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52. Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates

Author

Garnier, Cyrille, Devred, Francois, Byrne, Deborah, Puppo, Remy, Roman, Andrei Yu., Malesinski, Soazig, Golovin, Andrey V., Lebrun, Regine, Ninkina, Natalia N., Tsvetkov, Philipp O., Mécanismes moléculaires dans les démences neurodégénératives (MMDN), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Microbiologie de la Méditerranée (IMM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institute of Physiologically Active Compounds, Russian Academy of Sciences - Chernogolovka, Lomonosov Moscow State University (MSU), School of Biosciences [Cardiff], Cardiff University, Devred, François, École pratique des hautes études (EPHE), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)

Subjects
Amyloid, Binding Sites, Science, [SDV]Life Sciences [q-bio], nutritional and metabolic diseases, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, macromolecular substances, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, nervous system diseases, DNA-Binding Proteins, Molecular Docking Simulation, [SDV] Life Sciences [q-bio], [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Zinc, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Protein Binding
Abstract

Aggregation of TDP-43 (transactive response DNA binding protein 43 kDa) is a hallmark of certain forms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Moreover, intracellular TDP-43-positive inclusions are often found in other neurodegenerative diseases. Recently it was shown that zinc ions can provoke the aggregation of endogenous TDP-43 in cells, allowing to assume a direct interaction of TDP-43 with zinc ions. In this work, we investigated zinc binding to the 102–269 TDP-43 fragment, which comprise the two RNA recognition motifs. Using isothermal titration calorimetry, mass spectrometry, and differential scanning fluorimetry, we showed that zinc binds to this TDP-43 domain with a dissociation constant in the micromolar range and modifies its tertiary structure leading to a decrease of its thermostability. Moreover, the study by dynamic light scattering and negative stain electron microscopy demonstrated that zinc ions induce auto-association process of this TDP-43 fragment into rope-like structures. These structures are thioflavin-T-positive allowing to hypothesize the direct implication of zinc ions in pathological aggregation of TDP-43.

Published
2017

53. The Global Redox Responding RegB/RegA Signal Transduction System Regulates the Genes Involved in Ferrous Iron and Inorganic Sulfur Compound Oxidation of the Acidophilic Acidithiobacillus ferrooxidans

Author

Moinier, Danielle, Byrne, Deborah, Amouric, Agnes, Bonnefoy, Violaine, Laboratoire de chimie bactérienne (LCB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Institut de Microbiologie de la Méditerranée (IMM)

Subjects
Microbiology (medical), inorganic chemicals, two-component signal transducing system, [SDV.GEN]Life Sciences [q-bio]/Genetics, inorganic sulfur compound oxidation, lcsh:QR1-502, Acidithiobacillus ferrooxidans, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Microbiology, lcsh:Microbiology, redox potential, RegB/RegA, [SDE]Environmental Sciences, ferrous iron oxidation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Original Research
Abstract

International audience; The chemical attack of ore by ferric iron and/or sulfuric acid releases valuable metals. The products of these reactions are recycled by iron and sulfur oxidizing microorganisms. These acidophilic chemolithotrophic prokaryotes, among which Acidithiobacillus ferrooxidans, grow at the expense of the energy released from the oxidation of ferrous iron and/or inorganic sulfur compounds (ISCs). In At. ferrooxidans, it has been shown that the expression of the genes encoding the proteins involved in these respiratory pathways is dependent on the electron donor and that the genes involved in iron oxidation are expressed before those responsible for ISCs oxidation when both iron and sulfur are present. Since the redox potential increases during iron oxidation but remains stable during sulfur oxidation, we have put forward the hypothesis that the global redox responding two components system RegB/RegA is involved in this regulation. To understand the mechanism of this system and its role in the regulation of the aerobic respiratory pathways in At. ferrooxidans, the binding of different forms of RegA (DNA binding domain, wild-type, unphosphorylated and phosphorylated-like forms of RegA) on the regulatory region of different genes/operons involved in ferrous iron and ISC oxidation has been analyzed. We have shown that the four RegA forms are able to bind specifically the upstream region of these genes. Interestingly, the phosphorylation of RegA did not change its affinity for its cognate DNA. The transcriptional start site of these genes/operons has been determined. In most cases, the RegA binding site(s) was (were) located upstream from the -35 (or -24) box suggesting that RegA does not interfere with the RNA polymerase binding. Based on the results presented in this report, the role of the RegB/RegA systemin the regulation of the ferrous iron and ISC oxidation pathways in At. ferrooxidans is discussed.

Published
2017

58. A divergent CheW confers plasticity to nucleoid-associated chemosensory arrays

Author

Guiseppi, Annick, primary, Vicente, Juan Jesus, additional, Herrou, Julien, additional, Byrne, Deborah, additional, Barneoud, Aurelie, additional, Moine, Audrey, additional, Espinosa, Leon, additional, Basse, Marie-Jeanne, additional, Molle, Virginie, additional, Mignot, Tâm, additional, Roche, Philippe, additional, and Mauriello, Emilia M.F., additional

Published
2017
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59. The nucleoid as a scaffold for the assembly of bacterial signaling complexes

Author

Moine, Audrey, primary, Espinosa, Leon, additional, Martineau, Eugenie, additional, Yaikhomba, Mutum, additional, Jazleena, P. J., additional, Byrne, Deborah, additional, Biondi, Emanuele G., additional, Notomista, Eugenio, additional, Brilli, Matteo, additional, Molle, Virginie, additional, Gayathri, Pananghat, additional, Mignot, Tâm, additional, and Mauriello, Emilia M. F., additional

Published
2017
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60. mRNA deep sequencing reveals 75 new genes and a complex transcriptional landscape in Mimivirus

Author

Legendre, Matthieu, Audic, Stephane, Poirot, Olivier, Hingamp, Pascal, Seltzer, Virginie, Byrne, Deborah, Lartigue, Audrey, Lescot, Magali, Bernadac, Alain, Poulain, Julie, Abergel, Chantal, and Claverie, Jean-Michel

Subjects
Nucleotide sequencing -- Usage, Genetic transcription -- Research, Protozoa -- Genetic aspects, Messenger RNA -- Research, Health
Published
2010

62. RAISING THE BAR.

Author

Byrne, Deborah

Subjects
*INTELLIGENCE levels
Abstract

The article discusses the architectural design of the Ken Soble Tower in Hamilton, Ontario designed by architect ERA Architects Inc.

Published
2021

66. Engaging Nursing Students in Advance Care Planning.

Author

Overbaugh, Kristen, Byrne, Deborah, and DiGiacomo, Pat

Abstract

The article presents the discussion on nurses responsible for assisting patients in end-of-life decision-making and goals of care conversations including undergraduate nursing students to developing competency in advance care planning (ACP).

Published
2023
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70. Cover Picture: Observation of the FeCN and FeCO Vibrations in the Active Site of [NiFe] Hydrogenase by Nuclear Resonance Vibrational Spectroscopy (Angew. Chem. Int. Ed. 2/2013)

Author

Kamali, Saeed, primary, Wang, Hongxin, additional, Mitra, Devrani, additional, Ogata, Hideaki, additional, Lubitz, Wolfgang, additional, Manor, Brian C., additional, Rauchfuss, Thomas B., additional, Byrne, Deborah, additional, Bonnefoy, Violaine, additional, Jenney, Francis E., additional, Adams, Michael W. W., additional, Yoda, Yoshitaka, additional, Alp, Ercan, additional, Zhao, Jiyong, additional, and Cramer, Stephen P., additional

Published
2012
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71. Titelbild: Detektion von Fe‐CN‐ und Fe‐CO‐Schwingungen im aktiven Zentrum der [NiFe]‐Hydrogenase durch inelastische kernresonante Streuung (Angew. Chem. 2/2013)

Author

Kamali, Saeed, primary, Wang, Hongxin, additional, Mitra, Devrani, additional, Ogata, Hideaki, additional, Lubitz, Wolfgang, additional, Manor, Brian C., additional, Rauchfuss, Thomas B., additional, Byrne, Deborah, additional, Bonnefoy, Violaine, additional, Jenney, Francis E., additional, Adams, Michael W. W., additional, Yoda, Yoshitaka, additional, Alp, Ercan, additional, Zhao, Jiyong, additional, and Cramer, Stephen P., additional

Published
2012
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72. Detektion von Fe‐CN‐ und Fe‐CO‐Schwingungen im aktiven Zentrum der [NiFe]‐Hydrogenase durch inelastische kernresonante Streuung

Author

Kamali, Saeed, primary, Wang, Hongxin, additional, Mitra, Devrani, additional, Ogata, Hideaki, additional, Lubitz, Wolfgang, additional, Manor, Brian C., additional, Rauchfuss, Thomas B., additional, Byrne, Deborah, additional, Bonnefoy, Violaine, additional, Jenney, Francis E., additional, Adams, Michael W. W., additional, Yoda, Yoshitaka, additional, Alp, Ercan, additional, Zhao, Jiyong, additional, and Cramer, Stephen P., additional

