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1. AB1173 CLINICAL CORRELATES OF PHYSICAL AND MENTAL HEALTH IN EARLY SYSTEMIC SCLEROSIS: BASELINE RESULTS FROM THE COLLABORATIVE NATIONAL QUALITY AND EFFICACY (CONQUER) REGISTRY USING THE PATIENT-REPORTED OUTCOMES MEASUREMENT INFORMATION SYSTEM (PROMIS)-V29

Author

Makol, A., primary, Lamba, I., additional, Khanna, D., additional, Vanburen, J., additional, Child, A., additional, Alvey, J., additional, Assassi, S., additional, Bernstein, E., additional, Castelino, F., additional, Chung, L., additional, Evnin, L., additional, Frech, T., additional, Hant, F., additional, Hummers, L., additional, Lakin, K., additional, Lebiedz-Odrobina, D., additional, Luo, Y., additional, Molitor, J., additional, Moore, D., additional, Richardson, C., additional, Sandorfi, N., additional, Shah, A. A., additional, Shah, A., additional, Skaug, B., additional, Steen, V., additional, Volkmann, E., additional, and Gordon, J., additional

Published
2024
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2. Bone Formation in Zebrafish: The Significance of DAF-FM DA Staining for Nitric Oxide Detection

Author

Ann Huysseune, Ulrike G. Larsen, Daria Larionova, Cecilie L. Matthiesen, Steen V. Petersen, Marc Muller, and P. Eckhard Witten

Subjects
zebrafish, osteoblasts, ossification, nitric oxide, notochord sheath, bulbus arteriosus, Microbiology, QR1-502
Abstract

DAF-FM DA is widely used as a live staining compound to show the presence of nitric oxide (NO) in cells. Applying this stain to live zebrafish embryos is known to indicate early centers of bone formation, but the precise (cellular) location of the signal has hitherto not been revealed. Using sections of zebrafish embryos live-stained with DAF-FM DA, we could confirm that the fluorescent signals were predominantly located in areas of ongoing bone formation. Signals were observed in the bone and tooth matrix, in the notochord sheath, as well as in the bulbus arteriosus. Surprisingly, however, they were exclusively extracellular, even after very short staining times. Von Kossa and Alizarin red S staining to reveal mineral deposits showed that DAF-FM DA stains both the mineralized and non-mineralized bone matrix (osteoid), excluding that DAF-FM DA binds non-specifically to calcified structures. The importance of NO in bone formation by osteoblasts is nevertheless undisputed, as shown by the absence of bone structures after the inhibition of NOS enzymes that catalyze the formation of NO. In conclusion, in zebrafish skeletal biology, DAF-FM DA is appropriate to reveal bone formation in vivo, independent of mineralization of the bone matrix, but it does not demonstrate intracellular NO.

Published
2023
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3. Reliability and Minimal Clinically Important Differences of FVC. Results from the Scleroderma Lung Studies (SLS-I and SLS-II)

Author

Kafaja, Suzanne, Clements, Philip J, Wilhalme, Holly, Tseng, Chi-hong, Furst, Daniel E, Kim, Grace Hyun, Goldin, Jonathan, Volkmann, Elizabeth R, Roth, Michael D, Tashkin, Donald P, Khanna, Dinesh, Arbor, Ann, Khanna, D, Angeles, Los, Clements, PJ, Tashkin, DP, Elashoff, R, Goldin, J, Roth, M, Furst, D, Bulpitt, K, Chung, W-LJ, Viasco, S, Sterz, M, Woolcock, L, Yan, X, Ho, J, Vasunilashorn, S, da Costa, I, Seibold, JR, Riley, DJ, Amorosa, JK, Hsu, VM, McCloskey, DA, Wilson, JE, Varga, J, Schraufnagel, D, Wilbur, A, Lapota, D, Arami, S, Cole-Saffold, P, Simms, R, Theodore, A, Clarke, P, Korn, J, Tobin, K, Nuite, M, Silver, R, Bolster, M, Strange, C, Schabel, S, Smith, E, Arnold, J, Caldwell, K, Bonner, M, Wise, R, Wigley, F, White, B, Hummers, L, Bohlman, M, Polito, A, Leatherman, G, Forbes, E, Daniel, M, Steen, V, Read, C, Cooper, C, Wheaton, S, Carey, A, Ortiz, A, Mayes, M, Parsley, E, Oldham, S, Filemon, T, Jordan, S, Perry, M, K. Connolly, Golden, J, Wolters, P, Webb, R, Davis, J, Antolos, C, Maynetto, C, Fessler, B, Olman, M, Sanders, C, Heck, L, Parkhill, T, Rothfield, N, Metersky, M, Cobb, R, Aberles, M, Ingenito, F, Breen, E, Mubarak, K, Granda, JL, Silva, J, Injic, Z, and Alexander, R

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Scleroderma, Lung, Autoimmune Disease, Cohort Studies, Disease Progression, Female, Humans, Lung Diseases, Interstitial, Male, Middle Aged, Minimal Clinically Important Difference, Reproducibility of Results, Scleroderma, Systemic, Vital Capacity, interstitial lung disease, systemic sclerosis, FVC%, minimal clinically important differences, patient-reported outcomes, Medical and Health Sciences, Respiratory System, Cardiovascular medicine and haematology, Clinical sciences
Abstract

ObjectivesTo assess the reliability and the minimal clinically important differences (MCID) for FVC% predicted in the Scleroderma Lung Study I and II.MethodsUsing data from SLS I and II (N=300), we evaluated the test-retest reliability for FVC% predicted (FVC%; screening vs. baseline) using intra-class correlation (ICC). MCID estimates at 12 months were calculated in the pooled cohort (SLS-I and II) using 2 anchors: Transition Dyspnea Index (≥change of 1.5 units for improvement and worsening, respectively) and the SF-36 Health Transition question: "Compared to one year ago, how would you rate your health in general now?", where "somewhat better" or "somewhat worse" were defined as the MCID estimates. We next assessed the association of MCID estimates for improvement and worsening of FVC% with patient reported outcomes (PROs) and computer-assisted quantitation of extent of fibrosis (QLF) and of total ILD (QILD) on HRCT.ResultsReliability of FVC%, assessed at a mean of 34 days, was 0.93 for the pooled cohort. The MCID estimates for the pooled cohort at 12 months for FVC% improvement ranged from 3.0 % to 5.3% and for worsening from -3.0% to -3.3%. FVC% improvement by ≥MCID was associated with either statistically significant or numerical improvements in some PROs, QILD, and QLF, while FVC% worsening ≥MCID was associated with statistically significant or numerical worsening of PROs, QILD, and QLF.ConclusionFVC% has acceptable test-retest reliability, and we have provided the MCID estimates for FVC% in SSc-ILD based changes at 12 months from baseline in two clinical trials. Clinical trial registration available at www.clinicaltrials.gov, IDs NCT00004563 and NCT00883129.

Published
2018

4. Cryo-EM analysis of complement C3 reveals a reversible major opening of the macroglobulin ring

Author

Gadeberg, Trine AF, primary, Joergensen, Martin H, additional, Olesen, Heidi G, additional, Lorentzen, Josefine, additional, Harwood, Seandean L, additional, Almeida, Ana V, additional, Fruergaard, Marlene U, additional, Jensen, Rasmus K, additional, Kanis, Philipp, additional, Pedersen, Henrik, additional, Tranchant, Emil, additional, Petersen, Steen V, additional, Thoegersen, Ida B, additional, Lyons, Joseph A, additional, Enghild, Jan J, additional, and Andersen, Gregers Rom R, additional

Published
2024
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9. POS1258 RESULTS FROM A NOMINAL GROUP TECHNIQUE EXERCISE FOR THE CREATION OF A COMBINED RESPONSE INDEX FOR LIMITED CUTANEOUS SYSTEMIC SCLEROSIS: THE CRISTAL PROJECT

Author

Lescoat, A., primary, Chen, Y., additional, Murphy, S. L., additional, Carroll, L., additional, Vann, N., additional, Didio, P., additional, Iya, S., additional, Phanhdone, T., additional, Farrington, S., additional, Allanore, Y., additional, Cella, D., additional, Chung, L., additional, Clements, P., additional, Del Galdo, F., additional, Denton, C. P., additional, Distler, O., additional, Hinchcliff, M., additional, Hughes, M., additional, Hummers, L., additional, Pauling, J., additional, Pope, J., additional, Steen, V., additional, Varga, J., additional, Buch, M. H., additional, and Khanna, D., additional

Published
2023
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10. The dynamic uptake and release of SOD3 from intracellular stores in macrophages modulates the inflammatory response

Author

Lili Hu, Elias D. Zachariae, Ulrike G. Larsen, Frederik Vilhardt, and Steen V. Petersen

Subjects
Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Superoxide dismutase 3 (SOD3) is an extracellular enzyme with the capacity to modulate extracellular redox conditions by catalyzing the dismutation of superoxide to hydrogen peroxide. In addition to synthesis and release of this extracellular protein via the secretory pathway, several studies have shown that the protein also localizes to intracellular compartments in neutrophils and macrophages. Here we show that human macrophages release SOD3 from an intracellular compartment within 30 min following LPS stimulation. This release acutely increases the level of SOD3 on the cell surface as well as in the extracellular environment. Generation of the intracellular compartment in macrophages is supported by endocytosis of extracellular SOD3 via the LDL receptor-related protein 1 (LRP1). Using bone marrow-derived macrophages established from wild-type and SOD3−/− mice, we further show that the pro-inflammatory profile established in LPS-stimulated cells is altered in the absence of SOD3, suggesting that the active release of this protein affects the inflammatory response. The internalization and acute release from stimulated macrophages indicates that SOD3 not only functions as a passive antioxidant in the extracellular environment, but also plays an active role in modulating redox signaling to support biological responses. Keywords: Superoxide dismutase 3 (SOD3), Macrophage, Internalization, Secretion, Extracellular redox regulation, LRP1

Published
2019
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11. Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System

Author

Dennis V. Pedersen, Trine A. F. Gadeberg, Caroline Thomas, Yong Wang, Nicolas Joram, Rasmus K. Jensen, Sofia M. M. Mazarakis, Margot Revel, Carine El Sissy, Steen V. Petersen, Kresten Lindorff-Larsen, Steffen Thiel, Nick S. Laursen, Véronique Fremeaux-Bacchi, and Gregers R. Andersen

Subjects
complement, convertase, properdin, complement component C3, crystal structure, regulation, Immunologic diseases. Allergy, RC581-607
Abstract

Properdin (FP) is a positive regulator of the immune system stimulating the activity of the proteolytically active C3 convertase C3bBb in the alternative pathway of the complement system. Here we present two crystal structures of FP and two structures of convertase bound FP. A structural core formed by three thrombospondin repeats (TSRs) and a TB domain harbors the convertase binding site in FP that mainly interacts with C3b. Stabilization of the interaction between the C3b C-terminus and the MIDAS bound Mg2+ in the Bb protease by FP TSR5 is proposed to underlie FP convertase stabilization. Intermolecular contacts between FP and the convertase subunits suggested by the structure were confirmed by binding experiments. FP is shown to inhibit C3b degradation by FI due to a direct competition for a common binding site on C3b. FP oligomers are held together by two sets of intermolecular contacts, where the first is formed by the TB domain from one FP molecule and TSR4 from another. The second and largest interface is formed by TSR1 and TSR6 from the same two FP molecules. Flexibility at four hinges between thrombospondin repeats is suggested to enable the oligomeric, polydisperse, and extended architecture of FP. Our structures rationalize the effects of mutations associated with FP deficiencies and provide a structural basis for the analysis of FP function in convertases and its possible role in pattern recognition.

