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26. Interdisciplinary synergies : opening up new perspectives for data-driven research of the Southern Dutch Dialects

Author

De Tier, Veronique, de Does, Jesse, Depuydt, Katrien, Schoonheim, Tanneke, Mertens, Koen, Van Keymeulen, Jacques, Vandenberghe, Roxane, Hellebaut, Lien, and Chambers, Sally

Subjects
FAIR (Findable, language atlases, linguistic data, DSDD, Reusable) data, Languages and Literatures, geo-visualisation, dialectology, CLARIN, Open Science, CLARIAH, Interoperable, lexicography, Accessible, digital humanities
Abstract

The Database of the Southern Dutch Dialects (DSDD) aims to aggregate and standardise three existing comprehensive lexicographic dialect databases of the Flemish, Brabantic and Limburgian dialects into one integrated dataset (Van Keymeulen, et al., 2019; Van Hout, et al., 2018, De Vriend, et al., 2006). In 2016, the Research Foundation Flanders funded a medium-scale research infrastructure project, the Database of Southern Dutch Dialects (DSDD)[1], which ran from 2017 until 2020 and resulted in a harmonised dataset of concepts (Van den Heuvel, et al., 2016), a user-friendly search engine and a geo-visualisation tool. The application backend provides an Application Programming Interface (API) which will be further developed and made available to researchers to export subsets of the data for analysis using existing digital research tools. At the previous DH Benelux conferences the project team introduced the project (2017), explored the cartographic tools (2018) and demonstrated the prototype (2019). Following the launch of the DSDD platform in 2020, the team will now present the importance of the interdisciplinary approach, the final results of the project, as well as future directions beyond the project lifetime.

Published
2021

27. Probing activation-driven changes in coagulation factor IX by mass spectrometry

Author

Afd Pharmaceutics, Afd Biomol.Mass Spect. and Proteomics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics, Freato, Nadia, van Alphen, Floris P J, Boon-Spijker, