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4. Specific proteome changes in platelets from individuals with GATA1-, GFI1B-, and RUNX1-linked bleeding disorders

Author

Van Bergen, M G J M, Marneth, A E, Hoogendijk, A J, Van Alphen, F P J, Van den Akker, E, Laros-Van Gorkom, B A P, Hoeks, M, Simons, A, De Munnik, S A, Janssen, J J W M, Martens, J H A, Jansen, J H, Meijer, A B, Van der Reijden, B A, Afd Biomol.Mass Spect. and Proteomics, and Biomolecular Mass Spectrometry and Proteomics

Subjects
Blood Platelet Disorders/metabolism, Mutation/genetics, Repressor Proteins/metabolism, Core Binding Factor Alpha 2 Subunit/metabolism, Proteome/metabolism, Transcription Factors/genetics, Homeostasis, Humans, Blood Platelets/metabolism, Proto-Oncogene Proteins/metabolism, GATA1 Transcription Factor/metabolism, Signal Transduction
Abstract

Mutations in the transcription factors GATA binding factor 1 (GATA1), growth factor independence 1B (GFI1B), and Runt-related transcription factor 1 (RUNX1) cause familial platelet and bleeding disorders. Mutant platelets exhibit common abnormalities including an α-granule reduction resulting in a grayish appearance in blood smears. This suggests that similar pathways are deregulated by different transcription factor mutations. To identify common factors, full platelet proteomes from 11 individuals with mutant GATA1R216Q, GFI1BQ287*, RUNX1Q154Rfs, or RUNX1TD2-6 and 28 healthy controls were examined by label-free quantitative mass spectrometry. In total, 2875 platelet proteins were reliably quantified. Clustering analysis of more than 300 differentially expressed proteins revealed profound differences between cases and controls. Among cases, 44 of 143 significantly downregulated proteins were assigned to platelet function, hemostasis, and granule biology, in line with platelet dysfunction and bleedings. Remarkably, none of these proteins were significantly diminished in all affected cases. Similarly, no proteins were commonly overrepresented in all affected cases compared with controls. These data indicate that the studied transcription factor mutations alter platelet proteomes in distinct largely nonoverlapping manners. This work provides the quantitative landscape of proteins that affect platelet function when deregulated by mutated transcription factors in inherited bleeding disorders.

Published
2021

5. Specific proteome changes in platelets from individuals with GATA1-, GFI1B-, and RUNX1-linked bleeding disorders

Author

Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Van Bergen, M G J M, Marneth, A E, Hoogendijk, A J, Van Alphen, F P J, Van den Akker, E, Laros-Van Gorkom, B A P, Hoeks, M, Simons, A, De Munnik, S A, Janssen, J J W M, Martens, J H A, Jansen, J H, Meijer, A B, Van der Reijden, B A, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Van Bergen, M G J M, Marneth, A E, Hoogendijk, A J, Van Alphen, F P J, Van den Akker, E, Laros-Van Gorkom, B A P, Hoeks, M, Simons, A, De Munnik, S A, Janssen, J J W M, Martens, J H A, Jansen, J H, Meijer, A B, and Van der Reijden, B A

Published
2021

6. Specific proteome changes in platelets from individuals with GATA1-, GFI1B-, and RUNX1-linked bleeding disorders

Author

Van Bergen, M. G. J. M., primary, Marneth, A. E., additional, Hoogendijk, A. J., additional, Van Alphen, F. P. J., additional, Van den Akker, E., additional, Laros-Van Gorkom, B. A. P., additional, Hoeks, M., additional, Simons, A., additional, De Munnik, S. A., additional, Janssen, J. J. W. M., additional, Martens, J. H. A., additional, Jansen, J. H., additional, Meijer, A. B., additional, and Van der Reijden, B. A., additional

Published
2021
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7. Hemolysis in the spleen drives erythrocyte turnover

Author

Klei, T R L, Dalimot, J, Nota, B, Veldthuis, M, Mul, F P J, Rademakers, T, Hoogenboezem, M, Nagelkerke, S Q, van IJcken, W F J, Oole, E, Svendsen, P, Moestrup, S K, van Alphen, F P J, Meijer, A B, Kuijpers, T W, van Zwieten, R, van Bruggen, R, Klei, T R L, Dalimot, J, Nota, B, Veldthuis, M, Mul, F P J, Rademakers, T, Hoogenboezem, M, Nagelkerke, S Q, van IJcken, W F J, Oole, E, Svendsen, P, Moestrup, S K, van Alphen, F P J, Meijer, A B, Kuijpers, T W, van Zwieten, R, and van Bruggen, R

Abstract

Red pulp macrophages (RPMs) of the spleen mediate turnover of billions of senescent erythrocytes per day. However, the molecular mechanisms involved in sequestration of senescent erythrocytes, their recognition, and their subsequent degradation by RPMs remain unclear. In this study, we provide evidence that the splenic environment is of substantial importance in facilitating erythrocyte turnover through induction of hemolysis. Upon isolating human spleen RPMs, we noted a substantial lack of macrophages that were in the process of phagocytosing intact erythrocytes. Detailed characterization of erythrocyte and macrophage subpopulations from human spleen tissue led to the identification of erythrocytes that are devoid of hemoglobin, so-called erythrocyte ghosts. By using in vivo imaging and transfusion experiments, we further confirmed that senescent erythrocytes that are retained in the spleen are subject to hemolysis. In addition, we showed that erythrocyte adhesion molecules, which are specifically activated on aged erythrocytes, cause senescent erythrocytes to interact with extracellular matrix proteins that are exposed within the splenic architecture. Such adhesion molecule-driven retention of senescent erythrocytes under low shear conditions was found to result in steady shrinkage of the cell and ultimately resulted in hemolysis. In contrast to intact senescent erythrocytes, the remnant erythrocyte ghost shells were prone to recognition and breakdown by RPMs. These data identify hemolysis as a key event in the turnover of senescent erythrocytes, which alters our current understanding of how erythrocyte degradation is regulated.

Published
2020

8. Hemolysis in the spleen drives erythrocyte turnover

Author

Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Klei, T R L, Dalimot, J, Nota, B, Veldthuis, M, Mul, F P J, Rademakers, T, Hoogenboezem, M, Nagelkerke, S Q, van IJcken, W F J, Oole, E, Svendsen, P, Moestrup, S K, van Alphen, F P J, Meijer, A B, Kuijpers, T W, van Zwieten, R, van Bruggen, R, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Klei, T R L, Dalimot, J, Nota, B, Veldthuis, M, Mul, F P J, Rademakers, T, Hoogenboezem, M, Nagelkerke, S Q, van IJcken, W F J, Oole, E, Svendsen, P, Moestrup, S K, van Alphen, F P J, Meijer, A B, Kuijpers, T W, van Zwieten, R, and van Bruggen, R

Published
2020

11. Csde1 cooperates with Strap to control translation of erythroid transcripts

Author

t Hoen Pa, van Alphen F, Kat Moore, Alexander B. Meijer, Nurcan Yagci, and von Lindern M

Subjects
Gene knockdown, Messenger RNA, Translational regulation, RNA splicing, Erythrocyte enucleation, Erythropoiesis, Translation (biology), Biology, Molecular biology, EIF4G3
Abstract

Erythropoiesis is regulated at many levels, including control of mRNA translation. Changing environmental conditions, such as hypoxia, or the availability of nutrients and growth factors, require a rapid response enacted by the enhanced or repressed translation of existing transcripts. Csde1 is an RNA-binding protein required for erythropoiesis and strongly upregulated in erythroblasts relative to other hematopoietic progenitors. The aim of this study is to identify the Csde1-containing protein complexes, and investigate their role in regulating the translation of Csde1-bound transcripts. We show that Strap, also called Unrip, was the protein most strongly associated with Csde1 in erythroblasts. Strap is a WD40 protein involved in signaling and RNA splicing, but its role is unknown when associated with Csde1. Reduced expression of Strap did not alter the pool of transcripts bound by Csde1. Instead, it reduced the mRNA and/or protein expression of several Csde1-bound transcript, that encode for proteins essential for translational regulation during hypoxia, such as Hmbs, eIF4g3 and Pabpc4. Also affected by Strap knockdown were Vim, a Gata-1 target crucial for erythrocyte enucleation, and Elavl1, which stabilizesGata-1mRNA. Thus, we found that the Csde1/Strap complex is at the crossroad of multiple pathways governing translation in erythroblasts.

Published
2017
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12. Hemolysis in the spleen drives erythrocyte turnover

Author

Klei, T. R. L., Dalimot, J., Nota, B., Veldthuis, M., Mul, F. P. J., Rademakers, T., Hoogenboezem, M., Nagelkerke, S. Q., van IJcken, W. F. J., Oole, E., Svendsen, P., Moestrup, S. K., van Alphen, F. P. J., Meijer, A. B., Kuijpers, T. W., van Zwieten, R., and van Bruggen, R.

