciuc, Rostislav, Al-Habsi, Ruqaiya, McAlinden, Gavan, Sterne, Jonathan, Wong, Matthew Lynch, Patil, Sunit, Ridha, Ali, Rasidovic, Damir, Searle, Henry, Choudhry, Jamaal, Farhan-Alanie, Muhamed M, Tanagho, Andy, Sharma, Sidharth, Thomas, Suresh, Smith, Ben, McMullan, Mark, Winstanley, Robert, Mirza, Saqeb, Hamlin, Katharine, Elgayar, Lugman, Larsen, Matthew P, Eissa, Mohamed, Stevens, Samuel, Hopper, Graeme P, Fang Soh, Terrence Chi, Doorgakant, Ashtin, Yogeswaran, Apimaan, Myatt, Darren, Mahon, Joseph, Ward, Nicholas, Reid, Susan, Deierl, Krisztian, Brogan, Declan, Little, Max, Deakin, Sue, Baines, Elliott, Jones, Georgie, Boulton, Helen, Douglas, Trixie, Jeyaseelan, Lucky, Abdale, Abdirizak, Islam, Aminul, Atkinson, Kate V, Mohamedfaris, Khalid, Mmerem, Kingsley, Jamal, Shazil, Wharton, Danielle, Rana, Anurag, McAllister, Ross, Sasi, Sijith, Thomas, Terin, Pillai, Anand, Flaherty, David, Khan, Munir, Akkena, Sudheer, Shandala, Yaseen, Lankester, Benedict, Hainsworth, Louis, Ahmed, Hussam Elamin, Walshaw, Thomas, Walker, Reece, and Eardley, William G.P.

Published
2023
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19. Targeting natural products to counter the challenge of MRSA

Author

Fazakerley, David, Mur, Luis, and Shah, Ifat Parveen

Subjects
615.7, natural product chemistry, metabolomics, antibiotic, antibacterial, mode of action, MRSA
Abstract

As the global threat of antibiotic resistance grows the approval rate of new antibiotics falls. Pharma companies are dropping their antibiotic research programmes at the time when new antibiotics are needed the most due to antibiotic resistance. Paradoxically antibiotic resistance is one of the many reasons that the discovery of new antibiotics is not lucrative enough for it to be a financially viable pursuit. Promising high-throughput technologies have been unsuccessfully employed to streamline drug discovery due to the lack of novel chemicals within libraries. Natural products have contributed massively to drug discovery in the past although its contribution to the declining number of antibiotics discovered recently has also diminished. To revive the drug discovery pipeline invasive weeds were targeted as a potential source of novel chemical compounds. Three species; Fallopia japonica, Impatiens glandulifera and Rhododendron ponticum were collected. Each species was extracted and fractioned to discover any potential antimicrobial compounds. A particularly active compound 2-methoxy-1,4naphthoquinone (MNQ) was discovered. This compound was found to have a broad range of activity against clinically relevant bacteria. The methoxy group was found to be crucial for the potent antimicrobial activity of this compound. It was also a potent inhibitor of Schistosoma mansoni. Cytotoxicity of this compound was found to be a potential issue with mixed results. High throughput metabolomic methodologies were developed to understand the mechanism by which MNQ inhibits the growth of MRSA. The metabolomic effect of MNQ was compared to other antibiotics, it was found that MNQ had a distinctive metabolomic effect. This unique effect was further investigated with in-depth metabolic pathway analysis using statistical methods twinned with KEGG metabolomics pathway database. Once a tentative mode of action was identified transmission electron microscopy and specific antimicrobial assays were used to support this theory. This research project has discovered a promising antimicrobial and anthelminthic compound and the developed metabolomic methodology yielded a large amount of useful data regarding the mode of action of MNQ and other antibiotics.

Published
2020

20. Phosphoproteomics reveals rewiring of the insulin signaling network and multi-nodal defects in insulin resistance

Author

Daniel J. Fazakerley, Julian van Gerwen, Kristen C. Cooke, Xiaowen Duan, Elise J. Needham, Alexis Díaz-Vegas, Søren Madsen, Dougall M. Norris, Amber S. Shun-Shion, James R. Krycer, James G. Burchfield, Pengyi Yang, Mark R. Wade, Joseph T. Brozinick, David E. James, and Sean J. Humphrey

Subjects
Science
Abstract

The failure of metabolic tissues to respond to insulin is an early marker of type 2 diabetes. Here, the authors show, using global phosphoproteomics, that insulin resistance is caused by a marked rewiring of both canonical and non-canonical insulin signalling, and includes dysregulated GSK3 activity.

Published
2023
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21. ORthopaedic trauma hospital outcomes - Patient operative delays (ORTHOPOD) Study: The management of day-case orthopaedic trauma in the United Kingdom

Author

Stevenson, Iain, Yoong, Andrel, Rankin, Iain, Dixon, James, Lim, Jun Wei, Sattar, Mariam, McDonald, Stephen, Scott, Sharon, Davies, Helen, Jones, Louise, Nolan, Michelle, McGinty, Rebecca, Stevenson, Helene, Bowe, David, Sim, Francis, Vun, James, Strain, Ritchie, Giannoudis, Vasileios, Talbot, Christopher, Gunn, Christopher, Le, Ha Phuong Do, Bradley, Matthew, Lloyd, William, Hanratty, Brian, Lim, Yizhe, Brookes-Fazakerley, Steven, Varasteh, Amir, Francis, Jonathan, Choudhry, Nameer, Malik, Sheraz, Vats, Amit, Evans, Ashish, Garner, Madeleine, King, Stratton, Zbaeda, Mohamed, Diamond, Owen, Baker, Gavin, Napier, Richard, Guy, Stephen, McCauley, Gordon, King, Samuel, Edwards, Gray, Lin, Benjamin, Davoudi, Kaveh, Haines, Samuel, Raghuvanshi, Manav, Buddhdev, Pranai, Karam, Edward, Nimmyel, Enoch, Ekanem, George, Lateef, Razaq, Jayadeep, JS, Crowther, Ian, Mazur, Karolina, Hafiz, Nauman, Khan, Umair, Chettiar, Krissen, Ibrahim, Amr, Gopal, Prasanth, Tse, Shannon, Lakshmipathy, Raj, Towse, Claudia, Al-Musawi, Hashim, Walmsley, Matthew, Aspinall, Will, Metcalfe, James, Moosa, Aliabbas, Crome, George, Abdelmonem, Mohamed, Lakpriya, Sathya, Hawkins, Amanda, Waugh, Dominic, Kennedy, Matthew, Elsagheir, Mohamed, Kieffer, Will, Oyekan, Adekinte, Collis, Justin, Raad, Marjan, Raut, Pramin, Baker, Markus, Gorvett, Alexander, Gleeson, Hannah, Fahmy, John, Walters, Sam, Tinning, Craig, Chaturvedi, Abhishek, Russell, Heather, Alsawada, Osama, Sinnerton, Robert, Crane, Evan, Warwick, Catherine, Dimascio, Lucia, Ha, Taegyeong Tina, King, Thomas, Engelke, Daniel, Chan, Matthew, Gopireddy, Rajesh, Deo, Sunny, Vasarhelyi, Ferenc, Jhaj, Jasmeet, Dogramatzis, Kostas, McCartney, Sarah, Ardolino, Toni, Fraig, Hossam, Hiller-Smith, Ryan, Haughton, Benjamin, Greenwood, Heather, Stephenson, Nicola, Chong, Yuki, Sleat, Graham, Saedi, Farid, Gouda, Joe, Ravi, Sanjeev Musuvathy, Henari, Shwan, Imam, Sam, Howell, Charles, Theobald, Emma, Wright, Jan, Cormack, Jonathan, Borja, Karlou, Wood, Sandy, Khatri, Amulya, Bretherton, Chris, Tunstall, Charlotte, Lowery, Kathryn, Holmes, Benjamin, Nichols, Jennifer, Bashabayev, Beibit, Wildin, Clare, Sofat, Rajesh, Thiagarajan, Aarthi, Abdelghafour, Karim, Nicholl, James, Abdulhameed, Ahmed, Duke, Kathryn, Maling, Lucy, McCann, Matthew, Masud, Saqib, Marshman, James, Moreau, Joshua, Cheema, Kanwalnaini, Rageeb, Peter Morad, Mirza, Yusuf, Kelly, Andrew, Hassan, Abdul, Christie, Alexander, Davies, Angharad, Tang, Cary, Frostick, Rhiannon, Pemmaraju, Gopalakrishna, Handford, Charles, Chauhan, Govind, Dong, Huan, Choudri, Mohammed Junaid, Loveday, David, Bawa, Akshdeep, Baldwick, Cheryl, Roberton, Andrew, Burden, Eleanor, Nagi, Sameer, Johnson-Lynn, Sarah, Guiot, Luke, Kostusiak, Milosz, Appleyard, Thomas, Mundy, Gary, Basha, Amr, Abdeen, Bashar, Robertson-Smith, Bill, Hussainy, Haydar