Published
2012
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73. Observation of the FeCN and FeCO Vibrations in the Active Site of [NiFe] Hydrogenase by Nuclear Resonance Vibrational Spectroscopy

Author

Kamali, Saeed, primary, Wang, Hongxin, additional, Mitra, Devrani, additional, Ogata, Hideaki, additional, Lubitz, Wolfgang, additional, Manor, Brian C., additional, Rauchfuss, Thomas B., additional, Byrne, Deborah, additional, Bonnefoy, Violaine, additional, Jenney, Francis E., additional, Adams, Michael W. W., additional, Yoda, Yoshitaka, additional, Alp, Ercan, additional, Zhao, Jiyong, additional, and Cramer, Stephen P., additional

Published
2012
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74. Evidence for [2Fe-2S]2+and Linear [3Fe-4S]1+Clusters in a Unique Family of Glycine/Cysteine-Rich Fe-S Proteins from MegavirinaeGiant Viruses

Author

Villalta, Alejandro, Srour, Batoul, Lartigue, Audrey, Clémancey, Martin, Byrne, Deborah, Chaspoul, Florence, Loquet, Antoine, Guigliarelli, Bruno, Blondin, Geneviève, Abergel, Chantal, and Burlat, Bénédicte

Abstract

We have discovered a protein with an amino acid composition exceptionally rich in glycine and cysteine residues in the giant virus mimivirus. This small 6 kDa protein is among the most abundant proteins in the icosahedral 0.75 μm viral particles; it has no predicted function but is probably essential for infection. The aerobically purified red-brownish protein overproduced inEscherichia colicontained both iron and inorganic sulfide. UV/vis, EPR, and Mössbauer studies revealed that the viral protein, coined GciS, accommodated two distinct Fe-S clusters: a diamagnetic S= 0 [2Fe-2S]2+cluster and a paramagnetic S= 5/2 linear [3Fe-4S]1+cluster, a geometry rarely stabilized in native proteins. Orthologs of mimivirus GciS were identified within all clades of Megavirinae, a Mimiviridaesubfamily infecting Acanthamoeba, including the distantly related tupanviruses, and displayed the same spectroscopic features. Thus, these glycine/cysteine-rich proteins form a new family of viral Fe-S proteins sharing unique Fe-S cluster binding properties.

Published
2023
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81. Observation of the FeCN and FeCO Vibrations in the Active Site of [NiFe] Hydrogenase by Nuclear Resonance Vibrational Spectroscopy.

Author

Kamali, Saeed, Wang, Hongxin, Mitra, Devrani, Ogata, Hideaki, Lubitz, Wolfgang, Manor, Brian C., Rauchfuss, Thomas B., Byrne, Deborah, Bonnefoy, Violaine, Jenney, Francis E., Adams, Michael W. W., Yoda, Yoshitaka, Alp, Ercan, Zhao, Jiyong, and Cramer, Stephen P.

Abstract

Nuclear inelastic scattering of 57Fe labeled [NiFe] hydrogenase is shown to give information on different states of the enzyme. It was thus possible to detect and assign FeCO and FeCN bending and stretching vibrations of the active site outside the spectral range of the FeS cluster normal modes. [ABSTRACT FROM AUTHOR]

Published
2013
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82. Detektion von Fe-CN- und Fe-CO-Schwingungen im aktiven Zentrum der [NiFe]-Hydrogenase durch inelastische kernresonante Streuung.

Author

Kamali, Saeed, Wang, Hongxin, Mitra, Devrani, Ogata, Hideaki, Lubitz, Wolfgang, Manor, Brian C., Rauchfuss, Thomas B., Byrne, Deborah, Bonnefoy, Violaine, Jenney, Francis E., Adams, Michael W. W., Yoda, Yoshitaka, Alp, Ercan, Zhao, Jiyong, and Cramer, Stephen P.

Abstract

Blick ins Zentrum: Die Methode der inelastischen kernresonanten Streuung (NRVS) wurde genutzt, um 57Fe ‐ markierte [NiFe] ‐ Hydrogenase in unterschiedlichen Zuständen des Enzyms zu untersuchen. Damit gelang es, die Fe ‐ CO ‐ und Fe ‐ CN ‐ Beuge ‐ und ‐ Streckschwingung außerhalb des Spektralbereichs der Normalmoden der Fe ‐ S ‐ Cluster zu detektieren und zuzuordnen (siehe Spektrum). [ABSTRACT FROM AUTHOR]

Published
2013
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83. Mechanism of Zn 2+ and Ca 2+ Binding to Human S100A1.

Author

Baksheeva, Viktoriia E., Roman, Andrei Yu., Villard, Claude, Devred, François, Byrne, Deborah, Yatoui, Dahbia, Zalevsky, Arthur O., Vologzhannikova, Alisa A., Sokolov, Andrey S., Permyakov, Sergei E., Golovin, Andrey V., Shaw, Gary S., Tsvetkov, Philipp O., and Zernii, Evgeni Yu.

Subjects
ZINC ions, CELL differentiation, CELLULAR control mechanisms, CELLULAR signal transduction, MONOMERS, CALCIUM ions
Abstract

S100A1 is a member of the S100 family of small ubiquitous Ca2+-binding proteins, which participates in the regulation of cell differentiation, motility, and survival. It exists as homo- or heterodimers. S100A1 has also been shown to bind Zn2+, but the molecular mechanisms of this binding are not yet known. In this work, using ESI-MS and ITC, we demonstrate that S100A1 can coordinate 4 zinc ions per monomer, with two high affinity (KD~4 and 770 nm) and two low affinity sites. Using competitive binding experiments between Ca2+ and Zn2+ and QM/MM molecular modeling we conclude that Zn2+ high affinity sites are located in the EF-hand motifs of S100A1. In addition, two lower affinity sites can bind Zn2+ even when the EF-hands are saturated by Ca2+, resulting in a 2Ca2+:S100A1:2Zn2+ conformer. Finally, we show that, in contrast to calcium, an excess of Zn2+ produces a destabilizing effect on S100A1 structure and leads to its aggregation. We also determined a higher affinity to Ca2+ (KD~0.16 and 24 μm) than was previously reported for S100A1, which would allow this protein to function as a Ca2+/Zn2+-sensor both inside and outside cells, participating in diverse signaling pathways under normal and pathological conditions. [ABSTRACT FROM AUTHOR]

Published
2021
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85. Antihypertensive Effect of Carteolol in Thiazide-Treated Hypertensive Subjects.

Author

Velasquez, Manuel T., Byrne, Deborah, and Hoffmann, Raymond G.

Abstract

The antihypertensive effect of carteolol, a new potent nonselective beta-adrenergic antagonist, was investigated in a double-blind, parallel study of 35 patients with mild-to-moderate, essential hypertension whose blood pressures were not adequately controlled with a diuretic. Patients were randomly assigned to receive placebo, carteolol 5 mg, or carteolol 20 mg once a day in addition to hydrochlorothiazide 50 mg for six weeks. Thirty-four patients completed the study: 11 patients received placebo (group 1), 12 patients received carteolol 5 mg (group 2), and 11 patients received carteolol 20 mg (group 3). After six weeks of treatment, the two groups that received carteolol had significant reductions in systolic (SBP) and diastolic (DBP) blood pressure from baseline in both the supine and standing positions. In group 2, mean SBP decreases for supine and standing positions were 11 ± 2.1 and 11 ± 1.9 mm Hg, respectively (P < .01) and 8 ± 1.2 and 9 ± 1.3 mm Hg, respectively, for DBP (P < .01); whereas in group 3, values were 8 ± 2.8 and 12 ± 3.0 mm Hg for SBP, in 5 ± 1.9 and 9 ± 3.1 mm Hg, respectively, for DBP (P < .01). The hypotensive effect was associated with slight but significant decreases in heart rate (P < .01 in group 2 and P < .05 in group 3). Reductions in SBP and DBP with the 20-mg dose were not significantly different from those with the 5-mg dose. With both carteolol regimens, the fall in mean blood pressure did not correlate with the initial level; but in the group taking the 5-mg dose, it did correlate significantly with the decrease in heart rate (r = .72, P < .01). Side effects attributable to carteolol were infrequent and did not persist during continued therapy. It is concluded that carteolol, when combined with hydrochlorothiazide, is effective in reducing blood pressure in patients with mild to moderate hypertension. [ABSTRACT FROM AUTHOR]

Published
1985
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86. Female Genital Mutilation.

Author

Byrne, Deborah

Abstract

The article relates the views of the author and midwife on female genital mutilation for childbirth. She works at a maternity health facility in Salford, England and assisted a woman who had undergone female genital mutilation, which has led her to discover more about female genital mutilation and how it affects women. Evidently, the procedure has a significant life-long negative health impact on women.

Published
2006

87. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial

Author

Angus, Derek C, Derde, Lennie, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen, Beane, Abigail, Van Bentum-Puijk, Wilma, Berry, Lindsay, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Cheng, Allen C, De Jong, Menno, Detry, Michelle, Estcourt, Lise, Fitzgerald, Mark, Goossens, Herman, Green, Cameron, Haniffa, Rashan, Higgins, Alisa M, Horvat, Christopher, Hullegie, Sebastiaan J, Kruger, Peter, Lamontagne, Francois, Lawler, Patrick R, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, Marshall, John, McAuley, Daniel, McGlothin, Anna, McGuinness, Shay, McVerry, Bryan, Montgomery, Stephanie, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, Parke, Rachael, Parker, Jane, Rowan, Kathryn, Sanil, Ashish, Santos, Marlene, Saunders, Christina, Seymour, Christopher, Turner, Anne, Van De Veerdonk, Frank, Venkatesh, Balasubramanian, Zarychanski, Ryan, Berry, Scott, Lewis, Roger J, McArthur, Colin, Webb, Steven A, Gordon, Anthony C, Writing Committee For The REMAP-CAP Investigators, Angus, Derek, Cheng, Allen, Gordon, Anthony, Lawler, Patrick, Webb, Steve, Campbell, Lewis, Forbes, Andrew, Gattas, David, Heritier, Stephane, Higgins, Lisa, Peake, Sandra, Presneill, Jeffrey, Seppelt, Ian, Trapani, Tony, Young, Paul, Bagshaw, Sean, Daneman, Nick, Ferguson, Niall, Misak, Cheryl, Hullegie, Sebastiaan, Pletz, Mathias, Rohde, Gernot, Rowan, Kathy, Alexander, Brian, Basile, Kim, Girard, Timothy, Huang, David, Vates, Jennifer, Beasley, Richard, Fowler, Robert, McGloughlin, Steve, Morpeth, Susan, Paterson, David, Venkatesh, Bala, Uyeki, Tim, Baillie, Kenneth, Duffy, Eamon, Fowler, Rob, Hills, Thomas, Orr, Katrina, Patanwala, Asad, Tong, Steve, Netea, Mihai, Bihari, Shilesh, Carrier, Marc, Fergusson, Dean, Goligher, Ewan, Haidar, Ghady, Hunt, Beverley, Kumar, Anand, Laffan, Mike, Lawless, Patrick, Lother, Sylvain, McCallum, Peter, Middeldopr, Saskia, McQuilten, Zoe, Neal, Matthew, Pasi, John, Schutgens, Roger, Stanworth, Simon, Turgeon, Alexis, Weissman, Alexandra, Adhikari, Neill, Anstey, Matthew, Brant, Emily, De Man, Angelique, Lamonagne, Francois, Masse, Marie-Helene, Udy, Andrew, Arnold, Donald, Begin, Phillipe, Charlewood, Richard, Chasse, Michael, Coyne, Mark, Cooper, Jamie, Daly, James, Gosbell, Iain, Harvala-Simmonds, Heli, Hills, Tom, MacLennan, Sheila, Menon, David, McDyer, John, Pridee, Nicole, Roberts, David, Shankar-Hari, Manu, Thomas, Helen, Tinmouth, Alan, Triulzi, Darrell, Walsh, Tim, Wood, Erica, Calfee, Carolyn, O’Kane, Cecilia, Shyamsundar, Murali, Sinha, Pratik, Thompson, Taylor, Young, Ian, Bihari, Shailesh, Hodgson, Carol, Laffey, John, McAuley, Danny, Orford, Neil, Neto, Ary, Lewis, Roger, McGlothlin, Anna, Miller, Eliza, Singh, Vanessa, Zammit, Claire, Van Bentum Puijk, Wilma, Bouwman, Wietske, Mangindaan, Yara, Parker, Lorraine, Peters, Svenja, Rietveld, Ilse, Raymakers, Kik, Ganpat, Radhika, Brillinger, Nicole, Markgraf, Rene, Ainscough, Kate, Brickell, Kathy, Anjum, Aisha, Lane, Janis-Best, Richards-Belle, Alvin, Saull, Michelle, Wiley, Daisy, Bion, Julian, Connor, Jason, Gates, Simon, Manax, Victoria, Van Der Poll, Tom, Reynolds, John, Van Beurden, Marloes, Effelaar, Evelien, Schotsman, Joost, Boyd, Craig, Harland, Cain, Shearer, Audrey, Wren, Jess, Clermont, Giles, Garrard, William, Kalchthaler, Kyle, King, Andrew, Ricketts, Daniel, Malakoutis, Salim, Marroquin, Oscar, Music, Edvin, Quinn, Kevin, Cate, Heidi, Pearson, Karen, Collins, Joanne, Hanson, Jane, Williams, Penny, Jackson, Shane, Asghar, Adeeba, Dyas, Sarah, Sutu, Mihaela, Murphy, Sheenagh, Williamson, Dawn, Mguni, Nhlanhla, Potter, Alison, Porter, David, Goodwin, Jayne, Rook, Clare, Harrison, Susie, Williams, Hannah, Campbell, Hilary, Lomme, Kaatje, Williamson, James, Sheffield, Jonathan, Van’t Hoff, Willian, McCracken, Phobe, Young, Meredith, Board, Jasmin, Mart, Emma, Knott, Cameron, Smith, Julie, Boschert, Catherine, Affleck, Julia, Ramanan, Mahesh, D’Souza, Ramsy, Pateman, Kelsey, Shakih, Arif, Cheung, Winston, Kol, Mark, Wong, Helen, Shah, Asim, Wagh, Atul, Simpson, Joanne, Duke, Graeme, Chan, Peter, Cartner, Brittney, Hunter, Stephanie, Laver, Russell, Shrestha, Tapaswi, Regli, Adrian, Pellicano, Annamaria, McCullough, James, Tallott, Mandy, Kumar, Nikhil, Panwar, Rakshit, Brinkerhoff, Gail, Koppen, Cassandra, Cazzola, Federica, Brain, Matthew, Mineall, Sarah, Fischer, Roy, Biradar, Vishwanath, Soar, Natalie, White, Hayden, Estensen, Kristen, Morrison, Lynette, Smith, Joanne, Cooper, Melanie, Health, Monash, Shehabi, Yahya, Al-Bassam, Wisam, Hulley, Amanda, Whitehead, Christina, Lowrey, Julie, Gresha, Rebecca, Walsham, James, Meyer, Jason, Harward, Meg, Venz, Ellen, Williams, Patricia, Kurenda, Catherine, Smith, Kirsy, Smith, Margaret, Garcia, Rebecca, Barge, Deborah, Byrne, Deborah, Byrne, Kathleen, Driscoll, Alana, Fortune, Louise, Janin, Pierre, Yarad, Elizabeth, Hammond, Naomi, Bass, Frances, Ashelford, Angela, Waterson, Sharon, Wedd, Steve, McNamara, Robert, Buhr, Heidi, Coles, Jennifer, Schweikert, Sacha, Wibrow, Bradley, Rauniyar, Rashmi, Myers, Erina, Fysh, Ed, Dawda, Ashlish, Mevavala, Bhaumik, Litton, Ed, Ferrier, Janet, Nair, Priya, Buscher, Hergen, Reynolds, Claire, Santamaria, John, Barbazza, Leanne, Homes, Jennifer, Smith, Roger, Murray, Lauren, Brailsford, Jane, Forbes, Loretta, Maguire, Teena, Mariappa, Vasanth, Smith, Judith, Simpson, Scott, Maiden, Matthew, Bone, Allsion, Horton, Michelle, Salerno, Tania, Sterba, Martin, Geng, Wenli, Depuydt, Pieter, De Waele, Jan, De Bus, Liesbet, Fierens, Jan, Bracke, Stephanie, Reeve, Brenda, Dechert, William, Chassé, Michaël, Carrier, François Martin, Boumahni, Dounia, Benettaib, Fatna, Ghamraoui, Ali, Bellemare, David, Cloutier, Ève, Francoeur, Charles, Lamontagne, François, D’Aragon, Frédérick, Carbonneau, Elaine, Leblond, Julie, Vazquez-Grande, Gloria, Marten, Nicole, Wilson, Maggie, Albert, Martin, Serri, Karim, Cavayas, Alexandros, Duplaix, Mathilde, Williams, Virginie, Rochwerg, Bram, Karachi, Tim, Oczkowski, Simon, Centofanti, John, Millen, Tina, Duan, Erick, Tsang, Jennifer, Patterson, Lisa, English, Shane, Watpool, Irene, Porteous, Rebecca, Miezitis, Sydney, McIntyre, Lauralyn, Brochard, Laurent, Burns, Karen, Sandhu, Gyan, Khalid, Imrana, Binnie, Alexandra, Powell, Elizabeth, McMillan, Alexandra, Luk, Tracy, Aref, Noah, Andric, Zdravko, Cviljevic, Sabina, Đimoti, Renata, Zapalac, Marija, Mirković, Gordan, Baršić, Bruno, Kutleša, Marko, Kotarski, Viktor, Vujaklija Brajković, Ana, Babel, Jakša, Sever, Helena, Dragija, Lidija, Kušan, Ira, Vaara, Suvi, Pettilä, Leena, Heinonen, Jonna, Kuitunen, Anne, Karlsson, Sari, Vahtera, Annukka, Kiiski, Heikki, Ristimäki, Sanna, Azaiz, Amine, Charron, Cyril, Godement, Mathieu, Geri, Guillaume, Vieillard-Baron, Antoine, Pourcine, Franck, Monchi, Mehran, Luis, David, Mercier, Romain, Sagnier, Anne, Verrier, Nathalie, Caplin, Cecile, Siami, Shidasp, Aparicio, Christelle, Vautier, Sarah, Jeblaoui, Asma, Fartoukh, Muriel, Courtin, Laura, Labbe, Vincent, Leparco, Cécile, Muller, Grégoire, Nay, Mai-Anh, Kamel, Toufik, Benzekri, Dalila, Jacquier, Sophie, Mercier, Emmanuelle, Chartier, Delphine, Salmon, Charlotte, Dequin, PierreFrançois, Schneider, Francis, Morel, Guillaume, L’Hotellier, Sylvie, Badie, Julio, Berdaguer, Fernando Daniel, Malfroy, Sylvain, Mezher, Chaouki, Bourgoin, Charlotte, Megarbane, Bruno, Voicu, Sebastian, Deye, Nicolas, Malissin, Isabelle, Sutterlin, Laetitia, Guitton, Christophe, Darreau, Cédric, Landais, Mickaël, Chudeau, Nicolas, Robert, Alain, Moine, Pierre, Heming, Nicholas, Maxime, Virginie, Bossard, Isabelle, Nicholier, Tiphaine Barbarin, Colin, Gwenhael, Zinzoni, Vanessa, Maquigneau, Natacham, Finn, André, Kreß, Gabriele, Hoff, Uwe, Friedrich Hinrichs, Carl, Nee, Jens, Hagel, Stefan, Ankert, Juliane, Kolanos, Steffi, Bloos, Frank, Petros, Sirak, Pasieka, Bastian, Kunz, Kevin, Appelt, Peter, Schütze, Bianka, Kluge, Stefan, Nierhaus, Axel, Jarczak, Dominik, Roedl, Kevin, Weismann, Dirk, Frey, Anna, Klinikum Neukölln, Vivantes, Reill, Lorenz, Distler, Michael, Maselli, Astrid, Bélteczki, János, Magyar, István, Fazekas, Ágnes, Kovács, Sándor, Szőke, Viktória, Szigligeti, Gábor, Leszkoven, János, Collins, Daniel, Breen, Patrick, Frohlich, Stephen, Whelan, Ruth, McNicholas, Bairbre, Scully, Michael, Casey, Siobhan, Kernan, Maeve, Doran, Peter, O’Dywer, Michael, Smyth, Michelle, Hayes, Leanne, Hoiting, Oscar, Peters, Marco, Rengers, Els, Evers, Mirjam, Prinssen, Anton, Bosch Ziekenhuis, Jeroen, Simons, Koen, Rozendaal, Wim, Polderman, F, De Jager, P, Moviat, M, Paling, A, Salet, A, Rademaker, Emma, Peters, Anna