Abstract

Red pulp macrophages (RPMs) of the spleen mediate turnover of billions of senescent erythrocytes per day. However, the molecular mechanisms involved in sequestration of senescent erythrocytes, their recognition, and their subsequent degradation by RPMs remain unclear. In this study, we provide evidence that the splenic environment is of substantial importance in facilitating erythrocyte turnover through induction of hemolysis. Upon isolating human spleen RPMs, we noted a substantial lack of macrophages that were in the process of phagocytosing intact erythrocytes. Detailed characterization of erythrocyte and macrophage subpopulations from human spleen tissue led to the identification of erythrocytes that are devoid of hemoglobin, so-called erythrocyte ghosts. By using in vivo imaging and transfusion experiments, we further confirmed that senescent erythrocytes that are retained in the spleen are subject to hemolysis. In addition, we showed that erythrocyte adhesion molecules, which are specifically activated on aged erythrocytes, cause senescent erythrocytes to interact with extracellular matrix proteins that are exposed within the splenic architecture. Such adhesion molecule–driven retention of senescent erythrocytes under low shear conditions was found to result in steady shrinkage of the cell and ultimately resulted in hemolysis. In contrast to intact senescent erythrocytes, the remnant erythrocyte ghost shells were prone to recognition and breakdown by RPMs. These data identify hemolysis as a key event in the turnover of senescent erythrocytes, which alters our current understanding of how erythrocyte degradation is regulated.

Published
2020
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14. Impaired killing of Candida albicans by granulocytes mobilized for transfusion purposes: a role for granule components

Author

Gazendam, R. P., primary, van de Geer, A., additional, van Hamme, J. L., additional, Tool, A. T. J., additional, van Rees, D. J., additional, Aarts, C. E. M., additional, van den Biggelaar, M., additional, van Alphen, F., additional, Verkuijlen, P., additional, Meijer, A. B., additional, Janssen, H., additional, Roos, D., additional, van den Berg, T. K., additional, and Kuijpers, T. W., additional

Published
2016
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16. Poster session 3

Author

Nanka, O., primary, Krejci, E., additional, Pesevski, Z., additional, Sedmera, D., additional, Smart, N., additional, Rossdeutsch, A., additional, Dube, K. N., additional, Riegler, J., additional, Price, A. N., additional, Taylor, A., additional, Muthurangu, V., additional, Turner, M., additional, Lythgoe, M. F., additional, Riley, P. R., additional, Kryvorot, S., additional, Vladimirskaya, T., additional, Shved, I., additional, Schwarzl, M., additional, Seiler, S., additional, Huber, S., additional, Steendijk, P., additional, Maechler, H., additional, Truschnig-Wilders, M., additional, Pieske, B., additional, Post, H., additional, Caprio, C., additional, Baldini, A., additional, Chiavacci, E., additional, Dolfi, L., additional, Verduci, L., additional, Meghini, F., additional, Cremisi, F., additional, Pitto, L., additional, Kuan, T.-C., additional, Chen, M.-C., additional, Yang, T.-H., additional, Wu, W.-T., additional, Lin, C. S., additional, Rai, H., additional, Kumar, S., additional, Sharma, A. K., additional, Mastana, S., additional, Kapoor, A., additional, Pandey, C. M., additional, Agrawal, S., additional, Sinha, N., additional, Orlowska-Baranowska, E. H., additional, Placha, G., additional, Gora, J., additional, Baranowski, R., additional, Abramczuk, E., additional, Hryniewiecki, T., additional, Gaciong, Z., additional, Verschuren, J. J. W., additional, Wessels, J. A. M., additional, Trompet, S., additional, Stott, D. J., additional, Sattar, N., additional, Buckley, B., additional, Guchelaar, H. J., additional, Jukema, J. W., additional, Gharanei, M., additional, Hussain, A., additional, Mee, C. J., additional, Maddock, H. L., additional, Wijnen, W. J., additional, Van Den Oever, S., additional, Van Der Made, I., additional, Hiller, M., additional, Tijsen, A. J., additional, Pinto, Y. M., additional, Creemers, E. E., additional, Nikulina, S. U. Y., additional, Chernova, A., additional, Petry, A., additional, Rzymski, T., additional, Kracun, D., additional, Riess, F., additional, Pike, L., additional, Harris, A. L., additional, Gorlach, A., additional, Katare, R., additional, Oikawa, A., additional, Riu, F., additional, Beltrami, A. P., additional, Cesseli, D., additional, Emanueli, C., additional, Madeddu, P., additional, Zaglia, T., additional, Milan, G., additional, Franzoso, M., additional, Pesce, P., additional, Sarais, C., additional, Sandri, M., additional, Mongillo, M., additional, Butler, T. J., additional, Seymour, A.-M. L., additional, Ashford, D., additional, Jaffre, F., additional, Bussen, M., additional, Flohrschutz, I., additional, Martin, G. R., additional, Engelhardt, S., additional, Kararigas, G., additional, Nguyen, B. T., additional, Jarry, H., additional, Regitz-Zagrosek, V., additional, Van Bilsen, M., additional, Daniels, A., additional, Munts, C., additional, Janssen, B. J. A., additional, Van Der Vusse, G. J., additional, Van Nieuwenhoven, F. A., additional, Montalvo, C., additional, Villar, A. V., additional, Merino, D., additional, Garcia, R., additional, Llano, M., additional, Ares, M., additional, Hurle, M. A., additional, Nistal, J. F., additional, Dembinska-Kiec, A., additional, Beata Kiec-Wilk, B. K. W., additional, Anna Polus, A. P., additional, Urszula Czech, U. C., additional, Tatiana Konovaleva, T. K., additional, Gerd Schmitz, G. S., additional, Bertrand, L., additional, Balteau, M., additional, Timmermans, A., additional, Viollet, B., additional, Sakamoto, K., additional, Feron, O., additional, Horman, S., additional, Vanoverschelde, J. L., additional, Beauloye, C., additional, De Meester, C., additional, Martinez, E., additional, Martin, R., additional, Miana, M., additional, Jurado, R., additional, Gomez-Hurtado, N., additional, Bartolome, M. V., additional, San Roman, J. A., additional, Lahera, V., additional, Nieto, M. L., additional, Cachofeiro, V., additional, Rochais, F., additional, Sturny, R., additional, Mesbah, K., additional, Miquerol, L., additional, Kelly, R. G., additional, Messaoudi, S., additional, Gravez, B., additional, Tarjus, A., additional, Pelloux, V., additional, Samuel, J. L., additional, Delcayre, C., additional, Launay, J. M., additional, Clement, K., additional, Farman, N., additional, Jaisser, F., additional, Hadyanto, L., additional, Castellani, C., additional, Vescovo, G., additional, Ravara, B., additional, Tavano, R., additional, Pozzobon, M., additional, De Coppi, P., additional, Papini, E., additional, Vettor, R., additional, Thiene, G., additional, Angelini, A., additional, Meloni, M., additional, Caporali, A., additional, Cesselli, D., additional, Fortunato, O., additional, Avolio, E., additional, Schindler, R., additional, Simrick, S., additional, Brand, T., additional, Smart, N. S., additional, Herman, A., additional, Roura Ferrer, S., additional, Rodriguez Bago, J., additional, Soler-Botija, C., additional, Pujal, J. M., additional, Galvez-Monton, C., additional, Prat-Vidal, C., additional, Llucia-Valldeperas, A., additional, Blanco, J., additional, Bayes-Genis, A., additional, Foldes, G., additional, Maxime, M., additional, Ali, N. N., additional, Schneider, M. D., additional, Harding, S. E., additional, Reni, C., additional, Mangialardi, G., additional, De Pauw, A., additional, Sekkali, B., additional, Friart, A., additional, Ding, H., additional, Graffeuil, A., additional, Catalucci, D., additional, Balligand, J. L., additional, Azibani, F., additional, Tournoux, F., additional, Schlossarek, S., additional, Polidano, E., additional, Fazal, L., additional, Merval, R., additional, Carrier, L., additional, Chatziantoniou, C., additional, Buyandelger, B., additional, Linke, W., additional, Zou, P., additional, Kostin, S., additional, Ku, C., additional, Felkin, L., additional, Birks, E., additional, Barton, P., additional, Sattler, M., additional, Knoell, R., additional, Schroder, K., additional, Benkhoff, S., additional, Shimokawa, H., additional, Grisk, O., additional, Brandes, R. P., additional, Parepa, I. R., additional, Mazilu, L., additional, Suceveanu, A. I., additional, Suceveanu, A., additional, Rusali, L., additional, Cojocaru, L., additional, Matei, L., additional, Toringhibel, M., additional, Craiu, E., additional, Pires, A. L., additional, Pinho, M., additional, Pinho, S., additional, Sena, C., additional, Seica, R., additional, Leite-Moreira, A., additional, Dabroi, F., additional, Schiaffino, S., additional, Kiseleva, E., additional, Krukov, N., additional, Nikitin, O., additional, Ardatova, L., additional, Mourouzis, I., additional, Pantos, C., additional, Kokkinos, A. D., additional, Cokkinos, D. V., additional, Scoditti, E., additional, Massaro, M., additional, Carluccio, M. A., additional, Pellegrino, M., additional, Calabriso, N., additional, Gastaldelli, A., additional, Storelli, C., additional, De Caterina, R., additional, Lindner, D., additional, Zietsch, C., additional, Schultheiss, H.-P., additional, Tschope, C., additional, Westermann, D., additional, Everaert, B. R., additional, Nijenhuis, V. J., additional, Reith, F. C. M., additional, Hoymans, V. Y., additional, Timmermans, J. P., additional, Vrints, C. J., additional, Simova, I., additional, Mateev, H., additional, Katova, T., additional, Haralanov, L., additional, Dimitrov, N., additional, Mironov, N., additional, Golitsyn, S. P., additional, Sokolov, S. F., additional, Yuricheva, Y. U. A., additional, Maikov, E. B., additional, Shlevkov, N. B., additional, Rosenstraukh, L. V., additional, Chazov, E. I., additional, Radosinska, J., additional, Knezl, V., additional, Benova, T., additional, Slezak, J., additional, Urban, L., additional, Tribulova, N., additional, Virag, L., additional, Kristof, A., additional, Kohajda, Z. S., additional, Szel, T., additional, Husti, Z., additional, Baczko, I., additional, Jost, N., additional, Varro, A., additional, Sarusi, A., additional, Farkas, A. S., additional, Orosz, S. Z., additional, Forster, T., additional, Farkas, A., additional, Zakhrabova-Zwiauer, O. M., additional, Hardziyenka, M., additional, Nieuwland, R., additional, Tan, H. L., additional, Raaijmakers, A. J. A., additional, Bourgonje, V. J. A., additional, Kok, G. J. M., additional, Van Veen, A. A. B., additional, Anderson, M. E., additional, Vos, M. A., additional, Bierhuizen, M. F. A., additional, Benes, J., additional, Sebestova, B., additional, Ghouri, I. A., additional, Kemi, O. J., additional, Kelly, A., additional, Burton, F. L., additional, Smith, G. L., additional, Ozdemir, S., additional, Acsai, K., additional, Doisne, N., additional, Van Der Nagel, R., additional, Beekman, H. D. M., additional, Van Veen, T. A. B., additional, Sipido, K. R., additional, Antoons, G., additional, Harmer, S. C., additional, Mohal, J. S., additional, Kemp, D., additional, Tinker, A., additional, Beech, D., additional, Burley, D. S., additional, Cox, C. D., additional, Wann, K. T., additional, Baxter, G. F., additional, Wilders, R., additional, Verkerk, A., additional, Fragkiadaki, P., additional, Germanakis, G., additional, Tsarouchas, K., additional, Tsitsimpikou, C., additional, Tsardi, M., additional, George, D., additional, Tsatsakis, A., additional, Rodrigues, P., additional, Barros, C., additional, Najmi, A. K., additional, Khan, V., additional, Akhtar, M., additional, Pillai, K. K., additional, Mujeeb, M., additional, Aqil, M., additional, Bayliss, C. R., additional, Messer, A. E., additional, Leung, M.-C., additional, Ward, D., additional, Van Der Velden, J., additional, Poggesi, C., additional, Redwood, C. S., additional, Marston, S., additional, Vite, A., additional, Gandjbakhch, E., additional, Gary, F., additional, Fressart, V., additional, Leprince, P., additional, Fontaine, G., additional, Komajda, M., additional, Charron, P., additional, Villard, E., additional, Falcao-Pires, I., additional, Gavina, C., additional, Hamdani, N., additional, Stienen, G. J. M., additional, Niessens, H. W. M., additional, Leite-Moreira, A. F., additional, Paulus, W. J., additional, Memo, M., additional, Marston, S. B., additional, Vafiadaki, E., additional, Qian, J., additional, Arvanitis, D. A., additional, Sanoudou, D., additional, Kranias, E. G., additional, Elmstedt, N., additional, Lind, B., additional, Ferm-Widlund, K., additional, Westgren, M., additional, Brodin, L.-A., additional, Mansfield, C., additional, West, T., additional, Ferenczi, M., additional, Wijnker, P. J. M., additional, Foster, D. B., additional, Coulter, A., additional, Frazier, A., additional, Murphy, A. M., additional, Shah, M., additional, Sikkel, M. B., additional, Desplantez, T., additional, Collins, T. P., additional, O' Gara, P., additional, Lyon, A. R., additional, Macleod, K. T., additional, Ottesen, A. H., additional, Louch, W. E., additional, Carlson, C., additional, Landsverk, O. J. B., additional, Stridsberg, M., additional, Sjaastad, I., additional, Oie, E., additional, Omland, T., additional, Christensen, G., additional, Rosjo, H., additional, Cartledge, J., additional, Clark, L. A., additional, Ibrahim, M., additional, Siedlecka, U., additional, Navaratnarajah, M., additional, Yacoub, M. H., additional, Camelliti, P., additional, Terracciano, C. M., additional, Chester, A., additional, Gonzalez-Tendero, A., additional, Torre, I., additional, Garcia-Garcia, F., additional, Dopazo, J., additional, Gratacos, E., additional, Taylor, D., additional, Bhandari, S., additional, Seymour, A.-M., additional, Fliegner, D., additional, Jost, J., additional, Bugger, H., additional, Ventura-Clapier, R., additional, Carpi, A., additional, Campesan, M., additional, Canton, M., additional, Menabo, R., additional, Pelicci, P. G., additional, Giorgio, M., additional, Di Lisa, F., additional, Hancock, M., additional, Venturini, A., additional, Al-Shanti, N., additional, Stewart, C., additional, Ascione, R., additional, Angelini, G., additional, Suleiman, M.-S., additional, Kravchuk, E., additional, Grineva, E., additional, Galagudza, M., additional, Kostareva, A., additional, Bairamov, A., additional, Krychtiuk, K. A., additional, Watzke, L., additional, Kaun, C., additional, Demyanets, S., additional, Pisoni, J., additional, Kastl, S. P., additional, Huber, K., additional, Maurer, G., additional, Wojta, J., additional, Speidl, W. S., additional, Varga, Z. V., additional, Farago, N., additional, Zvara, A., additional, Kocsis, G. F., additional, Pipicz, M., additional, Csonka, C., additional, Csont, T., additional, Puskas, G. L., additional, Ferdinandy, P., additional, Klevstigova, M., additional, Silhavy, J., additional, Manakov, D., additional, Papousek, F., additional, Novotny, J., additional, Pravenec, M., additional, Kolar, F., additional, Novakova, O., additional, Novak, F., additional, Neckar, J., additional, Barallobre-Barreiro, J., additional, Didangelos, A., additional, Yin, X., additional, Fernandez-Caggiano, M., additional, Drozdov, I., additional, Willeit, P., additional, Domenech, N., additional, Mayr, M., additional, Lemoine, S., additional, Allouche, S., additional, Coulbault, L., additional, Galera, P., additional, Gerard, J. L., additional, Hanouz, J. L., additional, Suveren, E., additional, Whiteman, M., additional, Studneva, I. M., additional, Pisarenko, O., additional, Shulzhenko, V., additional, Serebryakova, L., additional, Tskitishvili, O., additional, Timoshin, A., additional, Fauconnier, J., additional, Meli, A. C., additional, Thireau, J., additional, Roberge, S., additional, Lompre, A. M., additional, Jacotot, E., additional, Marks, A. M., additional, Lacampagne, A., additional, Dietel, B., additional, Altendorf, R., additional, Daniel, W. G., additional, Kollmar, R., additional, Garlichs, C. D., additional, Parente, V., additional, Balasso, S., additional, Pompilio, G., additional, Colombo, G., additional, Milano, G., additional, Squadroni, L., additional, Cotelli, F., additional, Pozzoli, O., additional, Capogrossi, M. C., additional, Ajiro, Y., additional, Saegusa, N., additional, Iwade, K., additional, Giles, W. R., additional, Stafforini, D. M., additional, Spitzer, K. W., additional, Sirohi, R., additional, Candilio, L., additional, Babu, G., additional, Roberts, N., additional, Lawrence, D., additional, Sheikh, A., additional, Kolvekar, S., additional, Yap, J., additional, Hausenloy, D. J., additional, Yellon, D. M., additional, Aslam, M., additional, Rohrbach, S., additional, Schlueter, K.-D., additional, Piper, H. M., additional, Noll, T., additional, Guenduez, D., additional, Malinova, L., additional, Ryabukho, V. P., additional, Lyakin, D. V., additional, Denisova, T. P., additional, Montoro-Garcia, S., additional, Shantsila, E., additional, Lip, G. Y. H., additional, Kalaska, B., additional, Sokolowska, E., additional, Kaminski, K., additional, Szczubialka, K., additional, Kramkowski, K., additional, Mogielnicki, A., additional, Nowakowska, M., additional, Buczko, W., additional, Stancheva, N., additional, Mekenyan, E., additional, Gospodinov, K., additional, Tisheva, S., additional, Darago, A., additional, Rutkai, I., additional, Kalasz, J., additional, Czikora, A., additional, Orosz, P., additional, Bjornson, H. D., additional, Edes, I., additional, Papp, Z., additional, Toth, A., additional, Riches, K., additional, Warburton, P., additional, O'regan, D. J., additional, Ball, S. G., additional, Turner, N. A., additional, Wood, I. C., additional, Porter, K. E., additional, Kogaki, S., additional, Ishida, H., additional, Nawa, N., additional, Takahashi, K., additional, Baden, H., additional, Ichimori, H., additional, Uchikawa, T., additional, Mihara, S., additional, Miura, K., additional, Ozono, K., additional, Lugano, R., additional, Padro, T., additional, Garcia-Arguinzonis, M., additional, Badimon, L., additional, Ferraro, F., additional, Viner, R., additional, Ho, J., additional, Cutler, D., additional, Matchkov, V., additional, Aalkjaer, C., additional, Krijnen, P. A. J., additional, Hahn, N. E., additional, Kholova, I., additional, Sipkens, J. A., additional, Van Alphen, F. P., additional, Simsek, S., additional, Schalkwijk, C. G., additional, Van Buul, J. D., additional, Van Hinsbergh, V. W. M., additional, Niessen, H. W. M., additional, Caro, C. G., additional, Seneviratne, A., additional, Monaco, C., additional, Hou, D., additional, Singh, J., additional, Gilson, P., additional, Burke, M. G., additional, Heraty, K. B., additional, Krams, R., additional, Coppola, G., additional, Albrecht, K., additional, Schgoer, W., additional, Wiedemann, D., additional, Bonaros, N., additional, Steger, C., additional, Theurl, M., additional, Stanzl, U., additional, Kirchmair, R., additional, Amadesi, S., additional, Spinetti, G., additional, Cangiano, E., additional, Valgimigli, M., additional, Miller, A. M., additional, Cardinali, A., additional, Vierlinger, K., additional, Pagano, G., additional, Liccardo, D., additional, Zincarelli, C., additional, Femminella, G. D., additional, Lymperopoulos, A., additional, De Lucia, C., additional, Koch, W. J., additional, Leosco, D., additional, Rengo, G., additional, Hinkel, R., additional, Husada, W., additional, Trenkwalder, T., additional, Di, Q., additional, Lee, S., additional, Petersen, B., additional, Bock-Marquette, I., additional, Niemann, H., additional, Di Maio, M., additional, Kupatt, C., additional, Nourian, M., additional, Yassin, Z., additional, Kelishadi, R., additional, Memarian, S. H., additional, Heidari, A., additional, Leuner, A., additional, Poitz, D. M., additional, Brunssen, C., additional, Ravens, U., additional, Strasser, R. H., additional, Morawietz, H., additional, Vogt, F., additional, Grahl, A., additional, Flege, C., additional, Marx, N., additional, Borinski, M., additional, De Geest, B., additional, Jacobs, F., additional, Muthuramu, I., additional, Gordts, S. C., additional, Van Craeyveld, E., additional, Herijgers, P., additional, Weinert, S., additional, Medunjanin, S., additional, Herold, J., additional, Schmeisser, A., additional, Braun-Dullaeus, R. C., additional, Wagner, A. H., additional, Moeller, K., additional, Adolph, O., additional, Schwarz, M., additional, Schwale, C., additional, Bruehl, C., additional, Nobiling, R., additional, Wieland, T., additional, Schneider, S. W., additional, Hecker, M., additional, Cross, A., additional, Strom, A., additional, Cole, J., additional, Goddard, M., additional, Hultgardh-Nilsson, A., additional, Nilsson, J., additional, Mauri, C., additional, Mitkovskaya, N. P., additional, Kurak, T. A., additional, Oganova, E. G., additional, Shkrebneva, E. I., additional, Kot, Z. H. N., additional, Statkevich, T. V., additional, Molica, F., additional, Burger, F., additional, Matter, C. M., additional, Thomas, A., additional, Staub, C., additional, Zimmer, A., additional, Cravatt, B., additional, Pacher, P., additional, Steffens, S., additional, Blanco, R., additional, Sarmiento, R., additional, Parisi, C., additional, Fandino, S., additional, Blanco, F., additional, Gigena, G., additional, Szarfer, J., additional, Rodriguez, A., additional, Garcia Escudero, A., additional, Riccitelli, M. A., additional, Wantha, S., additional, Simsekyilmaz, S., additional, Megens, R. T., additional, Van Zandvoort, M. A., additional, Liehn, E., additional, Zernecke, A., additional, Klee, D., additional, Weber, C., additional, Soehnlein, O., additional, Lima, L. M., additional, Carvalho, M. G., additional, Gomes, K. B., additional, Santos, I. R., additional, Sousa, M. O., additional, Morais, C. A. S., additional, Oliveira, S. H. V., additional, Gomes, I. F., additional, Brandao, F. C., additional, Lamego, M. R. A., additional, Fornai, L., additional, Kiss, A., additional, Giskes, F., additional, Eijkel, G., additional, Fedrigo, M., additional, Valente, M. L., additional, Heeren, R. M. A., additional, Grdinic, A., additional, Vojvodic, D., additional, Djukanovic, N., additional, Grdinic, A. G., additional, Obradovic, S., additional, Majstorovic, I., additional, Rusovic, S., additional, Vucinic, Z., additional, Tavciovski, D., additional, Ostojic, M., additional, Lai, S.-C., additional, Chen, M.-Y., additional, Wu, H.-T., additional, Gouweleeuw, L., additional, Oberdorf-Maass, S. U., additional, De Boer, R. A., additional, Van Gilst, W. H., additional, Maass, A. H., additional, Van Gelder, I. C., additional, Benard, L., additional, Li, C., additional, Warren, D., additional, Shanahan, C. M., additional, Zhang, Q. P., additional, Bye, A., additional, Vettukattil, R., additional, Aspenes, S. T., additional, Giskeodegaard, G., additional, Gribbestad, I. S., additional, Wisloff, U., additional, Bathen, T. F., additional, Cubedo, J., additional, Alonso, R., additional, Mata, P., additional, Ivic, I., additional, Vamos, Z., additional, Cseplo, P., additional, Kosa, D., additional, Torok, O., additional, Hamar, J., additional, Koller, A., additional, Norita, K., additional, De Noronha, S. V., additional, Sheppard, M. N., additional, Amat-Roldan, I., additional, Iruretagoiena, I., additional, Psilodimitrakopoulos, S., additional, Crispi, F., additional, Artigas, D., additional, Loza-Alvarez, P., additional, Harrison, J. C., additional, Smart, S. D., additional, Besely, E. H., additional, Kelly, J. R., additional, Yao, Y., additional, Sammut, I. A., additional, Hoepfner, M., additional, Kuzyniak, W., additional, Sekhosana, E., additional, Hoffmann, B., additional, Litwinski, C., additional, Pries, A., additional, Ermilov, E., additional, Fontoura, D., additional, Lourenco, A. P., additional, Vasques-Novoa, F., additional, Pinto, J. P., additional, Roncon-Albuquerque, R., additional, Oyeyipo, I. P., additional, Olatunji, L. A., additional, Usman, T. O., additional, Olatunji, V. A., additional, Bacova, B., additional, Viczenczova, C., additional, Dosenko, V., additional, Goncalvesova, E., additional, Vanrooyen, J., additional, Maulik, S. K., additional, Seth, S., additional, Dinda, A. K., additional, Jaiswal, A., additional, Mearini, G., additional, Khajetoorians, D., additional, Kraemer, E., additional, Gedicke-Hornung, C., additional, Precigout, G., additional, Eschenhagen, T., additional, Voit, T., additional, Garcia, L., additional, Lorain, S., additional, Mendes-Ferreira, P., additional, Maia-Rocha, C., additional, Adao, R., additional, Cerqueira, R. J., additional, Mendes, M. J., additional, Castro-Chaves, P., additional, De Keulenaer, G. W., additional, Bras-Silva, C., additional, Ruiter, G., additional, Wong, Y. Y., additional, Lubberink, M., additional, Knaapen, P., additional, Raijmakers, P., additional, Lammertsma, A. A., additional, Marcus, J. T., additional, Westerhof, N., additional, Van Der Laarse, W. J., additional, Vonk-Noordegraaf, A., additional, Steinbronn, N., additional, Koch, E., additional, Steiner, G., additional, Berezin, A., additional, Lisovaya, O. A., additional, Soldatova, A. M., additional, Kuznetcov, V. A., additional, Yenina, T. N., additional, Rychkov, A. Y. U., additional, Shebeko, P. V., additional, Altara, R., additional, Hessel, M. H. M., additional, Hermans, J. J. R., additional, Blankesteijn, W. M., additional, Berezina, T. A., additional, Seden, V., additional, Bonanad, C., additional, Nunez, J., additional, Navarro, D., additional, Chilet, M. F., additional, Sanchis, F., additional, Bodi, V., additional, Minana, G., additional, Chaustre, F., additional, Forteza, M. J., additional, Llacer, A., additional, Galasso, G., additional, Ferrara, N., additional, Akhmedov, A., additional, Klingenberg, R., additional, Brokopp, C., additional, Hof, D., additional, Zoller, S., additional, Corti, R., additional, Gay, S., additional, Von Eckardstein, A., additional, Hoerstrup, S. P., additional, Luescher, T. F., additional, Heijman, J., additional, Zaza, A., additional, Johnson, D. M., additional, Rudy, Y., additional, Peeters, R. L. M., additional, Volders, P. G. A., additional, Westra, R. L., additional, Fujita, S., additional, Okamoto, R., additional, Taniguchi, M., additional, Konishi, K., additional, Goto, I., additional, Sugimoto, K., additional, Nakamura, M., additional, Shiraki, K., additional, Buechler, C., additional, and Ito, M., additional

Published
2012
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18. The Effect of Low-level Laser Treatment on Maxillary Arch Dimensions after Palatal Surgery on Beagle Dogs.

Author

IN DE BRAEKT, M. M. H., VAN ALPHEN, F. A. M., KUIJPERS-JAGTMAN, A. M., and MALTHA, J. C.

Subjects
LASERS in dentistry, PALATE surgery, DENTAL arch, BEAGLE (Dog breed), DENTAL casting, TOOTH eruption, ALVEOLAR process surgery, PHYSIOLOGY
Abstract

The effect of low-level laser treatment on maxillary arch dimensions after palatal surgery was investigated in Beagle dogs at an age of 12 weeks. A total of 30 dogs was used, and they were assigned to either a control group (Group C, n = 6) or one of two experimental groups (Group L, n = 12; and group LL, n = 12). After Von Langenbeck's palatal repair in the two experimental groups, denuded bony areas in the LL group were irradiated with a continuous Ga-As-Al laser beam (830 nm) and energy output set at 30 mW. A dosage of 1 J/cm² wound surface area was used. Treatment was carried out three times a week, with a total of ten treatments. The animals of the L group served as non-treated control animals. Dental casts were made of all animals of all groups at regular intervals until they reached 25 weeks of age. Maxillary arch dimensions were studied. Dental arch dimensions in the deciduous dentition of both experimental groups were not disturbed by surgery, but after eruption of permanent teeth, mainly transvere maxillary arch dimensions in the premolar region increased less in both experimental groups than in the control group. It was concluded that low-level laser treatment under the conditions used in this study did not decrease the adverse iatrogenic effects of palatal surgery on maxillary arch dimensions. [ABSTRACT FROM AUTHOR]

Published
1991
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22. Endothelial ICAM-1 Adhesome Recruits CD44 for Optimal Transcellular Migration of Human CTLs.

Author

van Steen ACI, Grönloh MLB, Joosten S, van Alphen F, van den Biggelaar M, Nolte MA, Spaargaren M, van Buul JD, and Schoppmeyer R

Subjects
Humans, Intercellular Adhesion Molecule-1 metabolism, Endothelium metabolism, Cell Adhesion physiology, Leukocytes metabolism, Hyaluronan Receptors metabolism, Endothelial Cells metabolism, Hyaluronic Acid metabolism
Abstract

The endothelial lining of blood vessels is covered with a thin polysaccharide coat called the glycocalyx. This layer of polysaccharides contains hyaluronan that forms a protective coat on the endothelial surface. Upon inflammation, leukocytes leave the circulation and enter inflamed tissue by crossing inflamed endothelial cells, mediated by adhesion molecules such as ICAM-1/CD54. To what extent the glycocalyx participates in the regulation of leukocyte transmigration is not clear. During extravasation, leukocyte integrins cluster ICAM-1, resulting in the recruitment of a number of intracellular proteins and subsequent downstream effects in the endothelial cells. For our studies, we used primary human endothelial and immune cells. With an unbiased proteomics approach, we identified the full ICAM-1 adhesome and identified 93 (to our knowledge) new subunits of the ICAM-1 adhesome. Interestingly, we found the glycoprotein CD44 as part of the glycocalyx to be recruited to clustered ICAM-1 specifically. Our data demonstrate that CD44 binds hyaluronan to the endothelial surface, where it locally concentrates and presents chemokines that are essential for leukocytes to cross the endothelial lining. Taken together, we discover a link between ICAM-1 clustering and hyaluronan-mediated chemokine presentation by recruiting hyaluronan to sites of leukocyte adhesion via CD44., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Published
2023
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23. Defective AP-3-dependent VAMP8 trafficking impairs Weibel-Palade body exocytosis in Hermansky-Pudlak Syndrome type 2 blood outgrowth endothelial cells.

Author

Karampini E, Schillemans M, Hofman M, van Alphen F, de Boer M, Kuijpers TW, van den Biggelaar M, Voorberg J, and Bierings R

Subjects
Calcium Signaling, Cells, Cultured, Humans, Mutation, Protein Transport, R-SNARE Proteins genetics, Adaptor Protein Complex 3 genetics, Adaptor Protein Complex 3 metabolism, Adaptor Protein Complex beta Subunits genetics, Adaptor Protein Complex beta Subunits metabolism, Endothelial Cells metabolism, Endothelial Cells pathology, Exocytosis, Hermanski-Pudlak Syndrome genetics, Hermanski-Pudlak Syndrome metabolism, Hermanski-Pudlak Syndrome pathology, R-SNARE Proteins metabolism, Weibel-Palade Bodies genetics, Weibel-Palade Bodies metabolism, Weibel-Palade Bodies pathology
Abstract

Weibel-Palade bodies are endothelial secretory organelles that contain von Willebrand factor, P-selectin and CD63. Release of von Willebrand factor from Weibel-Palade bodies is crucial for platelet adhesion during primary hemostasis. Endosomal trafficking of proteins like CD63 to Weibel-Palade bodies during maturation is dependent on the adaptor protein complex 3 complex. Mutations in the AP3B1 gene, which encodes the adaptor protein complex 3 β1 subunit, result in Hermansky-Pudlak syndrome 2, a rare genetic disorder that leads to neutropenia and a mild bleeding diathesis. This is caused by abnormal granule formation in neutrophils and platelets due to defects in trafficking of cargo to secretory organelles. The impact of these defects on the secretory pathway of the endothelium is largely unknown. In this study, we investigated the role of adaptor protein complex 3-dependent mechanisms in trafficking of proteins during Weibel-Palade body maturation in endothelial cells. An ex vivo patient-derived endothelial model of Hermansky-Pudlak syndrome type 2 was established using blood outgrowth endothelial cells that were isolated from a patient with compound heterozygous mutations in AP3B1 Hermansky-Pudlak syndrome type 2 endothelial cells and CRISPR-Cas9-engineered AP3B1 -/- endothelial cells contain Weibel-Palade bodies that are entirely devoid of CD63, indicative of disrupted endosomal trafficking. Hermansky-Pudlak syndrome type 2 endothelial cells have impaired Ca2 +- mediated and cAMP-mediated exocytosis. Whole proteome analysis revealed that, apart from adaptor protein complex 3 β1, also the μ1 subunit and the v-SNARE VAMP8 were depleted. Stimulus-induced von Willebrand factor secretion was impaired in CRISPR-Cas9-engineered VAMP8 -/- endothelial cells. Our data show that defects in adaptor protein complex 3-dependent maturation of Weibel-Palade bodies impairs exocytosis by affecting the recruitment of VAMP8., (Copyright© 2019 Ferrata Storti Foundation.)

Published
2019
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24. A Homozygous Mutation on the HBA1 Gene Coding for Hb Charlieu (HBA1: c.320T>C) Together with β-Thalassemia Trait Results in Severe Hemolytic Anemia.