Al, Reed, Mike, Jamalfar, Aral, Flintoft, Emily, McGovern, Julia, Alcock, Liam, Koziara, Michal, Ollivere, Benjamin, Zheng, Amy, Atia, Fady, Goff, Thomas, Slade, Henry, Teoh, Kar, Shah, Nikhil, Al-Obaedi, Ossama, Jamal, Bilal, Bell, Stuart, Macey, Alistair, Brown, Cameron, Simpson, Cameron, Alho, Roberto, Wilson, Victoria, Lewis, Charlotte, Blyth, Daniel, Chapman, Laura, Woods, Lisa, Katmeh, Rateb, Pasapula, Chandra, Youssef, Hesham, Tan, Jerry, Famure, Steven, Grazette, Andrew, Lloyd, Adam, Beaven, Alastair, Jackowski, Anna, Piper, Dani, Lotfi, Naeil, Chakravarthy, Jagannath, Elzawahry, Ahmed, Trew, Christopher, Neo, Chryssa, Elamin-Ahmed, Hussam, Ashwood, Neil, Wembridge, Kevin, Eyre-Brook, Alistair, Greaves, Amy, Watts, Anna, Stedman, Tobias, Ker, Andrew, Wong, Li Siang, Fullarton, Mairi, Phelan, Sean, Choudry, Qaisar, Qureshi, Alham, Moulton, Lawrence, Cadwallader, Craig, Jenvey, Cara, Aqeel, Aqeel, Francis, Daniel, Simpson, Robin, Phillips, Jon, Matthews, Edward, Thomas, Ellen, Williams, Mark, Jones, Robin, White, Tim, Ketchen, Debbie, Bell, Katrina, Swain, Keri, Chitre, Amol, Lum, Joann, Syam, Kevin, Dupley, Leanne, O'Brien, Sarah, Ford, David, Chapman, Taya, Zahra, Wajiha, Guryel, Enis, McLean, Elizabeth, Dhaliwal, Kawaljit, Regan, Nora, Berstock, James, Deano, Krisna, Donovan, Richard, Blythe, Andrew, Salmon, Jennifer, Craig, Julie, Hickland, Patrick, Matthews, Scott, Brown, William, Borland, Steven, Aminat, Akinsemoyin, Stamp, Gregory, Zaheen, Humayoon, Jaibaji, Monketh, Egglestone, Anthony, Sampalli, Sridhar Rao, Goodier, Henry, Gibb, Julia, Islam, Saad, Ranaboldo, Tom, Theivendran, Kanthan, Bond, Georgina, Richards, Joanna, Sanghera, Ranjodh, Robinson, Karen, Fong, Angus, Tsang, Bonita, Dalgleish, James, McGregor-Riley, Jonathan, Barkley, Sarah, Eardley, William, Elhassan, Almutasim, Tyas, Ben, Chandler, Henry, McVie, James, Wei, Nicholas, Negus, Oliver, Baldock, Thomas, Ravi, Kuppuswamy, Qazzaz, Layth, Mohamed, Muawia, Sivayoganthan, Sriharan, Poole, William, Slade, George, Beaumont, Hugo, Beaumont, Oliver, Taha, Rowa, Lever, Caroline, Sood, Abhay, Moss, Maximillian, Khatir, Mohammed, Trompeter, Alex, Jeffers, Aisha, Brookes, Charlotte, Dadabhoy, Maria, Bhattacharya, Rajarshi, Singh, Abhinav, Beer, Alexander, Hodgson, Harry, Rahman, Kashed, Barter, Reece, Mackinnon, Thomas, Frasquet-Garcia, Antonio, Aldarragi, Ameer, Warner, Christian, Pantelides, Christopher, Attwood, Joseph, Al-Uzri, Muntadhir, Qaoud, Qaiys Abu, Green, Stephen, Osborne, Alex, Griffiths, Alexandra, Emmerson, Benjamin, Slater, Duncan, Altahoo, Hasan, Scott, Helen, Rowland, David, O'Donnell, Janine, Edwards, Taff, Hafez, Ahmed, Khan, Basharat, Crane, Emily, Axenciuc, Rostislav, Al-Habsi, Ruqaiya, McAlinden, Gavan, Sterne, Jonathan, Wong, Matthew Lynch, Patil, Sunit, Ridha, Ali, Rasidovic, Damir, Searle, Henry, Choudhry, Jamaal, Farhan-Alanie, Muhamed M, Tanagho, Andy, Sharma, Sidharth, Thomas, Suresh, Smith, Ben, McMullan, Mark, Winstanley, Robert, Mirza, Saqeb, Hamlin, Katharine, Elgayar, Lugman, Larsen, Matthew P, Eissa, Mohamed, Stevens, Samuel, Hopper, Graeme P, Fang Soh, Terrence Chi, Doorgakant, Ashtin, Yogeswaran, Apimaan, Myatt, Darren, Mahon, Joseph, Ward, Nicholas, Reid, Susan, Deierl, Krisztian, Brogan, Declan, Little, Max, Deakin, Sue, Baines, Elliott, Jones, Georgie, Boulton, Helen, Douglas, Trixie, Jeyaseelan, Lucky, Abdale, Abdirizak, Islam, Aminul, Atkinson, Kate V, Mohamedfaris, Khalid, Mmerem, Kingsley, Jamal, Shazil, Wharton, Danielle, Rana, Anurag, McAllister, Ross, Sasi, Sijith, Thomas, Terin, Pillai, Anand, Flaherty, David, Khan, Munir, Akkena, Sudheer, Shandala, Yaseen, Lankester, Benedict, Hainsworth, Louis, Baldock, Thomas E., Walshaw, Thomas, Walker, Reece, and Eardley, William P.G.

Published
2023
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22. What are the fundamental modes of energy transfer and partitioning in the coupled Magnetosphere-Ionosphere system?

Author

Rae, Jonathan, Forsyth, Colin, Dunlop, Malcolm, Palmroth, Minna, Lester, Mark, Friedel, Reiner, Reeves, Geoff, Kepko, Larry, Turc, Lucille, Watt, Clare, Hajdas, Wojciech, Sarris, Theodoros, Saito, Yoshifumi, Santolik, Ondrej, Shprits, Yuri, Wang, Chi, Marchaudon, Aurelie, Berthomier, Matthieu, Marghitu, Octav, Hubert, Benoit, Volwerk, Martin, Kronberg, Elena A., Mann, Ian, Murphy, Kyle, Miles, David, Yao, Zhonghua, Fazakerley, Andrew, Sandhu, Jasmine, Allison, Hayley, and Shi, Quanqi

Published
2022
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23. A journey of exploration to the polar regions of a star: probing the solar poles and the heliosphere from high helio-latitude

Author

Harra, Louise, Andretta, Vincenzo, Appourchaux, Thierry, Baudin, Frédéric, Bellot-Rubio, Luis, Birch, Aaron C., Boumier, Patrick, Cameron, Robert H., Carlsson, Matts, Corbard, Thierry, Davies, Jackie, Fazakerley, Andrew, Fineschi, Silvano, Finsterle, Wolfgang, Gizon, Laurent, Harrison, Richard, Hassler, Donald M., Leibacher, John, Liewer, Paulett, Macdonald, Malcolm, Maksimovic, Milan, Murphy, Neil, Naletto, Giampiero, Nigro, Giuseppina, Owen, Christopher, Martínez-Pillet, Valentín, Rochus, Pierre, Romoli, Marco, Sekii, Takashi, Spadaro, Daniele, Veronig, Astrid, and Schmutz, W.

Published
2022
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28. Anti-scatter grids

Author

Shaw, Daniel, primary, Fazakerley, Jason, additional, Honey, Ian, additional, and Saunders, Debbie, additional

Published
2022
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30. Introduction

Author

Shaw, Daniel, primary, Fazakerley, Jason, additional, Honey, Ian, additional, and Saunders, Debbie, additional

Published
2022
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33. Safety features

Author

Shaw, Daniel, primary, Fazakerley, Jason, additional, Honey, Ian, additional, and Saunders, Debbie, additional

Published
2022
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35. Focal spot

Author

Shaw, Daniel, primary, Fazakerley, Jason, additional, Honey, Ian, additional, and Saunders, Debbie, additional

Published
2022
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36. Exposure time

Author

Shaw, Daniel, primary, Fazakerley, Jason, additional, Honey, Ian, additional, and Saunders, Debbie, additional

Published
2022
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37. Beam quality

Author

Shaw, Daniel, primary, Fazakerley, Jason, additional, Honey, Ian, additional, and Saunders, Debbie, additional

Published
2022
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39. Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections

Author

Divya Narayanan, Nagaraj Moily, Hayley A. McQuilten, Katherine Kedzierska, Jason M. Mackenzie, Lukasz Kedzierski, and John K. Fazakerley

Subjects
alphavirus, interferon, neuron, innate immunity, Medicine, Internal medicine, RC31-1245
Abstract

Virus infections of the central nervous system (CNS) cause important diseases of humans and animals. As in other tissues, innate antiviral responses mediated by type I interferons (IFNs) are crucially important in controlling CNS virus infections. The maturity of neuronal populations is an established critical factor determining the outcome of CNS virus infection. Using primary cultures of mouse cortical neurons, we investigated the relationships between neuronal maturation, type I IFN responses, and the outcome of Semliki Forest virus infection. The virus replicated better, infected more cells, and produced higher titres of infectious viruses in immature neurons. Complete transcriptome analysis demonstrated that resting immature neurons have low transcriptional competence to mount antiviral responses. They had no detectable transcription of the genes Ddx58 and Ifih1, which encode key RNA virus cytoplasmic sensors RIG-I and MDA5, and very low expression of genes encoding key regulators of associated signalling pathways. Upon infection, immature neurons failed to mount an antiviral response as evidenced by their failure to produce chemokines, IFNs, and other cytokines. Treatment of immature neurons with exogenous IFNβ prior to infection resulted in antiviral responses and lower levels of virus replication and infectious virus production. In contrast, resting mature neurons generated a robust antiviral response. This was augmented by pretreatment with IFNβ. Infection of mature neurons derived from IFNAR−/− mice did not make an antiviral response and replicated virus to high levels.

Published
2022
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40. Suprathermal electron strahl widths in the presence of narrow-band whistler waves in the solar wind

Author

Kajdic, P., Alexandrova, O., Maksimovic, M., Lacombe, C., and Fazakerley, A. N.

Subjects
Physics - Space Physics, Astrophysics - Earth and Planetary Astrophysics
Abstract

We perform the first statistical study of the effects of the interaction of suprathermal electrons with narrow-band whistler mode waves in the solar wind. We show that this interaction does occur and that it is associated with enhanced widths of the so called strahl component. The latter is directed along the inter- planetary magnetic field away from the Sun. We do the study by comparing the strahl pitch angle widths in the solar wind at 1AU in the absence of large scale discontinuities and transient structures, such as interplanetary shocks, interplanetary coronal mass ejections, stream interaction regions, etc. during times when the whistler mode waves were present and when they were absent. This is done by using the data from two Cluster instruments: STAFF data in frequency range between ~0.1 Hz and ~200 Hz were used for determining the wave properties and PEACE datasets at twelve central energies between ~57 eV (equivalent to ~10 typical electron thermal energies in the solar wind, E_T ) and ~676 eV (~113 E_T ) for pitch angle measurements. Statistical analysis shows that during the inter- vals with the whistler waves the strahl component on average exhibits pitch angle widths between 2 and 12 degrees larger than during the intervals when these waves are not present. The largest difference is obtained for the electron central energy of ~344 eV (~57 E_T )., Comment: Published in ApJ

Published
2017
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41. Systems-level analysis of insulin action in mouse strains provides insight into tissue- and pathway-specific interactions that drive insulin resistance

Author

Nelson, Marin E., Madsen, Søren, Cooke, Kristen C., Fritzen, Andreas M., Thorius, Ida H., Masson, Stewart W.C., Carroll, Luke, Weiss, Fiona C., Seldin, Marcus M., Potter, Meg, Hocking, Samantha L., Fazakerley, Daniel J., Brandon, Amanda E., Thillainadesan, Senthil, Senior, Alistair M., Cooney, Gregory J., Stöckli, Jacqueline, and James, David E.

Published
2022
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43. A new technique for determining Substorm Onsets and Phases from Indices of the Electrojet (SOPHIE)

Author

Forsyth, C., Rae, I. J., Coxon, J. C., Freeman, M. P., Jackman, C. M., Gjerloev, J., and Fazakerley, A. N.

Subjects
Physics - Space Physics
Abstract

We present a new quantitative technique that determines the times and durations of substorm expansion and recovery phases and possible growth phases based on percentiles of the rate of change of auroral electrojet indices. By being able to prescribe different percentile values, we can determine the onset and duration of substorm phases for smaller or larger variations of the auroral index or indeed any auroral zone ground-based magnetometer data. We apply this technique to the SuperMAG AL (SML) index and compare our expansion phase onset times with previous lists of substorm onsets. We find that more than 50% of events in previous lists occur within 20 min of our identified onsets. We also present a comparison of superposed epoch analyses of SML based on our onsets identified by our technique and existing onset lists and find that the general characteristics of the substorm bay are comparable. By prescribing user-defined thresholds, this automated, quantitative technique represents an improvement over any visual identification of substorm onsets or indeed any fixed threshold method.

Published
2016
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44. Cassini observations of Saturn's southern polar cusp

Author

Arridge, C. S., Jasinski, J. M., Achilleos, N., Bogdanova, Y. V., Bunce, E. J., Cowley, S. W. H., Fazakerley, A. N., Khurana, K. K., Lamy, L., Leisner, J. S., Roussos, E., Russell, C. T., Zarka, P., Coates, A. J., Dougherty, M. K., Jones, G. H., Krimigis, S. M., and Krupp, N.

Subjects
Astrophysics - Earth and Planetary Astrophysics, Physics - Space Physics
Abstract

The magnetospheric cusps are important sites of the coupling of a magnetosphere with the solar wind. The combination of both ground- and space-based observations at Earth have enabled considerable progress to be made in understanding the terrestrial cusp and its role in the coupling of the magnetosphere to the solar wind via the polar magnetosphere. Voyager 2 fully explored Neptune's cusp in 1989 but highly inclined orbits of the Cassini spacecraft at Saturn present the most recent opportunity to repeatedly studying the polar magnetosphere of a rapidly rotating planet. In this paper we discuss observations made by Cassini during two passes through Saturn's southern polar magnetosphere. Our main findings are that i) Cassini directly encounters the southern polar cusp with evidence for the entry of magnetosheath plasma into the cusp via magnetopause reconnection, ii) magnetopause reconnection and entry of plasma into the cusp can occur over a range of solar wind conditions, and iii) double cusp morphologies are consistent with the position of the cusp oscillating in phase with Saturn's global magnetospheric periodicities., Comment: Journal accepted version before copy-editing: 55 pages, 12 figures. Accepted for publication in J. Geophys. Res. Space Physics

Published
2016
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46. Prior infection with unrelated neurotropic virus exacerbates influenza disease and impairs lung T cell responses

Author

Foo, IJ-H, Chua, BY, Clemens, EB, Chang, SY, Jia, X, McQuilten, HA, Yap, AHY, Cabug, AF, Ashayeripanah, M, McWilliam, HEG, Villadangos, JA, Evrard, M, Mackay, LK, Wakim, LM, Fazakerley, JK, Kedzierska, K, Kedzierski, L, Foo, IJ-H, Chua, BY, Clemens, EB, Chang, SY, Jia, X, McQuilten, HA, Yap, AHY, Cabug, AF, Ashayeripanah, M, McWilliam, HEG, Villadangos, JA, Evrard, M, Mackay, LK, Wakim, LM, Fazakerley, JK, Kedzierska, K, and Kedzierski, L

Abstract

Immunity to infectious diseases is predominantly studied by measuring immune responses towards a single pathogen, although co-infections are common. In-depth mechanisms on how co-infections impact anti-viral immunity are lacking, but are highly relevant to treatment and prevention. We established a mouse model of co-infection with unrelated viruses, influenza A (IAV) and Semliki Forest virus (SFV), causing disease in different organ systems. SFV infection eight days before IAV infection results in prolonged IAV replication, elevated cytokine/chemokine levels and exacerbated lung pathology. This is associated with impaired lung IAV-specific CD8+ T cell responses, stemming from suboptimal CD8+ T cell activation and proliferation in draining lymph nodes, and dendritic cell paralysis. Prior SFV infection leads to increased blood brain barrier permeability and presence of IAV RNA in brain, associated with increased trafficking of IAV-specific CD8+ T cells and establishment of long-term tissue-resident memory. Relative to lung IAV-specific CD8+ T cells, brain memory IAV-specific CD8+ T cells have increased TCR repertoire diversity within immunodominant DbNP366+CD8+ and DbPA224+CD8+ responses, featuring suboptimal TCR clonotypes. Overall, our study demonstrates that infection with an unrelated neurotropic virus perturbs IAV-specific immune responses and exacerbates IAV disease. Our work provides key insights into therapy and vaccine regimens directed against unrelated pathogens.

Published
2024

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