Linda, De Jonge, E, Wigbers, J, Guilder, E, Butler, M, Cowdrey, Keri-Anne, Newby, Lynette, Chen, Yan, Simmonds, Catherine, McConnochie, Rachael, Ritzema Carter, Jay, Henderson, Seton, Van Der Heyden, Kym, Mehrtens, Jan, Williams, Tony, Kazemi, Alex, Song, Rima, Lai, Vivian, Girijadevi, Dinu, Everitt, Robert, Russell, Robert, Hacking, Danielle, Buehner, Ulrike, Williams, Erin, Browne, Troy, Grimwade, Kate, Goodson, Jennifer, Keet, Owen, Callender, Owen, Martynoga, Robert, Trask, Kara, Butler, Amelia, Schischka, Livia, Young, Chelsea, Lesona, Eden, Olatunji, Shaanti, Robertson, Yvonne, José, Nuno, Amaro Dos Santos Catorze, Teodoro, De Lima Pereira, Tiago Nuno Alfaro, Neves Pessoa, Lucilia Maria, Castro Ferreira, Ricardo Manuel, Pereira Sousa Bastos, Joana Margarida, Aysel Florescu, Simin, Stanciu, Delia, Zaharia, Miahela Florentina, Kosa, Alma Gabriela, Codreanu, Daniel, Marabi, Yaseen, Al Qasim, Eman, Moneer Hagazy, Mohamned, Al Swaidan, Lolowa, Arishi, Hatim, Muñoz-Bermúdez, Rosana, Marin-Corral, Judith, Salazar Degracia, Anna, Parrilla Gómez, Francisco, Mateo López, Maria Isabel, Rodriguez Fernandez, Jorge, Cárcel Fernández, Sheila, Carmona Flores, Rosario, León López, Rafael, De La Fuente Martos, Carmen, Allan, Angela, Polgarova, Petra, Farahi, Neda, McWilliam, Stephen, Hawcutt, Daniel, Rad, Laura, O’Malley, Laura, Whitbread, Jennifer, Kelsall, Olivia, Wild, Laura, Thrush, Jessica, Wood, Hannah, Austin, Karen, Donnelly, Adrian, Kelly, Martin, O’Kane, Sinéad, McClintock, Declan, Warnock, Majella, Johnston, Paul, Gallagher, Linda Jude, Mc Goldrick, Clare, Mc Master, Moyra, Strzelecka, Anna, Jha, Rajeev, Kalogirou, Michael, Ellis, Christine, Krishnamurthy, Vinodh, Deelchand, Vashish, Silversides, Jon, McGuigan, Peter, Ward, Kathryn, O’Neill, Aisling, Finn, Stephanie, Phillips, Barbara, Mullan, Dee, Oritz-Ruiz De Gordoa, Laura, Thomas, Matthew, Sweet, Katie, Grimmer, Lisa, Johnson, Rebekah, Pinnell, Jez, Robinson, Matt, Gledhill, Lisa, Wood, Tracy, Morgan, Matt, Cole, Jade, Hill, Helen, Davies, Michelle, Antcliffe, David, Templeton, Maie, Rojo, Roceld, Coghlan, Phoebe, Smee, Joanna, Mackay, Euan, Cort, Jon, Whileman, Amanda, Spencer, Thomas, Spittle, Nick, Kasipandian, Vidya, Patel, Amit, Allibone, Suzanne, Genetu, Roman Mary, Ramali, Mohamed, Ghosh, Alison, Bamford, Peter, London, Emily, Cawley, Kathryn, Faulkner, Maria, Jeffrey, Helen, Smith, Tim, Brewer, Chris, Gregory, Jane, Limb, James, Cowton, Amanda, O’Brien, Julie, Nikitas, Nikitas, Wells, Colin, Lankester, Liana, Pulletz, Mark, Birch, Jenny, Wiseman, Sophie, Horton, Sarah, Alegria, Ana, Turki, Salah, Elsefi, Tarek, Crisp, Nikki, Allen, Louise, McCullagh, Iain, Robinson, Philip, Hays, Carole, Babio-Galan, Maite, Stevenson, Hannah, Khare, Divya, Pinder, Meredith, Selvamoni, Selvin, Gopinath, Amitha, Pugh, Richard, Menzies, Daniel, Mackay, Callum, Allan, Elizabeth, Davies, Gwyneth, Puxty, Kathryn, McCue, Claire, Cathcart, Susanne, Hickey, Naomi, Ireland, Jane, Yusuff, Hakeem, Isgro, Graziella, Brightling, Chris, Bourne, Michelle, Craner, Michelle, Watters, Malcolm, Prout, Rachel, Davies, Louisa, Pegler, Suzannah, Kyeremeh, Lynsey, Arbane, Gill, Wilson, Karen, Gomm, Linda, Francia, Federica, Brett, Stephen, Sousa Arias, Sonia, Elin Hall, Rebecca, Budd, Joanna, Small, Charlotte, Birch, Janine, Collins, Emma, Henning, Jeremy, Bonner, Stephen, Hugill, Keith, Cirstea, Emanuel, Wilkinson, Dean, Karlikowski, Michal, Sutherland, Helen, Wilhelmsen, Elva, Woods, Jane, North, Julie, Sundaran, Dhinesh, Hollos, Laszlo, Coburn, Susan, Walsh, Joanne, Turns, Margaret, Hopkins, Phil, Smith, John, Noble, Harriet, Depante, Maria Theresa, Clarey, Emma, Laha, Shondipon, Verlander, Mark, Williams, Alexandra, Huckle, Abby, Hall, Andrew, Cooke, Jill, Gardiner-Hill, Caroline, Maloney, Carolyn, Qureshi, Hafiz, Flint, Neil, Nicholson, Sarah, Southin, Sara, Nicholson, Andrew, Borgatta, Barbara, Turner-Bone, Ian, Reddy, Amie, Wilding, Laura, Chamara Warnapura, Loku, Agno Sathianathan, Ronan, Golden, David, Hart, Ciaran, Jones, Jo, Bannard-Smith, Jonathan, Henry, Joanne, Birchall, Katie, Pomeroy, Fiona, Quayle, Rachael, Makowski, Arystarch, Misztal, Beata, Ahmed, Iram, KyereDiabour, Thyra, Naiker, Kevin, Stewart, Richard, Mwaura, Esther, Mew, Louise, Wren, Lynn, Willams, Felicity, Innes, Richard, Doble, Patricia, Hutter, Joanne, Shovelton, Charmaine, Plumb, Benjamin, Szakmany, Tamas, Hamlyn, Vincent, Hawkins, Nancy, Lewis, Sarah, Dell, Amanda, Gopal, Shameer, Ganguly, Saibal, Smallwood, Andrew, Harris, Nichola, Metherell, Stella, Lazaro, Juan Martin, Newman, Tabitha, Fletcher, Simon, Nortje, Jurgens, Fottrell-Gould, Deirdre, Randell, Georgina, Zaman, Mohsin, Elmahi, Einas, Jones, Andrea, Hall, Kathryn, Mills, Gary, Ryalls, Kim, Bowler, Helen, Sall, Jas, Bourne, Richard, Borrill, Zoe, Duncan, Tracey, Lamb, Thomas, Shaw, Joanne, Fox, Claire, Moreno Cuesta, Jeronimo, Xavier, Kugan, Purohit, Dharam, Elhassan, Munzir, Bakthavatsalam, Dhanalakshmi, Rowland, Matthew, Hutton, Paula, Bashyal, Archana, Davidson, Neil, Hird, Clare, Chhablani, Manish, Phalod, Gunjan, Kirkby, Amy, Archer, Simon, Netherton, Kimberley, Reschreiter, Henrik, Camsooksai, Julie, Patch, Sarah, Jenkins, Sarah, Pogson, David, Rose, Steve, Daly, Zoe, Brimfield, Lutece, Claridge, Helen, Parekh, Dhruv, Bergin, Colin, Bates, Michelle, Dasgin, Joanne, McGhee, Christopher, Sim, Malcolm, Hay, Sophie Kennedy, Henderson, Steven, Phull, Mandeep-Kaur, Zaidi, Abbas, Pogreban, Tatiana, Rosaroso, Lace Paulyn, Harvey, Daniel, Lowe, Benjamin, Meredith, Megan, Ryan, Lucy, Hormis, Anil, Walker, Rachel, Collier, Dawn, Kimpton, Sarah, Oakley, Susan, Rooney, Kevin, Rodden, Natalie, Hughes, Emma, Thomson, Nicola, McGlynn, Deborah, Walden, Andrew, Jacques, Nicola, Coles, Holly, Tilney, Emma, Vowell, Emma, Schuster-Bruce, Martin, Pitts, Sally, Miln, Rebecca, Purandare, Laura, Vamplew, Luke, Spivey, Michael, Bean, Sarah, Burt, Karen, Moore, Lorraine, Day, Christopher, Gibson, Charly, Gordon, Elizabeth, Zitter, Letizia, Keenan, Samantha, Baker, Evelyn, Cherian, Shiney, Cutler, Sean, Roynon-Reed, Anna, Harrington, Kate, Raithatha, Ajay, Bauchmuller, Kris, Ahmad, Norfaizan, Grecu, Irina, Trodd, Dawn, Martin, Jane, Wrey Brown, Caroline, Arias, Ana-Marie, Craven, Thomas, Hope, David, Singleton, Jo, Clark, Sarah, Rae, Nicola, Welters, Ingeborg, Hamilton, David Oliver, Williams, Karen, Waugh, Victoria, Shaw, David, Puthucheary, Zudin, Martin, Timothy, Santos, Filipa, Uddin, Ruzena, Somerville, Alastair, Tatham, Kate Colette, Jhanji, Shaman, Black, Ethel, Dela Rosa, Arnold, Howle, Ryan, Tully, Redmond, Drummond, Andrew, Dearden, Joy, Philbin, Jennifer, Munt, Sheila, Vuylsteke, Alain, Chan, Charles, Victor, Saji, Matsa, Ramprasad, Gellamucho, Minerva, Creagh-Brown, Ben, Tooley, Joe, Montague, Laura, De Beaux, Fiona, Bullman, Laetitia, Kersiake, Ian, Demetriou, Carrie, Mitchard, Sarah, Ramos, Lidia, White, Katie, Donnison, Phil, Johns, Maggie, Casey, Ruth, Mattocks, Lehentha, Salisbury, Sarah, Dark, Paul, Claxton, Andrew, McLachlan, Danielle, Slevin, Kathryn, Lee, Stephanie, Hulme, Jonathan, Joseph, Sibet, Kinney, Fiona, Senya, Ho Jan, Oborska, Aneta, Kayani, Abdul, Hadebe, Bernard, Orath Prabakaran, Rajalakshmi, Nichols, Lesley, Thomas, Matt, Worner, Ruth, Faulkner, Beverley, Gendall, Emma, Hayes, Kati, Hamilton-Davies, Colin, Chan, Carmen, Mfuko, Celina, Abbass, Hakam, Mandadapu, Vineela, Leaver, Susannah, Forton, Daniel, Patel, Kamal, Paramasivam, Elankumaran, Powell, Matthew, Gould, Richard, Wilby, Elizabeth, Howcroft, Clare, Banach, Dorota, Fernández De Pinedo Artaraz, Ziortza, Cabreros, Leilani, White, Ian, Croft, Maria, Holland, Nicky, Pereira, Rita, Zaki, Ahmed, Johnson, David, Jackson, Matthew, Garrard, Hywel, Juhaz, Vera, Roy, Alistair, Rostron, Anthony, Woods, Lindsey, Cornell, Sarah, Pillai, Suresh, Harford, Rachel, Rees, Tabitha, Ivatt, Helen, Sundara Raman, Ajay, Davey, Miriam, Lee, Kelvin, Barber, Russell, Chablani, Manish, Brohi, Farooq, Jagannathan, Vijay, Clark, Michele, Purvis, Sarah, Wetherill, Bill, Dushianthan, Ahilanandan, Cusack, Rebecca, De Courcy-Golder, Kim, Smith, Simon, Jackson, Susan, Attwood, Ben, Parsons, Penny, Page, Valerie, Zhao, Xiao Bei, Oza, Deepali, Rhodes, Jonathan, Anderson, Tom, Morris, Sheila, Xia Le Tai, Charlotte, Thomas, Amy, Keen, Alexandra, Digby, Stephen, Cowley, Nicholas, Southern, David, Reddy, Harsha, Campbell, Andy, Watkins, Claire, Smuts, Sara, Touma, Omar, Barnes, Nicky, Alexander, Peter, Felton, Tim, Ferguson, Susan, Sellers, Katharine, Bradley-Potts, Joanne, Yates, David, Birkinshaw, Isobel, Kell, Kay, Marshall, Nicola, and Carr-Knott, Lisa