Published
2019
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13. Optimal management of digital ulcers in systemic sclerosis

Author

Abraham S and Steen V

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

Shawn Abraham, Virginia SteenDivision of Rheumatology, Immunology, and Allergy, MedStar Georgetown University Hospital, Washington, DC, USAAbstract: Raynaud’s phenomenon and digital ulcerations are two common clinical features seen in patients with systemic sclerosis. They are painful and lead to significant morbidity and altered hand function within this patient population. While currently there are no US Food and Drug Administration (FDA)-approved medications for the treatment of digital ulcerations in the United States, clinical trials have supported the use of pharmacologic and nonpharmacologic modalities in facilitating healing of existing digital ulcers and preventing formation of new ulcers. This article reviews the published data on these therapeutic options.Keywords: scleroderma, systemic sclerosis, Raynaud’s phenomenon, digital ulcers, treatment

Published
2015

15. Genome-wide autozygosity is associated with lower general cognitive ability

Author

Howrigan, D P, Simonson, M A, Davies, G, Harris, S E, Tenesa, A, Starr, J M, Liewald, D C, Deary, I J, McRae, A, Wright, M J, Montgomery, G W, Hansell, N, Martin, N G, Payton, A, Horan, M, Ollier, W E, Abdellaoui, A, Boomsma, D I, DeRosse, P, Knowles, E E M, Glahn, D C, Djurovic, S, Melle, I, Andreassen, O A, Christoforou, A, Steen, V M, Hellard, S L, Sundet, K, Reinvang, I, Espeseth, T, Lundervold, A J, Giegling, I, Konte, B, Hartmann, A M, Rujescu, D, Roussos, P, Giakoumaki, S, Burdick, K E, Bitsios, P, Donohoe, G, Corley, R P, Visscher, P M, Pendleton, N, Malhotra, A K, Neale, B M, Lencz, T, and Keller, M C

Published
2016
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18. GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium

Author

Trampush, J W, Yang, M LZ, Yu, J, Knowles, E, Davies, G, Liewald, D C, Starr, J M, Djurovic, S, Melle, I, Sundet, K, Christoforou, A, Reinvang, I, DeRosse, P, Lundervold, A J, Steen, V M, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, J G, Giegling, I, Konte, B, Roussos, P, Giakoumaki, S, Burdick, K E, Payton, A, Ollier, W, Horan, M, Chiba-Falek, O, Attix, D K, Need, A C, Cirulli, E T, Voineskos, A N, Stefanis, N C, Avramopoulos, D, Hatzimanolis, A, Arking, D E, Smyrnis, N, Bilder, R M, Freimer, N A, Cannon, T D, London, E, Poldrack, R A, Sabb, F W, Congdon, E, Conley, E D, Scult, M A, Dickinson, D, Straub, R E, Donohoe, G, Morris, D, Corvin, A, Gill, M, Hariri, A R, Weinberger, D R, Pendleton, N, Bitsios, P, Rujescu, D, Lahti, J, Le Hellard, S, Keller, M C, Andreassen, O A, Deary, I J, Glahn, D C, Malhotra, A K, and Lencz, T

Published
2017
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19. Hydrogen peroxide induce modifications of human extracellular superoxide dismutase that results in enzyme inhibition

Author

Randi H. Gottfredsen, Ulrike G. Larsen, Jan J. Enghild, and Steen V. Petersen

Subjects
EC-SOD, Peroxidase activity, Inhibition, Oxidation, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Superoxide dismutase (EC-SOD) controls the level of superoxide in the extracellular space by catalyzing the dismutation of superoxide into hydrogen peroxide and molecular oxygen. In addition, the enzyme reacts with hydrogen peroxide in a peroxidase reaction which is known to disrupt enzymatic activity. Here, we show that the peroxidase reaction supports a site-specific bond cleavage. Analyses by peptide mapping and mass spectrometry shows that oxidation of Pro112 supports the cleavage of the Pro112–His113 peptide bond. Substitution of Ala for Pro112 did not inhibit fragmentation, indicating that the oxidative fragmentation at this position is dictated by spatial organization and not by side-chain specificity. The major part of EC-SOD inhibited by the peroxidase reaction was not fragmented but found to encompass oxidations of histidine residues involved in the coordination of copper (His98 and His163). These oxidations are likely to support the dissociation of copper from the active site and thus loss of enzymatic activity. Homologous modifications have also been described for the intracellular isozyme, Cu/Zn-SOD, reflecting the almost identical structures of the active site within these enzymes. We speculate that the inactivation of EC-SOD by peroxidase activity plays a role in regulating SOD activity in vivo, as even low levels of superoxide will allow for the peroxidase reaction to occur.

Published
2013
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20. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

Author

Davies, G, Armstrong, N, Bis, J C, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Ibrahim-Verbaas, C A, Kirin, M, Lahti, J, van der Lee, S J, Le Hellard, S, Liu, T, Marioni, R E, Oldmeadow, C, Postmus, I, Smith, A V, Smith, J A, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, S E, Hill, W D, Liewald, D C, Luciano, M, Adams, H, Ames, D, Amin, N, Amouyel, P, Assareh, A A, Au, R, Becker, J T, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, B M, Campbell, H, Corley, J, De Jager, P L, Dufouil, C, Eriksson, J G, Espeseth, T, Faul, J D, Ford, I, Scotland, Generation, Gottesman, R F, Griswold, M E, Gudnason, V, Harris, T B, Heiss, G, Hofman, A, Holliday, E G, Huffman, J, Kardia, S L R, Kochan, N, Knopman, D S, Kwok, J B, Lambert, J-C, Lee, T, Li, G, Li, S-C, Loitfelder, M, Lopez, O L, Lundervold, A J, Lundqvist, A, Mather, K A, Mirza, S S, Nyberg, L, Oostra, B A, Palotie, A, Papenberg, G, Pattie, A, Petrovic, K, Polasek, O, Psaty, B M, Redmond, P, Reppermund, S, Rotter, J I, Schmidt, H, Schuur, M, Schofield, P W, Scott, R J, Steen, V M, Stott, D J, van Swieten, J C, Taylor, K D, Trollor, J, Trompet, S, Uitterlinden, A G, Weinstein, G, Widen, E, Windham, B G, Jukema, J W, Wright, A F, Wright, M J, Yang, Q, Amieva, H, Attia, J R, Bennett, D A, Brodaty, H, de Craen, A J M, Hayward, C, Ikram, M A, Lindenberger, U, Nilsson, L-G, Porteous, D J, Räikkönen, K, Reinvang, I, Rudan, I, Sachdev, P S, Schmidt, R, Schofield, P R, Srikanth, V, Starr, J M, Turner, S T, Weir, D R, Wilson, J F, van Duijn, C, Launer, L, Fitzpatrick, A L, Seshadri, S, Mosley, Jr, T H, and Deary, I J

Published
2015
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21. POS0914 LATE SKIN FIBROSIS IN SYSTEMIC SCLEROSIS: A STUDY FROM THE EUSTAR COHORT

Author

Hughes, M., primary, Huang, S., additional, Alegre Sancho, J. J., additional, Carreira, P., additional, Engelhart, M., additional, Hachulla, E., additional, Henes, J., additional, Kerzberg, E., additional, Pozzi, M. R., additional, Riemekasten, G., additional, Smith, V., additional, Szucs, G., additional, Vanthuyne, M., additional, Zanatta, E., additional, Distler, O., additional, Gabrielli, A., additional, Hoffmann-Vold, A. M., additional, Steen, V., additional, and Khanna, D., additional

Published
2022
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22. FAM20C phosphorylation of the RGDSVVYGLR motif in osteopontin inhibits interaction with the αvβ3 integrin

Author

Jan J. Enghild, Esben S. Sørensen, Ida Bregenov, Carsten Scavenius, Gitte N Schytte, Katarzyna Kjøge, Brian Christensen, and Steen V. Petersen

Subjects
inorganic chemicals, 0301 basic medicine, osteopontin, Plasmin, alpha(v)beta(3) integrin, Cleavage (embryo), SEQUENCE, Biochemistry, 03 medical and health sciences, MILK, 0302 clinical medicine, Thrombin, stomatognathic system, In vivo, BINDING, medicine, Osteopontin, Molecular Biology, FAM20C, RGD motif, FRAGMENT, POSTTRANSLATIONAL MODIFICATIONS, SITES, IDENTIFICATION, biology, phosphorylation, Chemistry, Kinase, GLYCOSYLATION, Cell Biology, Cell biology, enzymes and coenzymes (carbohydrates), 030104 developmental biology, α β integrin, 030220 oncology & carcinogenesis, biology.protein, GROWTH, Phosphorylation, APPARATUS CASEIN KINASE, medicine.drug
Abstract

Osteopontin (OPN) is a ubiquitously expressed, multifunctional, and highly phosphorylated protein. OPN contains two neighboring integrin-binding motifs, RGD and SVVYGLR, which mediate interaction with cells. Phosphorylation and proteolytic processing affect the integrin-binding activities of OPN. Here we report that the kinase, FAM20C, phosphorylates Ser146 in the 143 RGDSVVYGLR152 motif of OPN and that Ser146 is phosphorylated in vivo in human and bovine milk. Ser146 is located right next to the RGD motif and close by the regulatory thrombin and plasmin cleavage sites in the OPN sequence. Phosphorylation of Ser146 could potentially affect the proteolytic processing and the integrin-binding activities of OPN. We show that phosphorylation of Ser146 does not affect the susceptibility of OPN for thrombin or plasmin cleavage. However, phosphorylation of Ser146 significantly reduces the RGD-mediated interaction with the αv β3 integrin in MDA-MB-435 and Moαv cells. This suggests a new mechanism by which specific phosphorylation of OPN can regulate interaction with the αv β3 integrin and thereby affect OPN-cell interaction.

Published
2020
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23. Covalent phenolic acid-grafted β-lactoglobulin conjugates: Synthesis, characterization, and evaluation of their multifunctional properties

Author

Ahmed Ali Abd El-Maksoud, Weiwei Cheng, Steen V. Petersen, R. Pandiselvam, and Zheng Guo

Subjects
Multifunctional properties, Phenolic acid, Covalent conjugates, β-lactoglobulin, Food Science
Abstract

In our work, covalent conjugates of β-Lactoglobulin (βLg) with different phenolic acids (PhAs) including caffeic (CA), ferulic (FA), sinapic (SA), and gallic (GA) acids were synthesized by using carbodiimide chemistry. The resulting βLg-PhA conjugates were characterized by matrix-assisted laser desorption ionization-time of flight mass spectrometry, Fourier transform infrared spectroscopy, and differential scanning colorimetry. Results showed that four kinds of PhAs were covalently bonded with the amino group of βLg at the grafting mole ratios of 7:1, 1:1, 1:1, and 2:1, respectively. βLg-PhA conjugates contained more α-helix and less β-sheet secondary structure than unmodified βLg. The DPPH and ABTS radical scavenging indexes of βLg-PhA conjugates were significantly higher than that of native βLg (by 2.18–2.55- and 2.66–3.12-fold, respectively) and βLg/PhA mixtures (1.15–2.01- and 1.13–1.47-fold, respectively). Fish O/W emulsions stabilized by βLg-PhA conjugates, excepting βLg-GA conjugate, exhibited smaller droplet size and narrower PDI, as well as better storage and oxidation stability compared with βLg-stabilized emulsion. βLg covalently grafted with CA, SA, and FA were endowed with improved surface-active property and antioxidant activity over native βLg. Accordingly, βLg-PhA conjugates, particularly βLg-CA, βLg-SA, and βLg-FA conjugates, were demonstrated to have great potential as novel group of multifunctional stabilizers in fabrication of emulsion-based deliver system.

Published
2022
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24. A genome-wide association study of anorexia nervosa

Author

Boraska, V, Franklin, C S, Floyd, J A B, Thornton, L M, Huckins, L M, Southam, L, Rayner, N W, Tachmazidou, I, Klump, K L, Treasure, J, Lewis, C M, Schmidt, U, Tozzi, F, Kiezebrink, K, Hebebrand, J, Gorwood, P, Adan, R A H, Kas, M J H, Favaro, A, Santonastaso, P, Fernández-Aranda, F, Gratacos, M, Rybakowski, F, Dmitrzak-Weglarz, M, Kaprio, J, Keski-Rahkonen, A, Raevuori, A, Van Furth, E F, Slof-Op 't Landt, M C T, Hudson, J I, Reichborn-Kjennerud, T, Knudsen, G P S, Monteleone, P, Kaplan, A S, Karwautz, A, Hakonarson, H, Berrettini, W H, Guo, Y, Li, D, Schork, N J, Komaki, G, Ando, T, Inoko, H, Esko, T, Fischer, K, Männik, K, Metspalu, A, Baker, J H, Cone, R D, Dackor, J, DeSocio, J E, Hilliard, C E, O'Toole, J K, Pantel, J, Szatkiewicz, J P, Taico, C, Zerwas, S, Trace, S E, Davis, O S P, Helder, S, Bühren, K, Burghardt, R, de Zwaan, M, Egberts, K, Ehrlich, S, Herpertz-Dahlmann, B, Herzog, W, Imgart, H, Scherag, A, Scherag, S, Zipfel, S, Boni, C, Ramoz, N, Versini, A, Brandys, M K, Danner, U N, de Kovel, C, Hendriks, J, Koeleman, B P C, Ophoff, R A, Strengman, E, van Elburg, A A, Bruson, A, Clementi, M, Degortes, D, Forzan, M, Tenconi, E, Docampo, E, Escaramís, G, Jiménez-Murcia, S, Lissowska, J, Rajewski, A, Szeszenia-Dabrowska, N, Slopien, A, Hauser, J, Karhunen, L, Meulenbelt, I, Slagboom, P E, Tortorella, A, Maj, M, Dedoussis, G, Dikeos, D, Gonidakis, F, Tziouvas, K, Tsitsika, A, Papezova, H, Slachtova, L, Martaskova, D, Kennedy, J L, Levitan, R D, Yilmaz, Z, Huemer, J, Koubek, D, Merl, E, Wagner, G, Lichtenstein, P, Breen, G, Cohen-Woods, S, Farmer, A, McGuffin, P, Cichon, S, Giegling, I, Herms, S, Rujescu, D, Schreiber, S, Wichmann, H-E, Dina, C, Sladek, R, Gambaro, G, Soranzo, N, Julia, A, Marsal, S, Rabionet, R, Gaborieau, V, Dick, D M, Palotie, A, Ripatti, S, Widén, E, Andreassen, O A, Espeseth, T, Lundervold, A, Reinvang, I, Steen, V M, Le Hellard, S, Mattingsdal, M, Ntalla, I, Bencko, V, Foretova, L, Janout, V, Navratilova, M, Gallinger, S, Pinto, D, Scherer, S W, Aschauer, H, Carlberg, L, Schosser, A, Alfredsson, L, Ding, B, Klareskog, L, Padyukov, L, Courtet, P, Guillaume, S, Jaussent, I, Finan, C, Kalsi, G, Roberts, M, Logan, D W, Peltonen, L, Ritchie, G R S, Barrett, J C, Estivill, X, Hinney, A, Sullivan, P F, Collier, D A, Zeggini, E, and Bulik, C M

Published
2014
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25. Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT)

Author

Lencz, T, Knowles, E, Davies, G, Guha, S, Liewald, D C, Starr, J M, Djurovic, S, Melle, I, Sundet, K, Christoforou, A, Reinvang, I, Mukherjee, S, DeRosse, Pamela, Lundervold, A, Steen, V M, John, M, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, J G, Giegling, I, Konte, B, Ikeda, M, Roussos, P, Giakoumaki, S, Burdick, K E, Payton, A, Ollier, W, Horan, M, Donohoe, G, Morris, D, Corvin, A, Gill, M, Pendleton, N, Iwata, N, Darvasi, A, Bitsios, P, Rujescu, D, Lahti, J, Hellard, S L, Keller, M C, Andreassen, O A, Deary, I J, Glahn, D C, and Malhotra, A K

Published
2014
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28. Erratum: GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium

Author

Trampush, J W, Yang, M L Z, Yu, J, Knowles, E, Davies, G, Liewald, D C, Starr, J M, Djurovic, S, Melle, I, Sundet, K, Christoforou, A, Reinvang, I, DeRosse, P, Lundervold, A J, Steen, V M, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, J G, Giegling, I, Konte, B, Roussos, P, Giakoumaki, S, Burdick, K E, Payton, A, Ollier, W, Horan, M, Chiba-Falek, O, Attix, D K, Need, A C, Cirulli, E T, Voineskos, A N, Stefanis, N C, Avramopoulos, D, Hatzimanolis, A, Arking, D E, Smyrnis, N, Bilder, R M, Freimer, N A, Cannon, T D, London, E, Poldrack, R A, Sabb, F W, Congdon, E, Conley, E D, Scult, M A, Dickinson, D, Straub, R E, Donohoe, G, Morris, D, Corvin, A, Gill, M, Hariri, A R, Weinberger, D R, Pendleton, N, Bitsios, P, Rujescu, D, Lahti, J, Le Hellard, S, Keller, M C, Andreassen, O A, Deary, I J, Glahn, D C, Malhotra, A K, and Lencz, T

Published
2017
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29. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N = 53 949)

Author

Davies, G, Armstrong, N, Bis, J C, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Ibrahim-Verbaas, C A, Kirin, M, Lahti, J, van der Lee, S J, Le Hellard, S, Liu, T, Marioni, R E, Oldmeadow, C, Postmus, I, Smith, A V, Smith, J A, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, S E, Hill, W D, Liewald, D C, Luciano, M, Adams, H, Ames, D, Amin, N, Amouyel, P, Assareh, A A, Au, R, Becker, J T, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, B M, Campbell, H, Corley, J, De Jager, P L, Dufouil, C, Eriksson, J G, Espeseth, T, Faul, J D, Ford, I, Scotland, Generation, Gottesman, R F, Griswold, M E, Gudnason, V, Harris, T B, Heiss, G, Hofman, A, Holliday, E G, Huffman, J, Kardia, S LR, Kochan, N, Knopman, D S, Kwok, J B, Lambert, J-C, Lee, T, Li, G, Li, S-C, Loitfelder, M, Lopez, O L, Lundervold, A J, Lundqvist, A, Mather, K A, Mirza, S S, Nyberg, L, Oostra, B A, Palotie, A, Papenberg, G, Pattie, A, Petrovic, K, Polasek, O, Psaty, B M, Redmond, P, Reppermund, S, Rotter, J I, Schmidt, H, Schuur, M, Schofield, P W, Scott, R J, Steen, V M, Stott, D J, van Swieten, J C, Taylor, K D, Trollor, J, Trompet, S, Uitterlinden, A G, Weinstein, G, Widen, E, Windham, B G, Jukema, J W, Wright, A F, Wright, M J, Yang, Q, Amieva, H, Attia, J R, Bennett, D A, Brodaty, H, de Craen, A JM, Hayward, C, Ikram, M A, Lindenberger, U, Nilsson, L-G, Porteous, D J, Räikkönen, K, Reinvang, I, Rudan, I, Sachdev, P S, Schmidt, R, Schofield, P R, Srikanth, V, Starr, J M, Turner, S T, Weir, D R, Wilson, J F, van Duijn, C, Launer, L, Fitzpatrick, A L, Seshadri, S, Mosley, TH, Jr, and Deary, I J

Published
2015
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30. PRO62 Qualitative Interviews to Assess the Content Validity of a Novel Raynaud Diary in Patients with Systemic Sclerosis

Author

Domsic, R.T., primary, Vampola, C.L., additional, Stassek, L., additional, Pokrzywinski, R., additional, Furst, D., additional, Chung, L.S., additional, Steen, V., additional, Mayes, M.D., additional, Shah, A., additional, Molitor, J., additional, Nagaraja, V., additional, Oliver, K., additional, Benton, W., additional, and Khanna, D., additional

Published
2021
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31. Superoxide dismutase 3 is expressed in bone tissue and required for normal bone homeostasis and mineralization

Author

Claus Oxvig, Ulrike G. Larsen, Jan J. Enghild, Ebbe Toftgaard Poulsen, Kasper Kjaer-Sorensen, Cecilie Linneberg Matthiesen, Annemarie Brüel, Steen V. Petersen, Astrid S. Torslev, Jesper Skovhus Thomsen, and Lili Hu

Subjects
0301 basic medicine, Bone mineralization, Superoxide dismutase 3 (SOD3), SOD3, In situ hybridization, Bone tissue, Biochemistry, Bone and Bones, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, In vivo, Physiology (medical), Extracellular, medicine, Animals, Homeostasis, Bone homeostasis, Zebrafish, Mice, Knockout, biology, Superoxide, Superoxide Dismutase, biology.organism_classification, Cell biology, 030104 developmental biology, medicine.anatomical_structure, chemistry, Redox regulation, Oxidation-Reduction, 030217 neurology & neurosurgery
Abstract

Superoxide dismutase 3 (SOD3) is an extracellular protein with the capacity to convert superoxide into hydrogen peroxide, an important secondary messenger in redox regulation. To investigate the utility of zebrafish in functional studies of SOD3 and its relevance for redox regulation, we have characterized the zebrafish orthologues; Sod3a and Sod3b. Our analyses show that both recombinant Sod3a and Sod3b express SOD activity, however, only Sod3b is able to bind heparin. Furthermore, RT-PCR analyses reveal that sod3a and sod3b are expressed in zebrafish embryos and are present primarily in separate organs in adult zebrafish, suggesting distinct functions in vivo. Surprisingly, both RT-PCR and whole mount in situ hybridization showed specific expression of sod3b in skeletal tissue. To further investigate this observation, we compared femoral bone obtained from wild-type and SOD3−/− mice to determine whether a functional difference was apparent in healthy adult mice. Here we report, that bone from SOD3−/− mice is less mineralized and characterized by significant reduction of cortical and trabecular thickness in addition to reduced mechanical strength. These analyses show that SOD3 plays a hitherto unappreciated role in bone development and homeostasis.

Published
2021
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32. Novel and converging ways of NOX2 and SOD3 in trafficking and redox signaling in macrophages

Author

Cecilie Linneberg Matthiesen, Steen V. Petersen, Nanna Bach Poulsen, and Frederik Vilhardt

Subjects
Redox signaling, Physiology, Clinical Biochemistry, hydrogen peroxide, Review, Membrane trafficking, Biochemistry, cellular sorting, Rab27, chemistry.chemical_compound, Paracrine signalling, NOX2, Small GTPase, Autocrine signalling, redox signaling, Molecular Biology, Lipid raft, chemistry.chemical_classification, Reactive oxygen species, NADPH oxidase, biology, Chemistry, Superoxide, membrane trafficking, Macrophages, lcsh:RM1-950, Cellular sorting, Cell Biology, Hydrogen peroxide, SOD3, Microvesicles, Cell biology, macrophages, lcsh:Therapeutics. Pharmacology, biology.protein, superoxide
Abstract

Macrophages and related tissue macrophage populations use the classical NADPH oxidase (NOX2) for the regulated production of superoxide and derived oxidants for pathogen combat and redox signaling. With an emphasis on macrophages, we discuss how sorting into secretory storage vesicles, agonist-responsive membrane trafficking, and segregation into sphingolipid and cholesterol-enriched microdomains (lipid rafts) determine the subcellular distribution and spatial organization of NOX2 and superoxide dismutase-3 (SOD3). We discuss how inflammatory activation of macrophages, in part through small GTPase Rab27A/B regulation of the secretory compartments, mediates the coalescence of these two proteins on the cell surface to deliver a focalized hydrogen peroxide output. In interplay with membrane-embedded oxidant transporters and redox sensitive target proteins, this arrangement allows for the autocrine and paracrine signaling, which govern macrophage activation states and transcriptional programs. By discussing examples of autocrine and paracrine redox signaling, we highlight why formation of spatiotemporal microenvironments where produced superoxide is rapidly converted to hydrogen peroxide and conveyed immediately to reach redox targets in proximal vicinity is required for efficient redox signaling. Finally, we discuss the recent discovery of macrophage-derived exosomes as vehicles of NOX2 holoenzyme export to other cells.