Author

Klei TRL, Kheradmand Kia S, Veldthuis M, Dehbozorgian J, Karimi M, Geissler J, Sellink E, Thiel-Valkhof M, Burger P, van Alphen F, Meijer AB, van Bruggen R, and van Zwieten R

Subjects
Child, Preschool, Humans, Male, Homozygote, Mutation genetics
Abstract

A 4-year-old boy, a β-thalassemia (β-thal) carrier, with an unexplained severe chronic microcytic anemia was referred to us. Sequencing of the α-globin genes revealed a Hb Charlieu [α106(G13)Leu→Pro, HBA1 : c.320T>C, p.Leu107Pro] mutation present on both HBA1 genes. Quantitative polymerase chain reaction (qPCR) confirmed α Charlieu mRNA in the proband and his parents, showing that the mutation does not affect mRNA stability. However, we were unable to detect the Hb Charlieu protein by capillary electrophoresis (CE), reverse phase electrophoresis, cation exchange electrophoresis or isoelectric focusing. Mass spectrometry (MS) allowed us to confirm the presence of the Hb Charlieu peptide in erythrocyte progenitors. These findings suggest that the mutation affects the stability of α Charlieu . As hemoglobin (Hb) heat stability tests showed no abnormalities in erythrocytes, we speculated that α Charlieu is already degraded during red blood cell (RBC) development. The clinical severity in the proband and the presence of new methylene blue-stained aggregates in his reticulocytes indicates that incorporation of α Charlieu destabilizes Hb. This, combined with an excess of unstable free α-globins as the result of β-thal minor, results in severely impaired erythropoiesis and, as a consequence, severe and chronic microcytic anemia in the proband.

Published
2019
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25. Strap associates with Csde1 and affects expression of select Csde1-bound transcripts.

Author

Moore KS, Yagci N, van Alphen F, Meijer AB, 't Hoen PAC, and von Lindern M

Subjects
Animals, Carrier Proteins genetics, Cell Cycle, Cell Differentiation, Erythroblasts cytology, Erythroblasts metabolism, Gene Knockdown Techniques, HEK293 Cells, Humans, Mice, Protein Binding, RNA, Messenger genetics, RNA, Messenger metabolism, Ribosomes metabolism, Carrier Proteins metabolism, DNA-Binding Proteins metabolism, Gene Expression Regulation, RNA-Binding Proteins metabolism
Abstract

Erythropoiesis is regulated at many levels, including control of mRNA translation. Changing environmental conditions, such as hypoxia or the availability of nutrients and growth factors, require a rapid response enacted by the enhanced or repressed translation of existing transcripts. Cold shock domain protein e1 (Csde1/Unr) is an RNA-binding protein required for erythropoiesis and strongly upregulated in erythroblasts relative to other hematopoietic progenitors. The aim of this study is to identify the Csde1-containing protein complexes and investigate their role in post-transcriptional expression control of Csde1-bound transcripts. We show that Serine/Threonine kinase receptor-associated protein (Strap/Unrip), was the protein most strongly associated with Csde1 in erythroblasts. Strap is a WD40 protein involved in signaling and RNA splicing, but its role when associated with Csde1 is unknown. Reduced expression of Strap did not alter the pool of transcripts bound by Csde1. Instead, it altered the mRNA and/or protein expression of several Csde1-bound transcripts that encode for proteins essential for translational regulation during hypoxia, such as Hmbs, eIF4g3 and Pabpc4. Also affected by Strap knockdown were Vim, a Gata-1 target crucial for erythrocyte enucleation, and Elavl1, which stabilizes Gata-1 mRNA. The major cellular processes affected by both Csde1 and Strap were ribosome function and cell cycle control., Competing Interests: The authors have declared that no competing interests exist.

Published
2018
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26. Mass spectrometry-assisted identification of ADAMTS13-derived peptides presented on HLA-DR and HLA-DQ.

Author

Hrdinová J, Verbij FC, Kaijen PHP, Hartholt RB, van Alphen F, Lardy N, Ten Brinke A, Vanhoorelbeke K, Hindocha PJ, De Groot AS, Meijer AB, Voorberg J, and Peyron I

Subjects
ADAMTS13 Protein metabolism, Animals, Antigen Presentation, Dendritic Cells, Epitope Mapping methods, Genotype, HEK293 Cells, HLA-DQ Antigens genetics, HLA-DQ Antigens metabolism, HLA-DR Antigens genetics, HLA-DR Antigens metabolism, High-Throughput Nucleotide Sequencing, Humans, Mice, Peptides metabolism, Protein Binding, ADAMTS13 Protein chemistry, ADAMTS13 Protein immunology, HLA-DQ Antigens immunology, HLA-DR Antigens immunology, Mass Spectrometry methods, Peptides chemistry, Peptides immunology
Abstract

Formation of microthrombi is a hallmark of acquired thrombotic thrombocytopenic purpura. These microthrombi originate from insufficient processing of ultra large von Willebrand factor multimers by ADAMTS13 due to the development of anti-ADAMTS13 autoantibodies. Several studies have identified the major histocompatibility complex class II alleles HLA-DRB1*11, HLA-DQB1*03 and HLA-DQB1*02:02 as risk factors for acquired thrombotic thrombocytopenic purpura development. Previous research in our department indicated that ADAMTS13 CUB2 domain-derived peptides FINVAPHAR and LIRDTHSLR are presented on HLA-DRB1*11 and HLA-DRB1*03, respectively. Here, we describe the repertoire of ADAMTS13 peptides presented on HLA-DQ. In parallel, the repertoire of ADAMTS13-derived peptides presented on HLA-DR was monitored. Using HLA-DR- and HLA-DQ-specific antibodies, we purified HLA/peptide complexes from ADAMTS13-pulsed monocyte-derived dendritic cells. Using this approach, we identified ADAMTS13-derived peptides presented on HLA-DR for all 9 samples analyzed; ADAMTS13-derived peptides presented on HLA-DQ were identified in 4 out of 9 samples. We were able to confirm the presentation of the CUB2 domain-derived peptides FINVAPHAR and LIRDTHSLR on HLA-DR. In total, 12 different core-peptide sequences were identified on HLA-DR and 8 on HLA-DQ. For HLA-DR11, several potential new core-peptides were found; 4 novel core-peptides were exclusively identified on HLA-DQ. Furthermore, an in silico analysis was performed using the EpiMatrix and JanusMatrix tools to evaluate the eluted peptides, in the context of HLA-DR, for putative effector or regulatory T-cell responses at the population level. The results from this study provide a basis for the identification of immuno-dominant epitopes on ADAMTS13 involved in the onset of acquired thrombotic thrombocytopenic purpura., (Copyright © 2018 Ferrata Storti Foundation.)

Published
2018
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27. Inflammation-Sensitive Myosin-X Functionally Supports Leukocyte Extravasation by Cdc42-Mediated ICAM-1-Rich Endothelial Filopodia Formation.

Author

Kroon J, Schaefer A, van Rijssel J, Hoogenboezem M, van Alphen F, Hordijk P, Stroes ESG, Strömblad S, van Rheenen J, and van Buul JD

Subjects
Actins metabolism, Cell Adhesion physiology, Cell Line, Cell Line, Tumor, Endothelium, Vascular metabolism, HL-60 Cells, HeLa Cells, Human Umbilical Vein Endothelial Cells, Humans, Signal Transduction physiology, Transendothelial and Transepithelial Migration physiology, Up-Regulation physiology, Endothelial Cells metabolism, GTP Phosphohydrolases metabolism, Inflammation metabolism, Intercellular Adhesion Molecule-1 metabolism, Leukocytes metabolism, Myosins metabolism, Pseudopodia metabolism
Abstract

Leukocyte transendothelial migration is key to inflammation. Leukocytes first start rolling over the inflamed endothelium, followed by firmly adhering to it. Under inflammatory conditions, endothelial cells express small finger-like protrusions that stick out into the lumen. The function and regulation of these structures are unclear. We present evidence that these ICAM-1- and F-actin-rich endothelial finger-like protrusions are filopodia and function as adhesive structures for leukocytes to transit from rolling to crawling but are dispensable for diapedesis. Mechanistically, these structures require the motor function of myosin-X, activity of the small GTPase Cdc42, and p21-activated kinase 4. Moreover, myosin-X expression is under control of TNF-α-mediated c-Jun N-terminal kinase activity and is upregulated in human atherosclerotic regions. To our knowledge, this is the first study to identify that regulation of endothelial filopodia is crucial for leukocyte extravasation, in particular for the initiation of leukocyte adhesion under flow conditions., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Published
2018
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28. Csde1 binds transcripts involved in protein homeostasis and controls their expression in an erythroid cell line.

Author

Moore KS, Yagci N, van Alphen F, Paolini NA, Horos R, Held NM, Houtkooper RH, van den Akker E, Meijer AB, 't Hoen PAC, and von Lindern M

Subjects
Animals, CRISPR-Cas Systems genetics, DNA-Binding Proteins genetics, Erythropoiesis, HEK293 Cells, Humans, Poly(A)-Binding Proteins metabolism, RNA, Messenger genetics, RNA-Binding Proteins genetics, Tumor Cells, Cultured, DNA-Binding Proteins metabolism, Erythroid Cells metabolism, Gene Expression Regulation, Proteostasis, RNA-Binding Proteins metabolism
Abstract

Expression of the RNA-binding protein Csde1 (Cold shock domain protein e1) is strongly upregulated during erythropoiesis compared to other hematopoietic lineages. Csde1 expression is impaired in the severe congenital anemia Diamond Blackfan Anemia (DBA), and reduced expression of Csde1 in healthy erythroblasts impaired their proliferation and differentiation. To investigate the cellular pathways controlled by Csde1 in erythropoiesis, we identified the transcripts that physically associate with Csde1 in erythroid cells. These mainly encoded proteins involved in ribogenesis, mRNA translation and protein degradation, but also proteins associated with the mitochondrial respiratory chain and mitosis. Crispr/Cas9-mediated deletion of the first cold shock domain of Csde1 affected RNA expression and/or protein expression of Csde1-bound transcripts. For instance, protein expression of Pabpc1 was enhanced while Pabpc1 mRNA expression was reduced indicating more efficient translation of Pabpc1 followed by negative feedback on mRNA stability. Overall, the effect of reduced Csde1 function on mRNA stability and translation of Csde1-bound transcripts was modest. Clones with complete loss of Csde1, however, could not be generated. We suggest that Csde1 is involved in feed-back control in protein homeostasis and that it dampens stochastic changes in mRNA expression.

Published
2018
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29. Comparative profiling of HLA-DR and HLA-DQ associated factor VIII peptides presented by monocyte-derived dendritic cells.

Author

Peyron I, Hartholt RB, Pedró-Cos L, van Alphen F, Brinke AT, Lardy N, Meijer AB, and Voorberg J

Subjects
Antigen-Presenting Cells immunology, Antigen-Presenting Cells metabolism, Factor VIII chemistry, Gene Expression Profiling, HLA-DQ Antigens genetics, HLA-DR Antigens genetics, Hemophilia A genetics, Hemophilia A immunology, Humans, Proteome, Proteomics methods, Antigen Presentation immunology, Dendritic Cells immunology, Dendritic Cells metabolism, Factor VIII immunology, HLA-DQ Antigens immunology, HLA-DR Antigens immunology, Peptides immunology
Abstract

The development of anti-factor VIII antibodies is a major complication of the treatment of patients with hemophilia A. Generation of high affinity anti-factor VIII antibodies is dependent on help provided by CD4 + T cells that recognize factor VIII-derived peptides presented on class II major histocompatibility complex on the surface of antigen-presenting cells. In order to identify the immune-dominant epitopes that can be presented to CD4 + T cells, we previously developed a mass spectrometry-based method to identify factor VIII-derived peptides that are presented on human leukocyte antigen (HLA)-DR. In the present work, we compared the repertoire of FVIII-derived peptide presented on HLA-DR and HLA-DQ. Monocyte-derived dendritic cells from nine HLA-typed healthy donors were pulsed with recombinant factor VIII. HLA-DR and HLA-DQ molecules were purified using monoclonal antibodies. Our data show that HLA-DQ and HLA-DR present a similar repertoire of factor VIII-derived peptides. However, the number of peptides associated with HLA-DQ was lower than that with HLA-DR. We also identified a peptide, within the acidic a3 domains of factor VIII, which is presented with higher frequency on HLA-DQ. Interestingly, this peptide was found to have a higher predicted affinity for HLA-DQ than for HLA-DR. Taken together, our data suggest that HLA-DQ participates in the presentation of factor VIII peptides, thereby contributing to the development of inhibitory antibodies in a proportion of patients with severe hemophilia A., (Copyright© 2018 Ferrata Storti Foundation.)

Published
2018
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30. Hermansky-Pudlak syndrome type 2: Aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils.

Author

de Boer M, van Leeuwen K, Geissler J, van Alphen F, de Vries E, van der Kuip M, Terheggen SWJ, Janssen H, van den Berg TK, Meijer AB, Roos D, and Kuijpers TW

Subjects
Adolescent, Adult, Child, Child, Preschool, Codon, Nonsense genetics, Exons genetics, Female, Hermanski-Pudlak Syndrome physiopathology, Humans, Infant, Male, Middle Aged, Neutrophils metabolism, Neutrophils pathology, Phenotype, Point Mutation, RNA Splice Sites genetics, Sequence Deletion genetics, Adaptor Protein Complex 3 genetics, Adaptor Protein Complex beta Subunits genetics, Hermanski-Pudlak Syndrome genetics, RNA Precursors genetics, RNA Splicing genetics
Abstract

Hermansky-Pudlak syndrome type 2 (HPS2) is a syndrome caused by mutations in the beta-3A subunit of the adaptor protein (AP)-3 complex (AP3B1 gene). We describe five unreported cases with four novel mutations, one of which caused aberrant pre-mRNA splicing. A point mutation c.2702C>G in exon 23 of the AP3B1 gene caused deletion of 112 bp in the mRNA in two siblings. This mutation activates a cryptic donor splice site that overrules the wild-type donor splice site of this exon. Three other novel mutations in AP3B1 were identified, that is, a nonsense mutation c.716G>A (p.Trp239Ter), a 1-bp and a 4-bp deletion c.177delA and c.1839_1842delTAGA, respectively, both causing frameshift and premature termination of translation. Mass spectrometry in four of these HPS2 patients demonstrated the (near) absence of all AP-3 complex subunits. Immunoelectron microscopy on the neutrophils of two of these patients showed abnormal granule formation. We found clear mislocalization of myeloperoxidase in the neutrophils even though the content of this protein but not the activity seemed to be present at normal levels. In sum, HPS2 is the result of the absence of the entire AP-3 complex, which results in severe neutropenia with a defect in granule formation as the major hematological finding., (© 2017 Wiley Periodicals, Inc.)

Published
2017
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31. Combined immunodeficiency with severe inflammation and allergy caused by ARPC1B deficiency.

Author

Kuijpers TW, Tool ATJ, van der Bijl I, de Boer M, van Houdt M, de Cuyper IM, Roos D, van Alphen F, van Leeuwen K, Cambridge EL, Arends MJ, Dougan G, Clare S, Ramirez-Solis R, Pals ST, Adams DJ, Meijer AB, and van den Berg TK

Subjects
Animals, Biomarkers, Biopsy, DNA Mutational Analysis, Disease Models, Animal, Disease Susceptibility, Humans, Hypersensitivity metabolism, Inflammation metabolism, Mice, Phenotype, Severe Combined Immunodeficiency metabolism, Severity of Illness Index, Skin immunology, Skin pathology, Actin-Related Protein 2-3 Complex deficiency, Hypersensitivity complications, Hypersensitivity genetics, Inflammation complications, Inflammation genetics, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency etiology
Published
2017
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32. Identification of glycans on plasma-derived ADAMTS13.

Author

Verbij FC, Stokhuijzen E, Kaijen PH, van Alphen F, Meijer AB, and Voorberg J

Subjects
ADAMTS13 Protein isolation & purification, Carbohydrate Conformation, Glycosylation, Humans, ADAMTS13 Protein chemistry, Polysaccharides chemistry
Abstract

Patients suffering from acquired thrombotic thrombocytopenic purpura develop autoantibodies directed toward the plasma glycoprotein ADAMTS13. Here, we studied the glycan composition of plasma-derived ADAMTS13. Purified ADAMTS13 was reduced, alkylated, and processed into peptides with either trypsin or chymotrypsin. Glycopeptides were enriched using zwitterionic HILIC zip-tips and analyzed by tandem mass spectrometry employing higher-energy collision dissociation fragmentation. Upon detection of a diagnostic ion of a glycan fragment, electron transfer dissociation fragmentation was performed on the same precursor ion. The majority of N-linked glycans were of the complex type containing terminal sialic acids and fucose residues. A high mannose-containing glycan was attached to Asn614 in the spacer domain. Six O-linked glycans mostly terminating in sialic acid were found dispersed over ADAMTS13. Five O-linked glycans were attached to a Ser and one to Thr. All 6 O-linked glycans contained a terminal sialic acid. O-fucosylation is a common posttranslational modification of thrombospondin type 1 repeats. We identified 7 O-fucosylation sites in the thrombospondin (TSP) type 1 repeats. Unexpectedly, one additional O-fucosylation site was found in the disintegrin domain. This O-fucosylation site did not meet the proposed consensus sequence CSX(S/T)CG. C-mannosylation sites were identified in TSP1, linker TSP4-TSP5, and TSP8. Overall, our findings highlight the complexity of glycan modifications on ADAMTS13, which may have implications for its interaction with immune- or clearance receptors containing carbohydrate recognition domains., (© 2016 by The American Society of Hematology.)

Published
2016
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33. The Construction of the Relation Between National Past and present in the Appropriation of Historical Master Narratives.

Author

van Alphen F and Carretero M

Subjects
Adolescent, Female, Humans, Male, History, Narration, Social Identification, Time
Abstract

Master narratives about national history have been recognized as powerful cultural tools, influencing both historical understanding and national identity construction. For example, by the work of James Wertsch and studies on national history representation from a sociocultural point of view. However, the appropriation of these narratives needs to be considered in more detail for a clearer picture of how the nation is imagined and how this representation could change. In this paper a contribution is made by analyzing how the relation between past and present is constructed in master narrative representation, based on interviews with high school students narrating national history and presidential discourse commemorating it. It is proposed that the relation between past and present is constructed in three ways: past and present are identified; the past is idealized and their relation is teleologically constructed. By looking at how past and present are related in representations of the national past, the functioning of national historical myths as cultural tool becomes more clear. This contributes to clarifying how the master narrative constrains historical understanding and how it might enable national identification processes.

Published
2015
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34. Tango and enactivism: first steps in exploring the dynamics and experience of interaction.

Author

van Alphen F

Subjects
Culture, Humans, Dancing psychology, Interpersonal Relations, Psychology, Social
Abstract

Tango dancing is not just ethnographically interesting, but might actually provide a way to study interaction as such. An orientation to this improvisational dance as an embodied practice and experience is given. Enactivism is proposed as an adequate framework for further study. It is argued that approaching tango in terms of participatory sense-making, mutual incorporation and consensually coordinated action helps in clarifying its possible contributions to (cultural) psychology. Possible contributions such as facilitating the study of the dynamics of interaction, of intersubjectivity and of culture as joint activity.

Published
2014
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35. Identities: never the same again?

Author

van Alphen F

Subjects
Humans, Education, Ego, Social Class
Abstract

In response to the suggestion of treating identity as a historically bound notion (Matusov and Smith Integrative Psychological and Behavioral Science 46, 2012), its genealogy is further explored. First establishing that identity has been understood in a particular personal way, and that genealogy might carry beyond this conception, as it also carries beyond the notions of class and adolescence that are used to contextualize identity. Then opting for treating historically bound notions as dynamic, studying them in the continuous interaction between conceptualization and practice, as processes and verbs rather than essences and substantives. Finally suggesting to dissociate identity from selfhood by looking at why, when and to whom we need to identify ourselves and also inverting the question: why and when do we ask others to identify themselves? After all, sameness and difference are two sides of a coin called identity, and what is looked at is a matter of how it is looked at.

Published
2012
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36. Frequent detection of human coronaviruses in clinical specimens from patients with respiratory tract infection by use of a novel real-time reverse-transcriptase polymerase chain reaction.

Author

van Elden LJ, van Loon AM, van Alphen F, Hendriksen KA, Hoepelman AI, van Kraaij MG, Oosterheert JJ, Schipper P, Schuurman R, and Nijhuis M

Subjects
Base Sequence, Coronavirus genetics, Coronavirus 229E, Human isolation & purification, Coronavirus OC43, Human isolation & purification, DNA Primers, Humans, Pneumonia complications, Polymerase Chain Reaction methods, Reference Values, Coronavirus isolation & purification, Coronavirus 229E, Human classification, Coronavirus Infections virology, Coronavirus OC43, Human classification, Respiratory Tract Infections complications
Abstract

During the past years, human coronaviruses (HCoVs) have been increasingly identified as pathogens associated with more-severe respiratory tract infection (RTI). Diagnostic tests for HCoVs are not frequently used in the routine setting. It is likely that, as a result, the precise role that HCoVs play in RTIs is greatly underestimated. We describe a rapid, sensitive, and highly specific quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) for the detection of HCoV that can easily be implemented in the routine diagnostic setting. HCoV was detected in 28 (11%) of the 261 clinical specimens obtained from patients presenting with symptoms of RTI ranging from common cold to severe pneumonia. Only 1 (0.4%) of the 243 control specimens obtained from patients without symptoms of RTI showed the presence of HCoV. We conclude that HCoVs can be frequently detected in patients presenting with RTI. Real-time RT-PCR provides a tool for large-scale epidemiological studies to further clarify the role that coronavirus infection plays in RTI in humans.

Published
2004
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37. Maxillary arch dimensions after palatal surgery and implantation of poly-(L-lactic) acid membranes in beagle dogs.

Author

In de Braekt MM, Van Alphen FA, Kuijpers-Jagtman AM, and Maltha JC

Subjects
Analysis of Variance, Animals, Cicatrix complications, Dental Arch growth & development, Dogs, Lactates, Polyesters, Polymers, Prostheses and Implants, Tooth Eruption, Ectopic prevention & control, Wound Healing, Lactic Acid, Maxilla growth & development, Membranes, Artificial, Osteotomy adverse effects, Palate surgery, Tooth Eruption, Ectopic etiology
Abstract

The effect of implantation of poly-(L-lactic) acid membranes after palatal surgery on dentoalveolar development was investigated. Beagle dogs were randomly assigned to four experimental groups and a control group. In the experimental groups, a soft tissue defect was created in the medial region of the palate by excising a standardized elliptical mucoperiosteal flap at 12 weeks of age. This defect was closed according to the Von Langenbeck technique, leaving two areas of denuded bone. Poly-(L-lactic) acid membranes were implanted on the denuded bony areas either directly or 3 weeks after surgery. Group L and LS served as sham groups. Dental casts were made at regular intervals until 25 weeks of age, and maxillary arch dimensions were studied. Dental arch dimensions in the deciduous dentition of the experimental groups were not markedly disturbed, but after transition of teeth, mainly transversal maxillary arch dimensions in the premolar region were reduced. It was concluded that implantation of poly-(L-lactic) acid membranes after palatal surgery in Beagle dogs did not prevent iatrogenic disturbances of dentoalveolar development under conditions used in this study.

Published
1993
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38. Wound healing and wound contraction after palatal surgery and implantation of poly-(L-lactic) acid membranes in beagle dogs.

Author

In de Braekt MM, van Alphen FA, Kuijpers-Jagtman AM, and Maltha JC

Subjects
Analysis of Variance, Animals, Cicatrix, Dogs, Polyesters, Lactates adverse effects, Lactic Acid, Membranes, Artificial, Palate surgery, Polymers adverse effects, Wound Healing
Abstract

The effect of implantation of poly-(L-lactic) acid membranes on wound healing and wound contraction after palatal surgery was investigated macroscopically in beagle dogs. Thirty beagle dogs were randomly assigned to two experimental groups (group L and LM; both n = 12) and a control group (group C; n = 6). At 12 weeks of age, a soft-tissue defect was created in the median region of the palate by excising a standardized elliptical mucoperiosteal flap. This defect was closed according to the Von Langenbeck technique, leaving two areas of denuded bone. Immediately after surgery, poly-(L-lactic) acid membranes were implanted on the denuded bony areas in the animals of the LM group. In the L group, no poly-(L-lactic) acid membrane was used. Tattoo points were placed in the mucoperiosteum on opposite wound margins in all groups to quantify wound contraction. Standardized intraoral photographs were taken at regular intervals. Wound surface areas and weekly increments of the distance between the tattoo points were calculated. Clinical wound healing was significantly retarded in animals of the LM group. Wound contraction was comparable in both experimental groups and was restricted to the first 2 weeks after surgery. Corresponding lateral migration of the tattoo points in the median region of the palate in these groups occurred in the first week after surgery, followed by wound contraction in the second week. Implantation of poly-(L-lactic) acid membranes following palatal wounding in beagle dogs had no beneficial short-term effects on wound healing and contraction.

Published
1992
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39. Effect of low level laser therapy on wound healing after palatal surgery in beagle dogs.

Author

In de Braekt MM, van Alphen FA, Kuijpers-Jagtman AM, and Maltha JC

Subjects
Animals, Cicatrix pathology, Connective Tissue pathology, Dogs, Granulation Tissue pathology, Mouth Mucosa pathology, Mouth Mucosa radiation effects, Mouth Mucosa surgery, Palate pathology, Periosteum pathology, Periosteum radiation effects, Periosteum surgery, Reproducibility of Results, Time Factors, Wound Healing radiation effects, Laser Therapy, Palate radiation effects, Palate surgery
Abstract

The effect of low level laser therapy on wound healing and wound contraction after palatal surgery in Beagle dogs of 12 weeks of age was investigated. A total of 30 Beagle dogs was used and assigned to a control group (Group C; n = 6) and two experimental groups (Group L; n = 12 and group LL; n = 12). In both experimental groups, Von Langenbeck's palatal repair was simulated. Then in the LL group the denuded bony areas were treated with low level laser therapy using a continuous Ga-As-A1 laser beam (830 nm) and energy output set at 30 mW. Per treatment a dosage of 1 J/cm2 wound surface area was used. Therapy was carried out three times a week with a total of ten treatments. Wound healing was observed clinically until wound healing was completed at 4 weeks p.o. and wound areas were measured at regular intervals on standardized intra-oral photographs. Wound contraction was measured as the increments of the distances between tattoo points on the opposite wound margins. No significant differences were found in the quality and rate of wound healing between the two experimental groups. The same held true for the increments of the distances between opposite tattoo points. It was concluded that macroscopically low level laser therapy under conditions used in this study did not have an influence on wound closure or wound contraction.

Published
1991
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