Subjects
2. Zero hunger, Adult, Male, Hydrocortisone, SARS-CoV-2, Pneumonia, Viral, Anti-Inflammatory Agents, COVID-19, Shock, Middle Aged, Respiration, Artificial, 3. Good health, Betacoronavirus, Intensive Care Units, Treatment Outcome, Adrenal Cortex Hormones, Early Termination of Clinical Trials, Humans, Female, Coronavirus Infections, Pandemics
Abstract

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

88. Becoming.

Author

Byrne, Deborah

Published
2015

89. A Water Birth Denied.

Author

Byrne, Deborah

Abstract

The article relates experiences and views of the author and midwife at a birth center during the labor and water birth by a patient named Lucy. Apparently, another midwife named Catherine did not allow Lucy to birth in the pool as she had not been trained in water births. The author expressed her concern over the fact that some birth center facilities would withheld some facilities to women during labor owing to lack of knowledge or experience on the midwife's part.

Published
2006

90. Cover Picture: Observation of the FeCN and FeCO Vibrations in the Active Site of [NiFe] Hydrogenase by Nuclear Resonance Vibrational Spectroscopy (Angew. Chem. Int. Ed. 2/2013).

Author

Kamali, Saeed, Wang, Hongxin, Mitra, Devrani, Ogata, Hideaki, Lubitz, Wolfgang, Manor, Brian C., Rauchfuss, Thomas B., Byrne, Deborah, Bonnefoy, Violaine, Jenney, Francis E., Adams, Michael W. W., Yoda, Yoshitaka, Alp, Ercan, Zhao, Jiyong, and Cramer, Stephen P.

Abstract

The active site of [NiFe] hydrogenase is an excellent catalyst for hydrogen conversion with an intriguing ability to recover from exposure to dioxygen. In their Communication on page 724 ff., W. Lubitz, S. P. Cramer, and co‐workers use the synchrotron technique of nuclear resonance vibrational spectroscopy to identify normal modes associated with active‐site FeCN and FeCO motion. [ABSTRACT FROM AUTHOR]

Published
2013
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91. Titelbild: Detektion von Fe-CN- und Fe-CO-Schwingungen im aktiven Zentrum der [NiFe]-Hydrogenase durch inelastische kernresonante Streuung (Angew. Chem. 2/2013).

Author

Kamali, Saeed, Wang, Hongxin, Mitra, Devrani, Ogata, Hideaki, Lubitz, Wolfgang, Manor, Brian C., Rauchfuss, Thomas B., Byrne, Deborah, Bonnefoy, Violaine, Jenney, Francis E., Adams, Michael W. W., Yoda, Yoshitaka, Alp, Ercan, Zhao, Jiyong, and Cramer, Stephen P.

Abstract

Das aktive Zentrum der [NiFe] ‐ Hydrogenase ist ein exzellenter Katalysator der Wasserstoffumsetzung mit der faszinierenden Fähigkeit, sich nach Sauerstoffexposition zurückzubilden. W. Lubitz, S. P. Cramer et al. nutzen in ihrer Zuschrift auf S. 752 ff. die Synchrotrontechnik der kernresonanten inelastischen Streuung, um Normalmoden der Fe ‐ CN ‐ und Fe ‐ CO ‐ Bewegung im aktiven Zentrum zu identifizieren. [ABSTRACT FROM AUTHOR]

Published
2013
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92. An enterprise directory solution with DB2.

Author

Shi, Shepherd S. B., Stokes, Ellen, Byrne, Deborah, Corn, Cindy F., Bachmann, David, and Jones, Tom

Subjects
*DIRECTORIES, *COMPUTER network protocols, *COMPUTER software, *COMPUTER network resources
Abstract

LDAP (Lightweight Directory Access Protocol) is a technology that can provide directory services to a range of applications. Directory service, a critical part of distributed computing, is the central point where network services, security services, and applications can form an integrated distributed computing environment. The simplicity of LDAP enables users to store and retrieve data easily from the directory. Nevertheless, as the use of directory services becomes more widespread, directories will need to scale to support millions of entries and millions of user requests with subsecond predictable performance. LDAP directories can be implemented using various storage mechanisms such as flat files, b-trees, or databases. This paper discusses an implementation of LDAP that uses the IBM DATABASE 2 Trademark relational database as the data store and query engine to meet the directory service requirements. Performance analysis is provided to show that a relational database can be used to successfully meet the performance and scale needs of an LDAP directory while remaining secure and competitive with other vendor implementations. [ABSTRACT FROM AUTHOR]

Published
2000
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93. The nucleoid as a scaffold for the assembly of bacterial signaling complexes

Author

Leon Espinosa, Virginie Molle, Audrey Moine, Eugenio Notomista, Emilia M. F. Mauriello, P. Gayathri, Deborah Byrne, Tâm Mignot, Emanuele G. Biondi, Matteo Brilli, P. J. Jazleena, Eugénie Martineau, Mutum Yaikhomba, Laboratoire de chimie bactérienne (LCB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Indian Institute of Science Education and Research Pune (IISER Pune), Institut de Microbiologie de la Méditerranée (IMM), Dipartimento di Biologia, University of Naples Federico II = Università degli studi di Napoli Federico II, Bioinformatique, phylogénie et génomique évolutive (BPGE), Département PEGASE [LBBE] (PEGASE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), ANR-14-CE11-0023,Bacterial sensing,Perception microbiénne pendant les comportements sociaux(2014), Università degli studi di Napoli Federico II, Universita degli Studi di Padova, Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Moine, Audrey, Espinosa, Leon, Martineau, Eugenie, Yaikhomba, Mutum, Jazleena, P. J., Byrne, Deborah, Biondi, Emanuele, Notomista, Eugenio, Brilli, Matteo, Molle, Virginie, Gayathri, Pananghat, Mignot, Tâm, Mauriello, Emilia M. F., Università degli Studi di Padova = University of Padua (Unipd), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon

Subjects
Cancer Research, Scaffold, Cytoplasm, Cell, Restriction Fragment Mapping, chemistry.chemical_compound, Cell Signaling, Electrophoretic mobility shift assay, Myxococcus xanthus, Genetics (clinical), Staining, 0303 health sciences, Chemotaxis, Chemotaxi, Myxococcus xanthu, Specimen preparation and treatment, Cell staining, Cell biology, medicine.anatomical_structure, Cell polarity, Chemical characterization, Protein Binding, Signal Transduction, Research Article, Cell Physiology, animal structures, lcsh:QH426-470, Bacterial Protein, DNA binding assay, Biology, Research and Analysis Methods, Central region, 03 medical and health sciences, Electrophoretic Techniques, Genetic, Bacterial Proteins, medicine, Binding analysis, Membrane receptor signaling, Nucleoid, Molecular Biology Techniques, Molecular Biology, Cell fusion, 030304 developmental biology, 030306 microbiology, Gene Mapping, fungi, DAPI staining, Biology and Life Sciences, Cell Biology, biology.organism_classification, Gel electrophoresis, Ecology, Evolution, Behavior and Systematic, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, lcsh:Genetics, chemistry, Nuclear staining, bacteria, DNA
Abstract

The FrzCD chemoreceptor from the gliding bacterium Myxococcus xanthus forms cytoplasmic clusters that occupy a large central region of the cell body also occupied by the nucleoid. In this work, we show that FrzCD directly binds to the nucleoid with its N-terminal positively charged tail and recruits active signaling complexes at this location. The FrzCD binding to the nucleoid occur in a DNA-sequence independent manner and leads to the formation of multiple distributed clusters that explore constrained areas. This organization might be required for cooperative interactions between clustered receptors as observed in membrane-bound chemosensory arrays., Author summary In this work, we show that the cytoplasmic chemoreceptor of the Frz chemosensory system, FrzCD, does not bind the cytoplasmic membrane like most MCPs but bind the bacterial nucleoid directly, thus forming distributed protein clusters also containing the FrzE kinase. In vitro and in vivo experiments show that DNA-binding is not sequence-specific and is mediated by a basic aminoacid sequence of the FrzCD N-terminal domain. The deletion of this motif abolishes FrzCD DNA-binding and cooperativity in the response to signals. This work shows the importance of the nucleoid in the organization and functioning of cytoplasmic signaling systems in bacteria.

Published
2017

94. Evidence for [2Fe-2S] 2+ and Linear [3Fe-4S] 1+ Clusters in a Unique Family of Glycine/Cysteine-Rich Fe-S Proteins from Megavirinae Giant Viruses.

Author

Villalta A, Srour B, Lartigue A, Clémancey M, Byrne D, Chaspoul F, Loquet A, Guigliarelli B, Blondin G, Abergel C, and Burlat B

Subjects
Cysteine chemistry, Glycine, Spectrum Analysis, Electron Spin Resonance Spectroscopy, Iron-Sulfur Proteins chemistry, Giant Viruses metabolism
Abstract

We have discovered a protein with an amino acid composition exceptionally rich in glycine and cysteine residues in the giant virus mimivirus. This small 6 kDa protein is among the most abundant proteins in the icosahedral 0.75 μm viral particles; it has no predicted function but is probably essential for infection. The aerobically purified red-brownish protein overproduced in Escherichia coli contained both iron and inorganic sulfide. UV/vis, EPR, and Mössbauer studies revealed that the viral protein, coined GciS, accommodated two distinct Fe-S clusters: a diamagnetic S = 0 [2Fe-2S] 2+ cluster and a paramagnetic S = 5/2 linear [3Fe-4S] 1+ cluster, a geometry rarely stabilized in native proteins. Orthologs of mimivirus GciS were identified within all clades of Megavirinae , a Mimiviridae subfamily infecting Acanthamoeba , including the distantly related tupanviruses, and displayed the same spectroscopic features. Thus, these glycine/cysteine-rich proteins form a new family of viral Fe-S proteins sharing unique Fe-S cluster binding properties.

Published
2023
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95. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Author