Published
2021
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33. A comprehensive framework for navigating patient care in systemic sclerosis: A global response to the need for improving the practice of diagnostic and preventive strategies in SSc

Author

Saketkoo, L.A., Frech, T., Varjú, C., Domsic, R., Farrell, Jessica, Gordon, J.K., Mihai, C., Sandorfi, N., Shapiro, L., Poole, J., Volkmann, E.R., Lammi, M., McAnally, K., Alexanderson, H., Pettersson, H., Hant, F., Kuwana, M., Shah, A.A., Smith, V., Hsu, V., Kowal-Bielecka, O., Assassi, S., Cutolo, M., Kayser, C., Shanmugam, V.K., Vonk, M.C., Fligelstone, K., Baldwin, N., Connolly, K., Ronnow, A., Toth, B., Suave, M., Farrington, S., Bernstein, E.J., Crofford, L.J., Czirják, L., Jensen, K., Hinchclif, M., Hudson, M., Lammi, M.R., Mansour, J., Morgan, N.D., Mendoza, F., Nikpour, M., Pauling, J., Riemekasten, G., Russell, A.M., Scholand, M.B., Seigart, E., Rodriguez-Reyna, T.S., Hummers, L., Walker, U., Steen, V., Saketkoo, L.A., Frech, T., Varjú, C., Domsic, R., Farrell, Jessica, Gordon, J.K., Mihai, C., Sandorfi, N., Shapiro, L., Poole, J., Volkmann, E.R., Lammi, M., McAnally, K., Alexanderson, H., Pettersson, H., Hant, F., Kuwana, M., Shah, A.A., Smith, V., Hsu, V., Kowal-Bielecka, O., Assassi, S., Cutolo, M., Kayser, C., Shanmugam, V.K., Vonk, M.C., Fligelstone, K., Baldwin, N., Connolly, K., Ronnow, A., Toth, B., Suave, M., Farrington, S., Bernstein, E.J., Crofford, L.J., Czirják, L., Jensen, K., Hinchclif, M., Hudson, M., Lammi, M.R., Mansour, J., Morgan, N.D., Mendoza, F., Nikpour, M., Pauling, J., Riemekasten, G., Russell, A.M., Scholand, M.B., Seigart, E., Rodriguez-Reyna, T.S., Hummers, L., Walker, U., and Steen, V.

Abstract

Item does not contain fulltext, Systemic sclerosis (SSc), the most lethal of rheumatologic conditions, is the cause of death in >50% of SSc cases, led by pulmonary fibrosis followed by pulmonary hypertension and then scleroderma renal crisis (SRC). Multiple other preventable and treatable SSc-related vascular, cardiac, gastrointestinal, nutritional and musculoskeletal complications can lead to disability and death. Vascular injury with subsequent inflammation transforming to irreversible fibrosis and permanent damage characterizes SSc. Organ involvement is often present early in the disease course of SSc, but requires careful history-taking and vigilance in screening to detect. Inflammation is potentially reversible provided that treatment intensity quells inflammation and other immune mechanisms. In any SSc phenotype, opportunities for early treatment are prone to be under-utilized, especially in slowly progressive phenotypes that, in contrast to severe progressive ILD, indolently accrue irreversible organ damage resulting in later-stage life-limiting complications such as pulmonary hypertension, cardiac involvement, and malnutrition. A single SSc patient visit often requires much more physician and staff time, organization, vigilance, and direct management for multiple organ systems compared to other rheumatic or pulmonary diseases. Efficiency and efficacy of comprehensive SSc care enlists trending of symptoms and bio-data. Financial sustainability of SSc care benefits from understanding insurance reimbursement and health system allocation policies for complex patients. Sharing care between recognised SSc centers and local cardiology/pulmonary/rheumatology/gastroenterology colleagues may prevent complications and poor outcomes, while providing support to local specialists. As scleroderma specialists, we offer a practical framework with tools to facilitate an optimal, comprehensive and sustainable approach to SSc care. Improved health outcomes in SSc relies upon recogntion, management and, to the

Published
2021

34. A comprehensive framework for navigating patient care in systemic sclerosis: A global response to the need for improving the practice of diagnostic and preventive strategies in SSc

Author

Saketkoo, LA, Frech, T, Varju, C, Domsic, R, Farrell, J, Gordon, JK, Mihai, C, Sandorfi, N, Shapiro, L, Poole, J, Volkmann, ER, Lammi, M, McAnally, K, Alexanderson, H, Pettersson, H, Hant, F, Kuwana, M, Shah, AA, Smith, V, Hsu, V, Kowal-Bielecka, O, Assassi, S, Cutolo, M, Kayser, C, Shanmugam, VK, Vonk, MC, Fligelstone, K, Baldwin, N, Connolly, K, Ronnow, A, Toth, B, Suave, M, Farrington, S, Bernstein, EJ, Crofford, LJ, Czirjak, L, Jensen, K, Hinchclif, M, Hudson, M, Lammi, MR, Mansour, J, Morgan, ND, Mendoza, F, Nikpour, M, Pauling, J, Riemekasten, G, Russell, A-M, Scholand, MB, Seigart, E, Rodriguez-Reyna, TS, Hummers, L, Walker, U, Steen, V, Saketkoo, LA, Frech, T, Varju, C, Domsic, R, Farrell, J, Gordon, JK, Mihai, C, Sandorfi, N, Shapiro, L, Poole, J, Volkmann, ER, Lammi, M, McAnally, K, Alexanderson, H, Pettersson, H, Hant, F, Kuwana, M, Shah, AA, Smith, V, Hsu, V, Kowal-Bielecka, O, Assassi, S, Cutolo, M, Kayser, C, Shanmugam, VK, Vonk, MC, Fligelstone, K, Baldwin, N, Connolly, K, Ronnow, A, Toth, B, Suave, M, Farrington, S, Bernstein, EJ, Crofford, LJ, Czirjak, L, Jensen, K, Hinchclif, M, Hudson, M, Lammi, MR, Mansour, J, Morgan, ND, Mendoza, F, Nikpour, M, Pauling, J, Riemekasten, G, Russell, A-M, Scholand, MB, Seigart, E, Rodriguez-Reyna, TS, Hummers, L, Walker, U, and Steen, V

Abstract

Systemic sclerosis (SSc), the most lethal of rheumatologic conditions, is the cause of death in >50% of SSc cases, led by pulmonary fibrosis followed by pulmonary hypertension and then scleroderma renal crisis (SRC). Multiple other preventable and treatable SSc-related vascular, cardiac, gastrointestinal, nutritional and musculoskeletal complications can lead to disability and death. Vascular injury with subsequent inflammation transforming to irreversible fibrosis and permanent damage characterizes SSc. Organ involvement is often present early in the disease course of SSc, but requires careful history-taking and vigilance in screening to detect. Inflammation is potentially reversible provided that treatment intensity quells inflammation and other immune mechanisms. In any SSc phenotype, opportunities for early treatment are prone to be under-utilized, especially in slowly progressive phenotypes that, in contrast to severe progressive ILD, indolently accrue irreversible organ damage resulting in later-stage life-limiting complications such as pulmonary hypertension, cardiac involvement, and malnutrition. A single SSc patient visit often requires much more physician and staff time, organization, vigilance, and direct management for multiple organ systems compared to other rheumatic or pulmonary diseases. Efficiency and efficacy of comprehensive SSc care enlists trending of symptoms and bio-data. Financial sustainability of SSc care benefits from understanding insurance reimbursement and health system allocation policies for complex patients. Sharing care between recognised SSc centers and local cardiology/pulmonary/rheumatology/gastroenterology colleagues may prevent complications and poor outcomes, while providing support to local specialists. As scleroderma specialists, we offer a practical framework with tools to facilitate an optimal, comprehensive and sustainable approach to SSc care. Improved health outcomes in SSc relies upon recogntion, management and, to the

Published
2021

35. Genome-wide association studies establish that human intelligence is highly heritable and polygenic

Author

Davies, G, Tenesa, A, Payton, A, Yang, J, Harris, S E, Liewald, D, Ke, X, Le Hellard, S, Christoforou, A, Luciano, M, McGhee, K, Lopez, L, Gow, A J, Corley, J, Redmond, P, Fox, H C, Haggarty, P, Whalley, L J, McNeill, G, Goddard, M E, Espeseth, T, Lundervold, A J, Reinvang, I, Pickles, A, Steen, V M, Ollier, W, Porteous, D J, Horan, M, Starr, J M, Pendleton, N, Visscher, P M, and Deary, I J

Published
2011
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36. Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

Author

Le Hellard, S, Mühleisen, T W, Djurovic, S, Fernø, J, Ouriaghi, Z, Mattheisen, M, Vasilescu, C, Raeder, M B, Hansen, T, Strohmaier, J, Georgi, A, Brockschmidt, F F, Melle, I, Nenadic, I, Sauer, H, Rietschel, M, Nöthen, M M, Werge, T, Andreassen, O A, Cichon, S, and Steen, V M

Published
2010
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40. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease

Author

Distler, O, Highland, Kb, Gahlemann, M, Azuma, A, Fischer, A, Mayes, Md, Raghu, G, Sauter, W, Girard, M, Alves, M, Clerisme-Beaty, E, Stowasser, S, Tetzlaff, K, Kuwana, M, Maher, Tm, Bergna, M, Casado, G, Mannucci Walter, P, Proudman, S, Stevens, W, Thakkar, V, Troy, L, Loeffler-Ragg, J, Olschewski, H, Bondue, B, Houssiau, F, Smith, V, Wuyts, W, Johnson, S, Keystone, E, Khalidi, N, Levesque, M, Maturana Rozas, R, Silva Orellana, A, Huang, C, Li, J, Jiang, Z, Liu, Y, Xiao, W, Xu, J, Zeng, X, Zheng, Y, Zou, H, Becvar, R, Madsen, H, Søndergaard, K, Kilpeläinen, M, Myllärniemi, M, Agard, C, Allanore, Y, Bourdin, A, Cottin, V, Crestani, B, Diot, E, Dominique, S, Hachulla, E, Jouneau, S, Leroy, S, Nunes, H, Prevot, G, Wallaert, B, Wemeau, L, Aringer, M, Bewig, B, Blaas, S, Distler, J, Ehrchen, J, Ewert, R, Gläser, S, Henes, J, Hunzelmann, N, König, R, Kötter, I, Kreuter, M, Prasse, A, Schulze-Koops, H, Sfikakis, P, Vlachoyiannopoulos, P, Losonczy, G, Behera, D, Gayathri Devi HJ, Kadel, J, Kawedia, M, Kumar, D, Kumar, U, Lokhande, R, Malpani, A, Mohan, M, Nalawade, A, Parakh, U, Swarnakar, R, Shobha, V, Thangakunam, B, Udwadia, Z, Henry, M, O'Reilly, K, Balbir-Gurman, A, Kramer, M, Litinsky, I, Rosner, I, Cutolo, M, Gabrielli, A, Iaccarino, L, Pesci, A, Riccieri, V, Vettori, S, Funakubo, Y, Inoue, Y, Kawakami, A, Kawaguchi, Y, Kawamura, T, Kondoh, Y, Nanki, T, Nishioka, Y, Nozawa, K, Oguragawa, T, Okamoto, M, Sano, H, Sasai, R, Sasaki, N, Suda, T, Takahashi, H, Takeuchi, T, Tanaka, S, Yamasaki, Y, Ch'Ng, Ss, Cheah, C, Kan, S, Raja Mohamed RB, Selman, M, de Vries-Bouwstra JK, van den Toorn, L, Vonken, M, Voskuyl, Ae, Hoffmann-Vold, Am, Seip, M, Dankiewicz-Fares, I, Olesiejuk, R, Pulka, G, Szepietowski, J, Alves, J, Bernardes, M, Cordeiro, A, Costa, J, Neves, S, Salvador, Mj, Alegre Sancho, J, Carreira Delgado, P, Castellví Barranco, I, Cifrián Martínez, J, Guillén Del Castillo, A, Ovalles, Jg, López-Longo, Fj, Rivera Gallego, A, Freire Dapena MC, Román Ivorra JA, Ekwall, Ah, Maurer, B, Mihai, Cm, Müller, R, Mahakkanukrauh, A, Nantiruj, K, Siripaitoon, B, Denton, Cp, Herrick, A, Madhok, R, West, A, Bascom, R, Criner, G, Csuka, Me, Dematte D'Amico, J, Ettinger, N, Gerbino, A, Gerke, A, Glassberg, M, Glazer, C, Golden, J, Gripaldo, R, Gupta, N, Hamblin, M, Highland, K, Ho, L, Huggins, Jt, Hummers, L, Jones, L, Kahaleh, M, Khanna, D, Kim, H, Lancaster, Lh, Luckhardt, T, Mayes, M, Mendoza Ballesteros, F, Mooney, J, Mohabir, P, Morrissey, B, Moua, T, Padilla, M, Patel, N, Perez, R, Roman, J, Rossman, M, Russell, T, Saketkoo, L, Shah, A, Shlobin, O, Scholand, Mb, Simmssetts, R, Spiera, R, Steen, V, Veeraraghavan, S, Weigt, S., Distler, O, Highland, Kb, Gahlemann, M, Azuma, A, Fischer, A, Mayes, Md, Raghu, G, Sauter, W, Girard, M, Alves, M, Clerisme-Beaty, E, Stowasser, S, Tetzlaff, K, Kuwana, M, Maher, Tm, SENSCIS Trial Investigators., Bergna M, Casado, G, Mannucci Walter, P, Proudman, S, Stevens, W, Thakkar, V, Troy, L, Loeffler-Ragg, J, Olschewski, H, Bondue, B, Houssiau, F, Smith, V, Wuyts, W, Johnson, S, Keystone, E, Khalidi, N, Levesque, M, Maturana Rozas, R, Silva Orellana, A, Huang, C, Li, J, Jiang, Z, Liu, Y, Xiao, W, Xu, J, Zeng, X, Zheng, Y, Zou, H, Becvar, R, Madsen, H, Søndergaard, K, Kilpeläinen, M, Myllärniemi, M, Agard, C, Allanore, Y, Bourdin, A, Cottin, V, Crestani, B, Diot, E, Dominique, S, Hachulla, E, Jouneau, S, Leroy, S, Nunes, H, Prevot, G, Wallaert, B, Wemeau, L, Aringer, M, Bewig, B, Blaas, S, Distler, J, Ehrchen, J, Ewert, R, Gläser, S, Henes, J, Hunzelmann, N, König, R, Kötter, I, Kreuter, M, Prasse, A, Schulze-Koops, H, Sfikakis, P, Vlachoyiannopoulos, P, Losonczy, G, Behera, D, Gayathri Devi, Hj, Kadel, J, Kawedia, M, Kumar, D, Kumar, U, Lokhande, R, Malpani, A, Mohan, M, Nalawade, A, Parakh, U, Swarnakar, R, Shobha, V, Thangakunam, B, Udwadia, Z, Henry, M, O'Reilly, K, Balbir-Gurman, A, Kramer, M, Litinsky, I, Rosner, I, Cutolo, M, Gabrielli, A, Iaccarino, Laura, Pesci, A, Riccieri, V, Vettori, S, Funakubo, Y, Inoue, Y, Kawakami, A, Kawaguchi, Y, Kawamura, T, Kondoh, Y, Nanki, T, Nishioka, Y, Nozawa, K, Oguragawa, T, Okamoto, M, Sano, H, Sasai, R, Sasaki, N, Suda, T, Takahashi, H, Takeuchi, T, Tanaka, S, Yamasaki, Y, Ch'Ng, S, Cheah, C, Kan, S, Raja Mohamed, Rb, Selman, M, de Vries-Bouwstra, Jk, van den Toorn, L, Vonken, M, Voskuyl, Ae, Hoffmann-Vold, Am, Seip, M, Dankiewicz-Fares, I, Olesiejuk, R, Pulka, G, Szepietowski, J, Alves, J, Bernardes, M, Cordeiro, A, Costa, J, Neves, S, Salvador, Mj, Alegre Sancho, J, Carreira Delgado, P, Castellví Barranco, I, Cifrián Martínez, J, Guillén Del Castillo, A, Ovalles, Jg, López-Longo, Fj, Rivera Gallego, A, Freire Dapena, Mc, Román Ivorra, Ja, Ekwall, Ah, Maurer, B, Mihai, Cm, Müller, R, Mahakkanukrauh, A, Nantiruj, K, Siripaitoon, B, Denton, Cp, Herrick, A, Madhok, R, West, A, Bascom, R, Criner, G, Csuka, Me, Dematte D'Amico, J, Ettinger, N, Gerbino, A, Gerke, A, Glassberg, M, Glazer, C, Golden, J, Gripaldo, R, Gupta, N, Hamblin, M, Highland, K, Ho, L, Huggins, Jt, Hummers, L, Jones, L, Kahaleh, M, Khanna, D, Kim, H, Lancaster, Lh, Luckhardt, T, Mayes, M, Mendoza Ballesteros, F, Mooney, J, Mohabir, P, Morrissey, B, Moua, T, Padilla, M, Patel, N, Perez, R, Roman, J, Rossman, M, Russell, T, Saketkoo, L, Shah, A, Shlobin, O, Scholand, Mb, Simmssetts, R, Spiera, R, Steen, V, Veeraraghavan, S, Weigt, S., National Institute for Health Research, British Lung Foundation, University of Zurich, and Distler, Oliver

Subjects
Male, Vital capacity, Indoles, Vital Capacity, Administration, Oral, 2700 General Medicine, 030204 cardiovascular system & hematology, Pulmonary function testing, law.invention, oral, Idiopathic pulmonary fibrosis, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, SENSCIS Trial Investigators, CYCLOPHOSPHAMIDE, Clinical endpoint, scleroderma, 030212 general & internal medicine, Enzyme Inhibitors, 11 Medical and Health Sciences, lung diseases, Lung Diseases, Interstitial -- drug therapy -- etiology -- physiopathology, 10051 Rheumatology Clinic and Institute of Physical Medicine, General Medicine, respiratory system, Sciences bio-médicales et agricoles, Middle Aged, Protein-Tyrosine Kinases, MANIFESTATIONS, Disease Progression, Nintedanib, Female, TYROSINE KINASE INHIBITOR, Life Sciences & Biomedicine, CLINICAL-TRIALS, Adult, Diarrhea, medicine.medical_specialty, FIBROBLASTS, 610 Medicine & health, Placebo, administration, behavioral disciplines and activities, 03 medical and health sciences, FEV1/FVC ratio, Medicine, General & Internal, Double-Blind Method, Internal medicine, General & Internal Medicine, Enzyme Inhibitors -- adverse effects -- therapeutic use, SCORE, medicine, Humans, Indoles -- adverse effects -- therapeutic use, Scleroderma, Systemic -- complications -- drug therapy, Science & Technology, Scleroderma, Systemic, Protein-Tyrosine Kinases -- antagonists & inhibitors, business.industry, MORTALITY, interstitial, PULMONARY-FUNCTION, systemic, STANDARDIZATION, medicine.disease, EFFICACY, respiratory tract diseases, body regions, chemistry, adult, diarrhea, disease progression, double-blind method, enzyme inhibitors, female, humans, indoles, lung diseases, interstitial, male, middle aged, protein-tyrosine kinases, scleroderma, systemic, vital capacity, business, Lung Diseases, Interstitial, Diarrhea -- chemically induced
Abstract

Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD., info:eu-repo/semantics/published

Published
2019

41. Associations Between Attention-Deficit/Hyperactivity Disorder and Various Eating Disorders: A Swedish Nationwide Population Study Using Multiple Genetically Informative Approaches

Author

Yao, S., Kuja-Halkola, R., Martin, J., Lu, Y., Lichtenstein, P., Hubel, C., Almqvist, C., Magnusson, P. K., Bulik, C. M., Larsson, H., Norring, C., Birgegard, A., Yilmaz, Z., Watson, H., Baker, J., Thornton, L. M., Adan, R., Ando, T., Bergen, A., Berrettini, W., Boni, C., Boraska Perica, V., Brandt, H., Burghardt, R., Cassina, M., Cesta, C., Clementi, M., Coleman, J., Cone, R., Courtet, P., Crawford, S., Crow, S., Crowley, J., Danner, U., Davis, O., de Zwaan, M., Dedoussis, G., Degortes, D., Desocio, J., Dick, D., Dikeos, D., Dmitrzak-Weglarz, M., Docampo, E., Egberts, K., Ehrlich, S., Escaramis, G., Esko, T., Estivill, X., Favaro, A., Fernandez-Aranda, F., Fichter, M., Finan, C., Fischer, K., Focker, M., Foretova, L., Forzan, M., Franklin, C., Gaspar, H., Gonidakis, F., Gorwood, P., Gratacos, M., Guillaume, S., Guo, Y., Hakonarson, H., Halmi, K., Hatzikotoulas, K., Hauser, J., Hebebrand, J., Helder, S., Hendriks, J., Herpertz-Dahlmann, B., Herzog, W., Hilliard, C., Hinney, A., Huckins, L., Hudson, J., Huemer, J., Imgart, H., Inoko, H., Jimenez-Murcia, S., Johnson, C., Jordan, J., Jureus, A., Kalsi, G., Kaminska, D., Kaplan, A., Kaprio, J., Karhunen, L., Karwautz, A., Kas, M., Kaye, W., Kennedy, J., Kennedy, M., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y. -R., Klump, K., Knudsen, G. P., Koeleman, B., Koubek, D., La Via, M., Landen, M., Levitan, R., Li, D., Lilenfeld, L., Lissowska, J., Magistretti, P., Maj, M., Mannik, K., Martin, N., Mcdevitt, S., Mcguffin, P., Merl, E., Metspalu, A., Meulenbelt, I., Micali, N., Mitchell, J., Mitchell, K., Monteleone, P., Monteleone, A. M., Mortensen, P., Munn-Chernoff, M., Nacmias, B., Nilsson, I., Ntalla, I., O'Toole, J., Pantel, J., Papezova, H., Parker, R., Rabionet, R., Raevuori, A., Rajewski, A., Ramoz, N., Rayner, N. W., Reichborn-Kjennerud, T., Ricca, V., Ripke, S., Ritschel, F., Roberts, M., Rotondo, A., Rybakowski, F., Santonastaso, P., Scherag, A., Schmidt, U., Schork, N., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op't Landt, M., Slopien, A., Smith, T., Sorbi, S., Strengman, E., Strober, M., Sullivan, P., Szatkiewicz, J., Szeszenia-Dabrowska, N., Tachmazidou, I., Tenconi, E., Thornton, L., Tortorella, A., Tozzi, F., Treasure, J., Tsitsika, A., Tziouvas, K., van Elburg, A., van Furth, E., Wade, T., Wagner, G., Walton, E., Woodside, D. B., Zeggini, E., Zerwas, S., Zipfel, S., Alfredsson, L., Andreassen, O., Aschauer, H., Barrett, J., Bencko, V., Carlberg, L., Cichon, S., Cohen-Woods, S., Dina, C., Ding, B., Espeseth, T., Floyd, J., Gallinger, S., Gambaro, G., Giegling, I., Herms, S., Janout, V., Julia, A., Klareskog, L., Le Hellard, S., Leboyer, M., Lundervold, A., Marsal, S., Mattingsdal, M., Navratilova, M., Ophoff, R., Palotie, A., Pinto, D., Ripatti, S., Rujescu, D., Scherer, S., Scott, L., Sladek, R., Soranzo, N., Southam, L., Steen, V., Wichmann, H. -E., Widen, E., Breen, G., Bulik, C., Yao, S., Kuja-Halkola, R., Martin, J., Lu, Y., Lichtenstein, P., Hubel, C., Almqvist, C., Magnusson, P. K., Bulik, C. M., Larsson, H., Norring, C., Birgegard, A., Yilmaz, Z., Watson, H., Baker, J., Thornton, L. M., Adan, R., Ando, T., Bergen, A., Berrettini, W., Boni, C., Boraska Perica, V., Brandt, H., Burghardt, R., Cassina, M., Cesta, C., Clementi, M., Coleman, J., Cone, R., Courtet, P., Crawford, S., Crow, S., Crowley, J., Danner, U., Davis, O., de Zwaan, M., Dedoussis, G., Degortes, D., Desocio, J., Dick, D., Dikeos, D., Dmitrzak-Weglarz, M., Docampo, E., Egberts, K., Ehrlich, S., Escaramis, G., Esko, T., Estivill, X., Favaro, A., Fernandez-Aranda, F., Fichter, M., Finan, C., Fischer, K., Focker, M., Foretova, L., Forzan, M., Franklin, C., Gaspar, H., Gonidakis, F., Gorwood, P., Gratacos, M., Guillaume, S., Guo, Y., Hakonarson, H., Halmi, K., Hatzikotoulas, K., Hauser, J., Hebebrand, J., Helder, S., Hendriks, J., Herpertz-Dahlmann, B., Herzog, W., Hilliard, C., Hinney, A., Huckins, L., Hudson, J., Huemer, J., Imgart, H., Inoko, H., Jimenez-Murcia, S., Johnson, C., Jordan, J., Jureus, A., Kalsi, G., Kaminska, D., Kaplan, A., Kaprio, J., Karhunen, L., Karwautz, A., Kas, M., Kaye, W., Kennedy, J., Kennedy, M., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y. -R., Klump, K., Knudsen, G. P., Koeleman, B., Koubek, D., La Via, M., Landen, M., Levitan, R., Li, D., Lilenfeld, L., Lissowska, J., Magistretti, P., Maj, M., Mannik, K., Martin, N., Mcdevitt, S., Mcguffin, P., Merl, E., Metspalu, A., Meulenbelt, I., Micali, N., Mitchell, J., Mitchell, K., Monteleone, P., Monteleone, A. M., Mortensen, P., Munn-Chernoff, M., Nacmias, B., Nilsson, I., Ntalla, I., O'Toole, J., Pantel, J., Papezova, H., Parker, R., Rabionet, R., Raevuori, A., Rajewski, A., Ramoz, N., Rayner, N. W., Reichborn-Kjennerud, T., Ricca, V., Ripke, S., Ritschel, F., Roberts, M., Rotondo, A., Rybakowski, F., Santonastaso, P., Scherag, A., Schmidt, U., Schork, N., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op't Landt, M., Slopien, A., Smith, T., Sorbi, S., Strengman, E., Strober, M., Sullivan, P., Szatkiewicz, J., Szeszenia-Dabrowska, N., Tachmazidou, I., Tenconi, E., Thornton, L., Tortorella, A., Tozzi, F., Treasure, J., Tsitsika, A., Tziouvas, K., van Elburg, A., van Furth, E., Wade, T., Wagner, G., Walton, E., Woodside, D. B., Zeggini, E., Zerwas, S., Zipfel, S., Alfredsson, L., Andreassen, O., Aschauer, H., Barrett, J., Bencko, V., Carlberg, L., Cichon, S., Cohen-Woods, S., Dina, C., Ding, B., Espeseth, T., Floyd, J., Gallinger, S., Gambaro, G., Giegling, I., Herms, S., Janout, V., Julia, A., Klareskog, L., Le Hellard, S., Leboyer, M., Lundervold, A., Marsal, S., Mattingsdal, M., Navratilova, M., Ophoff, R., Palotie, A., Pinto, D., Ripatti, S., Rujescu, D., Scherer, S., Scott, L., Sladek, R., Soranzo, N., Southam, L., Steen, V., Wichmann, H. -E., Widen, E., Breen, G., Bulik, C., Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Department Psychiatry [Chapel Hill], University of North Carolina System (UNC)-University of North Carolina System (UNC), Oregon Research Institute (ORI), Department of Psychiatry [Philadelphia], University of Pennsylvania [Philadelphia], Stockholm County Council, Analyse Phenotypique, Developpementale et Genetique des Comportements Addictifs, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), University of Split, Azienda Ospedaliera di Padova, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Nutrition-Dietetics, Harokopio University of Athens, University of Athens Medical School [Athens], MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Medstar Research Institute, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Masaryk Memorial Cancer Institute and Medical Faculty of Masaryk University, National and Kapodistrian University of Athens (NKUA), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Weill Medical College of Cornell University [New York], Department of Genomics, Department of Child and Adolescent Psychiatry and Psychotherapy, LVR-Klinikum Essen, Universität Duisburg-Essen [Essen], Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia., Tokai University, Institute for Marine and Antarctic Studies [Horbat] (IMAS), University of Tasmania [Hobart, Australia] (UTAS), National Institute for Health and Welfare [Helsinki], Medizinische Universität Wien = Medical University of Vienna, University of California [San Diego] (UC San Diego), University of California, Psychiatric Neurogenetics Section, Centre for Addiction and Mental Health, School of Computing [Dublin], Dublin City University [Dublin] (DCU), University of Helsinki, University Medical Center [Utrecht], Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Oak Ridge National Laboratory [Oak Ridge] (ORNL), UT-Battelle, LLC, The M Sklodowska-Curie Cancer Center and Institute of Oncology, Brain and Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Università degli studi della Campania 'Luigi Vanvitelli', Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Queensland Institute of Medical Research, MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, Estonian Genome and Medicine, University of Tartu, Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Institute of Psychiatry, King's College, Università degli Studi di Salerno (UNISA), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Vanderbilt University School of Medicine [Nashville], Charles University [Prague] (CU), Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K, Norwegian Institute of Public Health [Oslo] (NIPH), Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Institute of Medical Informatics, Biometry and Epidemiology, The Scripps Translational Science Institute and The Scripps Research Institute, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, Leiden University Medical Center (LUMC), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, The Jackson Laboratory [Bar Harbor] (JAX), The Nofer Institute of Occupational Medicine, Università degli Studi di Perugia (UNIPG), Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Utrecht University [Utrecht], SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department Biostatistics University of North Carolina, Human Genetics, The Wellcome Trust Sanger Institute [Cambridge], Institute of Environmental Medicine, Karolinska Institutet [Stockholm]-Sachs' Children's Hospital, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Institute of Hygiene and Epidemiology, Charles University and General University Hospital-First Faculty of Medicine, Life & Brain Center - Department of Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oslo (UiO), Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), Centre for Epidemiology and Biostatistics, Faculty of Medicine and Health Leeds, University of Leeds, Department of Optics [Univ Palacký], Faculty of Science [Univ Palacký], Palacky University Olomouc-Palacky University Olomouc, Vall d'Hebron University Hospital [Barcelona], Rheumatology Unit, University of Bergen (UiB), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Masaryk Memorial Cancer Institute (RECAMO), Department of Psychiatry, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians-Universität München (LMU)-Chair of Epidemiology, Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Institute of Psychiatry-King‘s College London, Cardiff University-Medical Research Council, and Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
Adult, Male, Multifactorial Inheritance, Adolescent, behavioral disciplines and activities, Article, Feeding and Eating Disorders, Young Adult, [SCCO]Cognitive science, Polygenic risk score, Risk Factors, mental disorders, Humans, ADHD, Genetic epidemiology, Registries, Child, Sweden, [SDV.GEN]Life Sciences [q-bio]/Genetics, Eating disorder, Anorexia nervosa, Bulimia nervosa, Eating disorders, Attention Deficit Disorder with Hyperactivity, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract

International audience; BACKGROUND:Although attention-deficit/hyperactivity disorder (ADHD) and eating disorders (EDs) frequently co-occur, little is known about the shared etiology. In this study, we comprehensively investigated the genetic association between ADHD and various EDs, including anorexia nervosa (AN) and other EDs such as bulimia nervosa.METHODS:We applied different genetically informative designs to register-based information of a Swedish nationwide population (N = 3,550,118). We first examined the familial coaggregation of clinically diagnosed ADHD and EDs across multiple types of relatives. We then applied quantitative genetic modeling in full-sisters and maternal half-sisters to estimate the genetic correlations between ADHD and EDs. We further tested the associations between ADHD polygenic risk scores and ED symptoms, and between AN polygenic risk scores and ADHD symptoms, in a genotyped population-based sample (N = 13,472).RESULTS:Increased risk of all types of EDs was found in individuals with ADHD (any ED: odds ratio [OR] = 3.97, 95% confidence interval [CI] = 3.81, 4.14; AN: OR = 2.68, 95% CI = 2.15, 2.86; other EDs: OR = 4.66, 95% CI = 4.47, 4.87; bulimia nervosa: OR = 5.01, 95% CI = 4.63, 5.41) and their relatives compared with individuals without ADHD and their relatives. The magnitude of the associations decreased as the degree of relatedness decreased, suggesting shared familial liability between ADHD and EDs. Quantitative genetic models revealed stronger genetic correlation of ADHD with other EDs (.37, 95% CI = .31, .42) than with AN (.14, 95% CI = .05, .22). ADHD polygenic risk scores correlated positively with ED symptom measures overall and with the subscales Drive for Thinness and Body Dissatisfaction despite small effect sizes.CONCLUSIONS:We observed stronger genetic association with ADHD for non-AN EDs than for AN, highlighting specific genetic correlation beyond a general genetic factor across psychiatric disorders.

Published
2019
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42. Extracellular superoxide dismutase (SOD3): An antioxidant or prooxidant in the extracellular space?

Author

Elias D. Zachariae, Steen V. Petersen, and Lili Hu

Subjects
chemistry.chemical_compound, Antioxidant, chemistry, Biochemistry, Superoxide, SOD3, medicine.medical_treatment, medicine, Extracellular, Hydrogen peroxide, Redox, Peroxynitrite, Nitric oxide
Abstract

Superoxide dismutase 3 (SOD3 or EC-SOD) is the only scavenger of superoxide in the extracellular space allowing for the catalyzed dismutation of the superoxide radical into hydrogen peroxide. The activity and distribution of the enzyme are regulated at several levels, suggesting the need for balanced activity in the extracellular space. The protein acts as an antioxidant by inhibiting reactions fueled by superoxide, including the reaction with nitric oxide, which generates peroxynitrite. However, the enzyme can also be categorized as a prooxidant providing hydrogen peroxide, which is known to control diverse redox-regulated processes by the oxidation of specific target proteins. The dual role of SOD3 as an antioxidant or prooxidant is central to fine-tuning the redox tone in the extracellular environment and warrants further investigations to fully understand the role of this protein in health and disease.

Published
2020
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43. The major allergen from birch tree pollen, Bet v 1, binds and permeabilizes membranes

Author

Mogensen, Jesper E., Ferreras, Mercedes, Wimmer, Reinhard, Petersen, Steen V., Enghild, Jan J., and Otzen, Daniel E.

Subjects
Circular dichroism -- Analysis, Fluorescence spectroscopy -- Analysis, Binding proteins -- Research, Biological sciences, Chemistry
Abstract

Circular dichroism and fluorescence spectroscopy is used to show that the 159 residue Bet v 1 binds to DOPC and DOPG phospholipid vesicles in a pH-dependent manner. The results have indicated that Bet v 1 is a membrane binding protein.