Angus DC, Derde L, Al-Beidh F, Annane D, Arabi Y, Beane A, van Bentum-Puijk W, Berry L, Bhimani Z, Bonten M, Bradbury C, Brunkhorst F, Buxton M, Buzgau A, Cheng AC, de Jong M, Detry M, Estcourt L, Fitzgerald M, Goossens H, Green C, Haniffa R, Higgins AM, Horvat C, Hullegie SJ, Kruger P, Lamontagne F, Lawler PR, Linstrum K, Litton E, Lorenzi E, Marshall J, McAuley D, McGlothin A, McGuinness S, McVerry B, Montgomery S, Mouncey P, Murthy S, Nichol A, Parke R, Parker J, Rowan K, Sanil A, Santos M, Saunders C, Seymour C, Turner A, van de Veerdonk F, Venkatesh B, Zarychanski R, Berry S, Lewis RJ, McArthur C, Webb SA, Gordon AC, Al-Beidh F, Angus D, Annane D, Arabi Y, van Bentum-Puijk W, Berry S, Beane A, Bhimani Z, Bonten M, Bradbury C, Brunkhorst F, Buxton M, Cheng A, De Jong M, Derde L, Estcourt L, Goossens H, Gordon A, Green C, Haniffa R, Lamontagne F, Lawler P, Litton E, Marshall J, McArthur, McAuley D, McGuinness S, McVerry B, Montgomery S, Mouncey P, Murthy S, Nichol A, Parke R, Rowan K, Seymour C, Turner A, van de Veerdonk F, Webb S, Zarychanski R, Campbell L, Forbes A, Gattas D, Heritier S, Higgins L, Kruger P, Peake S, Presneill J, Seppelt I, Trapani T, Young P, Bagshaw S, Daneman N, Ferguson N, Misak C, Santos M, Hullegie S, Pletz M, Rohde G, Rowan K, Alexander B, Basile K, Girard T, Horvat C, Huang D, Linstrum K, Vates J, Beasley R, Fowler R, McGloughlin S, Morpeth S, Paterson D, Venkatesh B, Uyeki T, Baillie K, Duffy E, Fowler R, Hills T, Orr K, Patanwala A, Tong S, Netea M, Bihari S, Carrier M, Fergusson D, Goligher E, Haidar G, Hunt B, Kumar A, Laffan M, Lawless P, Lother S, McCallum P, Middeldopr S, McQuilten Z, Neal M, Pasi J, Schutgens R, Stanworth S, Turgeon A, Weissman A, Adhikari N, Anstey M, Brant E, de Man A, Lamonagne F, Masse MH, Udy A, Arnold D, Begin P, Charlewood R, Chasse M, Coyne M, Cooper J, Daly J, Gosbell I, Harvala-Simmonds H, Hills T, MacLennan S, Menon D, McDyer J, Pridee N, Roberts D, Shankar-Hari M, Thomas H, Tinmouth A, Triulzi D, Walsh T, Wood E, Calfee C, O’Kane C, Shyamsundar M, Sinha P, Thompson T, Young I, Bihari S, Hodgson C, Laffey J, McAuley D, Orford N, Neto A, Detry M, Fitzgerald M, Lewis R, McGlothlin A, Sanil A, Saunders C, Berry L, Lorenzi E, Miller E, Singh V, Zammit C, van Bentum Puijk W, Bouwman W, Mangindaan Y, Parker L, Peters S, Rietveld I, Raymakers K, Ganpat R, Brillinger N, Markgraf R, Ainscough K, Brickell K, Anjum A, Lane JB, Richards-Belle A, Saull M, Wiley D, Bion J, Connor J, Gates S, Manax V, van der Poll T, Reynolds J, van Beurden M, Effelaar E, Schotsman J, Boyd C, Harland C, Shearer A, Wren J, Clermont G, Garrard W, Kalchthaler K, King A, Ricketts D, Malakoutis S, Marroquin O, Music E, Quinn K, Cate H, Pearson K, Collins J, Hanson J, Williams P, Jackson S, Asghar A, Dyas S, Sutu M, Murphy S, Williamson D, Mguni N, Potter A, Porter D, Goodwin J, Rook C, Harrison S, Williams H, Campbell H, Lomme K, Williamson J, Sheffield J, van’t Hoff W, McCracken P, Young M, Board J, Mart E, Knott C, Smith J, Boschert C, Affleck J, Ramanan M, D’Souza R, Pateman K, Shakih A, Cheung W, Kol M, Wong H, Shah A, Wagh A, Simpson J, Duke G, Chan P, Cartner B, Hunter S, Laver R, Shrestha T, Regli A, Pellicano A, McCullough J, Tallott M, Kumar N, Panwar R, Brinkerhoff G, Koppen C, Cazzola F, Brain M, Mineall S, Fischer R, Biradar V, Soar N, White H, Estensen K, Morrison L, Smith J, Cooper M, Health M, Shehabi Y, Al-Bassam W, Hulley A, Whitehead C, Lowrey J, Gresha R, Walsham J, Meyer J, Harward M, Venz E, Williams P, Kurenda C, Smith K, Smith M, Garcia R, Barge D, Byrne D, Byrne K, Driscoll A, Fortune L, Janin P, Yarad E, Hammond N, Bass F, Ashelford A, Waterson S, Wedd S, McNamara R, Buhr H, Coles J, Schweikert S, Wibrow B, Rauniyar R, Myers E, Fysh E, Dawda A, Mevavala B, Litton E, Ferrier J, Nair P, Buscher H, Reynolds C, Santamaria J, Barbazza L, Homes J, Smith R, Murray L, Brailsford J, Forbes L, Maguire T, Mariappa V, Smith J, Simpson S, Maiden M, Bone A, Horton M, Salerno T, Sterba M, Geng W, Depuydt P, De Waele J, De Bus L, Fierens J, Bracke S, Reeve B, Dechert W, Chassé M, Carrier FM, Boumahni D, Benettaib F, Ghamraoui A, Bellemare D, Cloutier È, Francoeur C, Lamontagne F, D’Aragon F, Carbonneau E, Leblond J, Vazquez-Grande G, Marten N, Wilson, Albert M, Serri K, Cavayas A, Duplaix M, Williams V, Rochwerg B, Karachi T, Oczkowski S, Centofanti J, Millen T, Duan E, Tsang J, Patterson L, English S, Watpool I, Porteous R, Miezitis S, McIntyre L, Brochard L, Burns K, Sandhu G, Khalid I, Binnie A, Powell E, McMillan A, Luk T, Aref N, Andric Z, Cviljevic S, Đimoti R, Zapalac M, Mirković G, Baršić B, Kutleša M, Kotarski V, Vujaklija Brajković A, Babel J, Sever H, Dragija L, Kušan I, Vaara S, Pettilä L, Heinonen J, Kuitunen A, Karlsson S, Vahtera A, Kiiski H, Ristimäki S, Azaiz A, Charron C, Godement M, Geri G, Vieillard-Baron A, Pourcine F, Monchi M, Luis D, Mercier R, Sagnier A, Verrier N, Caplin C, Siami S, Aparicio C, Vautier S, Jeblaoui A, Fartoukh M, Courtin L, Labbe V, Leparco C, Muller G, Nay MA, Kamel T, Benzekri D, Jacquier S, Mercier E, Chartier D, Salmon C, Dequin P, Schneider F, Morel G, L’Hotellier S, Badie J, Berdaguer FD, Malfroy S, Mezher C, Bourgoin C, Megarbane B, Voicu, Deye N, Malissin I, Sutterlin L, Guitton C, Darreau C, Landais M, Chudeau N, Robert A, Moine P, Heming N, Maxime V, Bossard I, Nicholier TB, Colin G, Zinzoni V, Maquigneau N, Finn A, Kreß G, Hoff U, Friedrich Hinrichs C, Nee J, Pletz M, Hagel S, Ankert J, Kolanos S, Bloos F, Petros S, Pasieka B, Kunz K, Appelt P, Schütze B, Kluge S, Nierhaus A, Jarczak D, Roedl K, Weismann D, Frey A, Klinikum Neukölln V, Reill L, Distler M, Maselli A, Bélteczki J, Magyar I, Fazekas Á, Kovács S, Szőke V, Szigligeti G, Leszkoven J, Collins D, Breen P, Frohlich S, Whelan R, McNicholas B, Scully M, Casey S, Kernan M, Doran P, O’Dywer M, Smyth M, Hayes L, Hoiting O, Peters M, Rengers E, Evers M, Prinssen A, Bosch Ziekenhuis J, Simons K, Rozendaal W, Polderman F, de Jager P, Moviat M, Paling A, Salet A, Rademaker E, Peters AL, de Jonge E, Wigbers J, Guilder E, Butler M, Cowdrey KA, Newby L, Chen Y, Simmonds C, McConnochie R, Ritzema Carter J, Henderson S, Van Der Heyden K, Mehrtens J, Williams T, Kazemi A, Song R, Lai V, Girijadevi D, Everitt R, Russell R, Hacking D, Buehner U, Williams E, Browne T, Grimwade K, Goodson J, Keet O, Callender O, Martynoga R, Trask K, Butler A, Schischka L, Young C, Lesona E, Olatunji S, Robertson Y, José N, Amaro dos Santos Catorze T, de Lima Pereira TNA, Neves Pessoa LM, Castro Ferreira RM, Pereira Sousa Bastos JM, Aysel Florescu S, Stanciu D, Zaharia MF, Kosa AG, Codreanu D, Marabi Y, Al Qasim E, Moneer Hagazy M, Al Swaidan L, Arishi H, Muñoz-Bermúdez R, Marin-Corral J, Salazar Degracia A, Parrilla Gómez F, Mateo López MI, Rodriguez Fernandez J, Cárcel Fernández S, Carmona Flores R, León López R, de la Fuente Martos C, Allan A, Polgarova P, Farahi N, McWilliam S, Hawcutt D, Rad L, O’Malley L, Whitbread J, Kelsall O, Wild L, Thrush J, Wood H, Austin K, Donnelly A, Kelly M, O’Kane S, McClintock D, Warnock M, Johnston P, Gallagher LJ, Mc Goldrick C, Mc Master M, Strzelecka A, Jha R, Kalogirou M, Ellis C, Krishnamurthy V, Deelchand V, Silversides J, McGuigan P, Ward K, O’Neill A, Finn S, Phillips B, Mullan D, Oritz-Ruiz de Gordoa L, Thomas M, Sweet K, Grimmer L, Johnson R, Pinnell J, Robinson M, Gledhill L, Wood T, Morgan M, Cole J, Hill H, Davies M, Antcliffe D, Templeton M, Rojo R, Coghlan P, Smee J, Mackay E, Cort J, Whileman A, Spencer T, Spittle N, Kasipandian V, Patel A, Allibone S, Genetu RM, Ramali M, Ghosh A, Bamford P, London E, Cawley K, Faulkner M, Jeffrey H, Smith T, Brewer C, Gregory J, Limb J, Cowton A, O’Brien J, Nikitas N, Wells C, Lankester L, Pulletz M, Williams P, Birch J, Wiseman S, Horton S, Alegria A, Turki S, Elsefi T, Crisp N, Allen L, McCullagh I, Robinson P, Hays C, Babio-Galan M, Stevenson H, Khare D, Pinder M, Selvamoni S, Gopinath A, Pugh R, Menzies D, Mackay C, Allan E, Davies G, Puxty K, McCue C, Cathcart S, Hickey N, Ireland J, Yusuff H, Isgro G, Brightling C, Bourne M, Craner M, Watters M, Prout R, Davies L, Pegler S, Kyeremeh L, Arbane G, Wilson K, Gomm L, Francia F, Brett S, Sousa Arias S, Elin Hall R, Budd J, Small C, Birch J, Collins E, Henning J, Bonner S, Hugill K, Cirstea E, Wilkinson D, Karlikowski M, Sutherland H, Wilhelmsen E, Woods J, North J, Sundaran D, Hollos L, Coburn S, Walsh J, Turns M, Hopkins P, Smith J, Noble H, Depante MT, Clarey E, Laha S, Verlander M, Williams A, Huckle A, Hall A, Cooke J, Gardiner-Hill C, Maloney C, Qureshi H, Flint N, Nicholson S, Southin S, Nicholson A, Borgatta B, Turner-Bone I, Reddy A, Wilding L, Chamara Warnapura L, Agno Sathianathan R, Golden D, Hart C, Jones J, Bannard-Smith J, Henry J, Birchall K, Pomeroy F, Quayle R, Makowski A, Misztal B, Ahmed I, KyereDiabour T, Naiker K, Stewart R, Mwaura E, Mew L, Wren L, Willams F, Innes R, Doble P, Hutter J, Shovelton C, Plumb B, Szakmany T, Hamlyn V, Hawkins N, Lewis S, Dell A, Gopal S, Ganguly S, Smallwood A, Harris N, Metherell S, Lazaro JM, Newman T, Fletcher S, Nortje J, Fottrell-Gould D, Randell G, Zaman M, Elmahi E, Jones A, Hall K, Mills G, Ryalls K, Bowler H, Sall J, Bourne R, Borrill Z, Duncan T, Lamb T, Shaw J, Fox C, Moreno Cuesta J, Xavier K, Purohit D, Elhassan M, Bakthavatsalam D, Rowland M, Hutton P, Bashyal A, Davidson N, Hird C, Chhablani M, Phalod G, Kirkby A, Archer S, Netherton K, Reschreiter H, Camsooksai J, Patch S, Jenkins S, Pogson D, Rose S, Daly Z, Brimfield L, Claridge H, Parekh D, Bergin C, Bates M, Dasgin J, McGhee C, Sim M, Hay SK, Henderson S, Phull MK, Zaidi A, Pogreban T, Rosaroso LP, Harvey D, Lowe B, Meredith M, Ryan L, Hormis A, Walker R, Collier D, Kimpton S, Oakley S, Rooney K, Rodden N, Hughes E, Thomson N, McGlynn D, Walden A, Jacques N, Coles H, Tilney E, Vowell E, Schuster-Bruce M, Pitts S, Miln R, Purandare L, Vamplew L, Spivey M, Bean S, Burt K, Moore L, Day C, Gibson C, Gordon E, Zitter L, Keenan S, Baker E, Cherian S, Cutler S, Roynon-Reed A, Harrington K, Raithatha A, Bauchmuller K, Ahmad N, Grecu I, Trodd D, Martin J, Wrey Brown C, Arias AM, Craven T, Hope D, Singleton J, Clark S, Rae N, Welters I, Hamilton DO, Williams K, Waugh V, Shaw D, Puthucheary Z, Martin T, Santos F, Uddin R, Somerville A, Tatham KC, Jhanji S, Black E, Dela Rosa A, Howle R, Tully R, Drummond A, Dearden J, Philbin J, Munt S, Vuylsteke A, Chan C, Victor S, Matsa R, Gellamucho M, Creagh-Brown B, Tooley J, Montague L, De Beaux F, Bullman L, Kersiake I, Demetriou C, Mitchard S, Ramos L, White K, Donnison P, Johns M, Casey R, Mattocks L, Salisbury S, Dark P, Claxton A, McLachlan D, Slevin K, Lee S, Hulme J, Joseph S, Kinney F, Senya HJ, Oborska A, Kayani A, Hadebe B, Orath Prabakaran R, Nichols L, Thomas M, Worner R, Faulkner B, Gendall E, Hayes K, Hamilton-Davies C, Chan C, Mfuko C, Abbass H, Mandadapu V, Leaver S, Forton D, Patel K, Paramasivam E, Powell M, Gould R, Wilby E, Howcroft C, Banach D, Fernández de Pinedo Artaraz Z, Cabreros L, White I, Croft M, Holland N, Pereira R, Zaki A, Johnson D, Jackson M, Garrard H, Juhaz V, Roy A, Rostron A, Woods L, Cornell S, Pillai S, Harford R, Rees T, Ivatt H, Sundara Raman A, Davey M, Lee K, Barber R, Chablani M, Brohi F, Jagannathan V, Clark M, Purvis S, Wetherill B, Dushianthan A, Cusack R, de Courcy-Golder K, Smith S, Jackson S, Attwood B, Parsons P, Page V, Zhao XB, Oza D, Rhodes J, Anderson T, Morris S, Xia Le Tai C, Thomas A, Keen A, Digby S, Cowley N, Wild L, Southern D, Reddy H, Campbell A, Watkins C, Smuts S, Touma O, Barnes N, Alexander P, Felton T, Ferguson S, Sellers K, Bradley-Potts J, Yates D, Birkinshaw I, Kell K, Marshall N, Carr-Knott L, and Summers C

Subjects
Adrenal Cortex Hormones therapeutic use, Adult, Anti-Inflammatory Agents adverse effects, Betacoronavirus, COVID-19, Coronavirus Infections mortality, Coronavirus Infections therapy, Early Termination of Clinical Trials, Female, Humans, Hydrocortisone adverse effects, Intensive Care Units, Male, Middle Aged, Pandemics, Pneumonia, Viral mortality, Pneumonia, Viral therapy, SARS-CoV-2, Shock drug therapy, Shock etiology, Treatment Outcome, COVID-19 Drug Treatment, Anti-Inflammatory Agents administration & dosage, Coronavirus Infections drug therapy, Hydrocortisone administration & dosage, Pneumonia, Viral drug therapy, Respiration, Artificial statistics & numerical data
Abstract

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited., Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19., Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020., Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108)., Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%)., Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively., Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Published
2020
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96. Zinc Induces Temperature-Dependent Reversible Self-Assembly of Tau.

Author

Roman AY, Devred F, Byrne D, La Rocca R, Ninkina NN, Peyrot V, and Tsvetkov PO

Subjects
Amyloid metabolism, Binding Sites drug effects, Heparin metabolism, Humans, Neurodegenerative Diseases metabolism, Neurons drug effects, Neurons metabolism, Polymerization drug effects, Protein Processing, Post-Translational drug effects, Temperature, Zinc pharmacology, tau Proteins metabolism
Abstract

Tau is an intrinsically disordered microtubule-associated protein that is implicated in several neurodegenerative disorders called tauopathies. In these diseases, Tau is found in the form of intracellular inclusions that consist of aggregated paired helical filaments (PHFs) in neurons. Given the importance of this irreversible PHF formation in neurodegenerative disease, Tau aggregation has been extensively studied. Several different factors, such as mutations or post translational modifications, have been shown to influence the formation of late-stage non-reversible Tau aggregates. It was recently shown that zinc ions accelerated heparin-induced oligomerization of Tau constructs. Indeed, in vitro studies of PHFs have usually been performed in the presence of additional co-factors, such as heparin, in order to accelerate their formation. Using turbidimetry, we investigated the impact of zinc ions on Tau in the absence of heparin and found that zinc is able to induce a temperature-dependent reversible oligomerization of Tau. The obtained oligomers were not amyloid-like and dissociated instantly following zinc chelation or a temperature decrease. Finally, a combination of isothermal titration calorimetry and dynamic light scattering experiments showed zinc binding to a high-affinity binding site and three low-affinity sites on Tau, accompanied by a change in Tau folding. Altogether, our findings stress the importance of zinc in Tau oligomerization. This newly identified Zn-induced oligomerization mechanism may be a part of a pathway different of and concurrent to Tau aggregation cascade leading to PHF formation., (Copyright © 2018. Published by Elsevier Ltd.)

Published
2019
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