Published
2007

44. Protocol for a partially nested randomised controlled trial to evaluate the effectiveness of the scleroderma patient-centered intervention network COVID-19 home-isolation activities together (SPIN-CHAT) program to reduce anxiety among at-risk scleroderma patients

Author

Thombs, BD, Kwakkenbos, L, Carrier, M-E, Bourgeault, A, Tao, L, Harb, S, Gagarine, M, Rice, D, Bustamante, L, Ellis, K, Duchek, D, Wu, Y, Bhandari, PM, Neupane, D, Carboni-Jimenez, A, Henry, RS, Krishnan, A, Sun, Y, Levis, B, He, C, Turner, KA, Benedetti, A, Culos-Reed, N, El-Baalbaki, G, Hebblethwaite, S, Bartlett, SJ, Dyas, L, Patten, S, Varga, J, Fortune, C, Gietzen, A, Guillot, G, Lewis, N, Nielsen, K, Richard, M, Sauve, M, Welling, J, Baron, M, Furst, DE, Gottesman, K, Malcarne, V, Mayes, MD, Mouthon, L, Nielson, WR, Riggs, R, Wigley, F, Assassi, S, Boutron, I, Ells, C, van den Ende, C, Fligelstone, K, Frech, T, Godard, D, Harel, D, Hinchcliff, M, Hudson, M, Johnson, SR, Larche, M, Leite, C, Nguyen, C, Pope, J, Portales, A, Rannou, F, Rodriguez Reyna, TS, Schouffoer, AA, Suarez-Almazor, ME, Agard, C, Albert, A, Andre, M, Arsenault, G, Benzidia, I, Bernstein, EJ, Berthier, S, Bissonnette, L, Boire, G, Bruns, A, Carreira, P, Casadevall, M, Chaigne, B, Chung, L, Cohen, P, Correia, C, Dagenais, P, Denton, C, Domsic, R, Dubois, S, Dunne, J, Dunogue, B, Fare, R, Farge-Bancel, D, Fortin, PR, Gill, A, Gordon, J, Granel-Rey, B, Gyger, G, Hachulla, E, Hatron, P-Y, Herrick, AL, Hij, A, Hoa, S, Ikic, A, Jones, N, Fernandes, AJDB, Kafaja, S, Khalidi, N, Lambert, M, Launay, D, Liang, P, Maillard, H, Maltez, N, Manning, J, Marie, I, Martin, M, Martin, T, Masetto, A, Maurier, F, Mekinian, A, Melchor, S, Nikpour, M, Olagne, L, Poindron, V, Proudman, S, Regent, A, Riviere, S, Robinson, D, Rodriguez, E, Roux, S, Smets, P, Smith, D, Sobanski, V, Spiera, R, Steen, V, Stevens, W, Sutton, E, Terrier, B, Thorne, C, Wilcox, P, Ayala, MC, Ostbo, N, Thombs, BD, Kwakkenbos, L, Carrier, M-E, Bourgeault, A, Tao, L, Harb, S, Gagarine, M, Rice, D, Bustamante, L, Ellis, K, Duchek, D, Wu, Y, Bhandari, PM, Neupane, D, Carboni-Jimenez, A, Henry, RS, Krishnan, A, Sun, Y, Levis, B, He, C, Turner, KA, Benedetti, A, Culos-Reed, N, El-Baalbaki, G, Hebblethwaite, S, Bartlett, SJ, Dyas, L, Patten, S, Varga, J, Fortune, C, Gietzen, A, Guillot, G, Lewis, N, Nielsen, K, Richard, M, Sauve, M, Welling, J, Baron, M, Furst, DE, Gottesman, K, Malcarne, V, Mayes, MD, Mouthon, L, Nielson, WR, Riggs, R, Wigley, F, Assassi, S, Boutron, I, Ells, C, van den Ende, C, Fligelstone, K, Frech, T, Godard, D, Harel, D, Hinchcliff, M, Hudson, M, Johnson, SR, Larche, M, Leite, C, Nguyen, C, Pope, J, Portales, A, Rannou, F, Rodriguez Reyna, TS, Schouffoer, AA, Suarez-Almazor, ME, Agard, C, Albert, A, Andre, M, Arsenault, G, Benzidia, I, Bernstein, EJ, Berthier, S, Bissonnette, L, Boire, G, Bruns, A, Carreira, P, Casadevall, M, Chaigne, B, Chung, L, Cohen, P, Correia, C, Dagenais, P, Denton, C, Domsic, R, Dubois, S, Dunne, J, Dunogue, B, Fare, R, Farge-Bancel, D, Fortin, PR, Gill, A, Gordon, J, Granel-Rey, B, Gyger, G, Hachulla, E, Hatron, P-Y, Herrick, AL, Hij, A, Hoa, S, Ikic, A, Jones, N, Fernandes, AJDB, Kafaja, S, Khalidi, N, Lambert, M, Launay, D, Liang, P, Maillard, H, Maltez, N, Manning, J, Marie, I, Martin, M, Martin, T, Masetto, A, Maurier, F, Mekinian, A, Melchor, S, Nikpour, M, Olagne, L, Poindron, V, Proudman, S, Regent, A, Riviere, S, Robinson, D, Rodriguez, E, Roux, S, Smets, P, Smith, D, Sobanski, V, Spiera, R, Steen, V, Stevens, W, Sutton, E, Terrier, B, Thorne, C, Wilcox, P, Ayala, MC, and Ostbo, N

Abstract

Objective Contagious disease outbreaks and related restrictions can lead to negative psychological outcomes, particularly in vulnerable populations at risk due to pre-existing medical conditions. No randomised controlled trials (RCTs) have tested interventions to reduce mental health consequences of contagious disease outbreaks. The primary objective of the Scleroderma Patient-centered Intervention Network COVID-19 Home-isolation Activities Together (SPIN-CHAT) Trial is to evaluate the effect of a videoconference-based program on symptoms of anxiety. Secondary objectives include evaluating effects on symptoms of depression, stress, loneliness, boredom, physical activity, and social interaction.

Published
2020

45. Changes in mental health symptoms from pre-COVID-19 to COVID-19 among participants with systemic sclerosis from four countries: A Scleroderma Patient-centered Intervention Network (SPIN) Cohort study

Author

Thombs, BD, Kwakkenbos, L, Henry, RS, Carrier, M-E, Patten, S, Harb, S, Bourgeault, A, Tao, L, Bartlett, SJ, Mouthon, L, Varga, J, Benedetti, A, Fortune, C, Gietzen, A, Guillot, G, Lewis, N, Richard, M, Sauve, M, Welling, J, Fligelstone, K, Gottesman, K, Leite, C, Perez, E, Baron, M, Malcarne, V, Mayes, MD, Nielson, WR, Riggs, R, Assassi, S, Ells, C, van den Ende, C, Frech, T, Harel, D, Hinchcliff, M, Hudson, M, Johnson, SR, Larche, M, Nguyen, C, Pope, J, Rannou, F, Reyna, TSR, Schouffoer, AA, Suarez-Almazor, ME, Agard, C, Albert, A, Bernstein, EJ, Berthier, S, Bissonnette, L, Bruns, A, Carreira, P, Chaigne, B, Chung, L, Correia, C, Denton, C, Domsic, R, Dunne, J, Dunogue, B, Farge-Bancel, D, Fortin, PR, Gordon, J, Granel-Rey, B, Hatron, P-Y, Herrick, AL, Hoa, S, Jones, N, Fernandes, AJDB, Kafaja, S, Khalidi, N, Launay, D, Manning, J, Marie, I, Martin, M, Mekinian, A, Melchor, S, Nikpour, M, Olagne, L, Proudman, S, Regent, A, Riviere, S, Robinson, D, Rodriguez, E, Roux, S, Sobanski, V, Steen, V, Sutton, E, Thorne, C, Wilcox, P, Ayala, MC, Carboni-Jimenez, A, Gagarine, M, Nordlund, J, Ostbo, N, Rice, DB, Turner, KA, Culos-Reed, N, Dyas, L, El-Baalbaki, G, Hebblethwaite, S, Bustamante, L, Duchek, D, Ellis, K, Thombs, BD, Kwakkenbos, L, Henry, RS, Carrier, M-E, Patten, S, Harb, S, Bourgeault, A, Tao, L, Bartlett, SJ, Mouthon, L, Varga, J, Benedetti, A, Fortune, C, Gietzen, A, Guillot, G, Lewis, N, Richard, M, Sauve, M, Welling, J, Fligelstone, K, Gottesman, K, Leite, C, Perez, E, Baron, M, Malcarne, V, Mayes, MD, Nielson, WR, Riggs, R, Assassi, S, Ells, C, van den Ende, C, Frech, T, Harel, D, Hinchcliff, M, Hudson, M, Johnson, SR, Larche, M, Nguyen, C, Pope, J, Rannou, F, Reyna, TSR, Schouffoer, AA, Suarez-Almazor, ME, Agard, C, Albert, A, Bernstein, EJ, Berthier, S, Bissonnette, L, Bruns, A, Carreira, P, Chaigne, B, Chung, L, Correia, C, Denton, C, Domsic, R, Dunne, J, Dunogue, B, Farge-Bancel, D, Fortin, PR, Gordon, J, Granel-Rey, B, Hatron, P-Y, Herrick, AL, Hoa, S, Jones, N, Fernandes, AJDB, Kafaja, S, Khalidi, N, Launay, D, Manning, J, Marie, I, Martin, M, Mekinian, A, Melchor, S, Nikpour, M, Olagne, L, Proudman, S, Regent, A, Riviere, S, Robinson, D, Rodriguez, E, Roux, S, Sobanski, V, Steen, V, Sutton, E, Thorne, C, Wilcox, P, Ayala, MC, Carboni-Jimenez, A, Gagarine, M, Nordlund, J, Ostbo, N, Rice, DB, Turner, KA, Culos-Reed, N, Dyas, L, El-Baalbaki, G, Hebblethwaite, S, Bustamante, L, Duchek, D, and Ellis, K

Abstract

INTRODUCTION: No studies have reported mental health symptom comparisons prior to and during COVID-19 in vulnerable medical populations. OBJECTIVE: To compare anxiety and depression symptoms among people with a pre-existing medical condition and factors associated with changes. METHODS: Pre-COVID-19 Scleroderma Patient-centered Intervention Network Cohort data were linked to COVID-19 data from April 2020. Multiple linear and logistic regression were used to assess factors associated with continuous change and ≥ 1 minimal clinically important difference (MCID) change for anxiety (PROMIS Anxiety 4a v1.0; MCID = 4.0) and depression (Patient Health Questionnaire-8; MCID = 3.0) symptoms, controlling for pre-COVID-19 levels. RESULTS: Mean anxiety symptoms increased 4.9 points (95% confidence interval [CI] 4.0 to 5.7). Depression symptom change was negligible (0.3 points; 95% CI -0.7 to 0.2). Compared to France (N = 159), adjusted anxiety symptom change scores were significantly higher in the United Kingdom (N = 50; 3.3 points, 95% CI 0.9 to 5.6), United States (N = 128; 2.5 points, 95% CI 0.7 to 4.2), and Canada (N = 98; 1.9 points, 95% CI 0.1 to 3.8). Odds of ≥1 MCID increase were 2.6 for the United Kingdom (95% CI 1.2 to 5.7) but not significant for the United States (1.6, 95% CI 0.9 to 2.9) or Canada (1.4, 95% CI 0.7 to 2.5). Older age and adequate financial resources were associated with less continuous anxiety increase. Employment and shorter time since diagnosis were associated with lower odds of a ≥ 1 MCID increase. CONCLUSIONS: Anxiety symptoms, but not depression symptoms, increased dramatically during COVID-19 among people with a pre-existing medical condition.

Published
2020

46. Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial.

Author

Khanna, D, Allanore, Y, Denton, CP, Kuwana, M, Matucci-Cerinic, M, Pope, JE, Atsumi, T, Bečvář, R, Czirják, L, Hachulla, E, Ishii, T, Ishikawa, O, Johnson, SR, De Langhe, E, Stagnaro, C, Riccieri, V, Schiopu, E, Silver, RM, Smith, V, Steen, V, Stevens, W, Szücs, G, Truchetet, M-E, Wosnitza, M, Laapas, K, de Oliveira Pena, J, Yao, Z, Kramer, F, Distler, O, Khanna, D, Allanore, Y, Denton, CP, Kuwana, M, Matucci-Cerinic, M, Pope, JE, Atsumi, T, Bečvář, R, Czirják, L, Hachulla, E, Ishii, T, Ishikawa, O, Johnson, SR, De Langhe, E, Stagnaro, C, Riccieri, V, Schiopu, E, Silver, RM, Smith, V, Steen, V, Stevens, W, Szücs, G, Truchetet, M-E, Wosnitza, M, Laapas, K, de Oliveira Pena, J, Yao, Z, Kramer, F, and Distler, O

Abstract

OBJECTIVES: Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression. METHODS: In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52. RESULTS: At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths. CONCLUSIONS: Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.

Published
2020

47. Genetic architecture of subcortical brain structures in 38,854 individuals worldwide

Author

Satizabal, C., Adams, H., Hibar, D., White, C., Knol, M., Stein, J., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G., Smith, A., Bis, J., Jian, X., Luciano, M., Hofer, E., Teumer, A., Van der Lee, S., Yang, J., Yanek, L., Lee, T., Li, S., Hu, Y., Koh, J., Eicher, J., Desrivières, S., Arias-Vasquez, A., Chauhan, G., Athanasiu, L., Renteria, M., Kim, S., Höhn, D., Armstrong, N., Chen, Q., Holmes, A., Den Braber, A., Kloszewska, I., Andersson, M., Espeseth, T., Grimm, O., Abramovic, L., Alhusaini, S., Milaneschi, Y., Papmeyer, M., Axelsson, T., Ehrlich, S., Roiz-Santiañez, R., Kraemer, B., Håberg, A., Jones, H., Pike, G., Stein, D., Stevens, A., Bralten, J., Vernooij, M., Harris, T., Filippi, I., Witte, A., Guadalupe, T., Wittfeld, K., Mosley, T., Becker, J., Doan, N., Hagenaars, S., Saba, Y., Cuellar-Partida, G., Amin, N., Hilal, S., Nho, K., Karbalai, N., Arfanakis, K., Becker, D., Ames, D., Goldman, A., Lee, P., Boomsma, D., Lovestone, S., Giddaluru, S., Le Hellard, S., Mattheisen, M., Bohlken, M., Kasperaviciute, D., Schmaal, L., Lawrie, S., Agartz, I., Walton, E., Tordesillas-Gutierrez, D., Davies, G., Shin, J., Ipser, J., Vinke, L., Hoogman, M., Jia, T., Burkhardt, R., Klein, M., Crivello, F., Janowitz, D., Carmichael, O., Haukvik, U., Aribisala, B., Schmidt, H., Strike, L., Cheng, C., Risacher, S., Pütz, B., Fleischman, D., Assareh, A., Mattay, V., Buckner, R., Mecocci, P., Dale, A., Cichon, S., Boks, M., Matarin, M., Penninx, B., Calhoun, V., Chakravarty, M., Marquand, A., Macare, C., Masouleh, S., Oosterlaan, J., Amouyel, P., Hegenscheid, K., Rotter, J., Schork, A., Liewald, D., De Zubicaray, G., Wong, T., Shen, L., Sämann, P., Brodaty, H., Roffman, J., De Geus, E., Tsolaki, M., Erk, S., Van Eijk, K., Cavalleri, G., Van der Wee, N., McIntosh, A., Gollub, R., Bulayeva, K., Bernard, M., Richards, J., Himali, J., Loeffler, M., Rommelse, N., Hoffmann, W., Westlye, L., Valdés Hernández, M., Hansell, N., Van Erp, T., Wolf, C., Kwok, J., Vellas, B., Heinz, A., Olde Loohuis, L., Delanty, N., Ho, B., Ching, C., Shumskaya, E., Singh, B., Hofman, A., Van der Meer, D., Homuth, G., Psaty, B., Bastin, M., Montgomery, G., Foroud, T., Reppermund, S., Hottenga, J., Simmons, A., Meyer-Lindenberg, A., Cahn, W., Whelan, C., Van Donkelaar, M., Yang, Q., Hosten, N., Green, R., Thalamuthu, A., Mohnke, S., Hulshoff Pol, H., Lin, H., Jack Jr., C., Schofield, P., Mühleisen, T., Maillard, P., Potkin, S., Wen, W., Fletcher, E., Toga, A., Gruber, O., Huentelman, M., Smith, G., Launer, L., Nyberg, L., Jönsson, E., Crespo-Facorro, B., Koen, N., Greve, D., Uitterlinden, A., Weinberger, D., Steen, V., Fedko, I., Groenewold, N., Niessen, W., Toro, R., Tzourio, C., Longstreth Jr., W., Ikram, M., Smoller, J., Van Tol, M., Sussmann, J., Paus, T., Lemaître, H., Schroeter, M., Mazoyer, B., Andreassen, O., Holsboer, F., Depondt, C., Veltman, D., Turner, J., Pausova, Z., Schumann, G., Van Rooij, D., Djurovic, S., Deary, I., McMahon, K., Müller-Myhsok, B., Brouwer, R., Soininen, H., Pandolfo, M., Wassink, T., Cheung, J., Wolfers, T., Martinot, J., Zwiers, M., Nauck, M., Melle, I., Martin, N., Kanai, R., Westman, E., Kahn, R., Sisodiya, S., White, T., Saremi, A., Van Bokhoven, H., Brunner, H., Völzke, H., Wright, M., Van 't Ent, D., Nöthen, M., Ophoff, R., Buitelaar, J., Fernández, G., Sachdev, P., Rietschel, M., Van Haren, N., Fisher, S., Beiser, A., Francks, C., Saykin, A., Mather, K., Romanczuk-Seiferth, N., Hartman, C., DeStefano, A., Heslenfeld, D., Weiner, M., Walter, H., Hoekstra, P., Nyquist, P., Franke, B., Bennett, D., Grabe, H., Johnson, A., Chen, C., Van Duijn, C., Lopez, O., Fornage, M., Wardlaw, J., Schmidt, R., DeCarli, C., De Jager, P., Villringer, A., Debette, S., Gudnason, V., Medland, S., Shulman, J., Thompson, P., and Seshadri, S.

Subjects
nervous system
Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Published
2019

48. Grafting phenolics onto milk protein via conjugated polymerization for delivery of multiple functionalities:Synthesis and characterization

Author

Ye Zhou, Ahmed A. Abd El-Maksoud, Zheng Guo, Sampson Anankanbil, Chiranjib Banerjee, Ismail H. Abd El-Ghany, Steen V. Petersen, and Hossam S. El-Beltagi

Subjects
Circular dichroism, Magnetic Resonance Spectroscopy, DPPH, PREDICTION, TRANSFER RADICAL POLYMERIZATION, Lactoglobulins, 01 natural sciences, Antioxidants, Analytical Chemistry, CAPACITY, Polymerization, chemistry.chemical_compound, Emulsion system, 0404 agricultural biotechnology, Caffeic Acids, Fish Oils, Phenols, Caffeic acid, NANOPARTICLES, Polymer grafting, ABTS, Calorimetry, Differential Scanning, STABILITY, beta-Lactoglobulin, Circular Dichroism, 010401 analytical chemistry, 04 agricultural and veterinary sciences, General Medicine, 040401 food science, Dynamic Light Scattering, 0104 chemical sciences, Matrix-assisted laser desorption/ionization, Creaming, Protein-phenolic conjugate, chemistry, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Emulsion, Emulsions, Lipid Peroxidation, Antioxidant, IN-WATER EMULSIONS, POLYMERS, Oxidation-Reduction, ANTIOXIDANT ACTIVITY, BEHAVIOR, Food Science, Nuclear chemistry
Abstract

A synthetic scenario for functionalization of β-lactoglobulin (βLg) with polymeric units containing caffeic acid (βLg-polyCA) was developed; and all intermediates and final products were structurally confirmed using nuclear magnetic resonance spectroscopy, matrix assisted laser desorption ionization time-of-flight mass spectrometry, and physico-chemically characterized using differential scanning calorimetry and circular dichroism. The antioxidant properties and emulsion stability of βLg, βLg-CA conjugate and βLg-polyCA based systems containing high percentage of fish oil (50%) were evaluated; and βLg-polyCA presented the highest antioxidant and free radical-scavenging activity based on DPPH, ABTS and HS scavenging assays (92.4, 87.92 and 67.35% respectively). Thiobarbituric acid (TBARS) test demonstrated that compared to native βLg, βLg-polyCA afford up 4–5 fold of inhibition of oxidative rancidity and displayed drastic secondary structure changes. Compared to native βLg based emulsions, βLg-polyCA had larger oil droplet sizes, stronger negative zeta potentials (−69.9 mv), narrower size distributions (PDI: 0.22) and less creaming index.

Published
2019
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49. Hemoglobin polymerization via disulfide bond formation in the hypoxia-tolerant turtleTrachemys scripta: implications for antioxidant defense and O2transport

Author

Asbjørn Graver Petersen, Angela Fago, Steen V. Petersen, Monika M. Golas, Bjoern Sander, Sebastian Frische, and Srdja Drakulic

Subjects
0301 basic medicine, endocrine system diseases, Physiology, Cooperativity, adaptation, DEOXYGENATION, RED-BLOOD-CELLS, OXYGEN-BINDING, 03 medical and health sciences, Physiology (medical), medicine, oxidative stress, chemistry.chemical_classification, Reactive oxygen species, CHICKEN HEMOGLOBIN, Chemistry, AVAILABILITY, Oxygen transport, nutritional and metabolic diseases, thiol, GEL-FILTRATION, hemoglobin, AGGREGATION, SUBUNIT DISSOCIATION, Red blood cell, ALLOSTERIC REGULATION, 030104 developmental biology, medicine.anatomical_structure, Biochemistry, Polymerization, polymerization, Thiol, Hemoglobin, Cysteine
Abstract

The ability of many reptilian hemoglobins (Hbs) to form high-molecular weight polymers, albeit known for decades, has not been investigated in detail. Given that turtle Hbs often contain a high number of cysteine (Cys), potentially contributing to the red blood cell defense against reactive oxygen species, we have examined whether polymerization of Hb could occur via intermolecular disulfide bonds in red blood cells of freshwater turtle Trachemys scripta, a species that is highly tolerant of hypoxia and oxidative stress. We find that one of the two Hb isoforms of the hemolysate HbA is prone to polymerization in vitro into linear flexible chains of different size that are visible by electron microscopy but not the HbD isoform. Polymerization of purified HbA is favored by hydrogen peroxide, a main cellular reactive oxygen species and a thiol oxidant, and inhibited by thiol reduction and alkylation, indicating that HbA polymerization is due to disulfide bonds. By using mass spectrometry, we identify Cys5 of the αA-subunit of HbA as specifically responsible for forming disulfide bonds between adjacent HbA tetramers. Polymerization of HbA does not affect oxygen affinity, cooperativity, and sensitivity to the allosteric cofactor ATP, indicating that HbA is still fully functional. Polymers also form in T. scripta blood after exposure to anoxia but not normoxia, indicating that they are of physiological relevance. Taken together, these results show that HbA polymers may form during oxidative stress and that Cys5αAof HbA is a key element of the antioxidant capacity of turtle red blood cells.

Published
2018
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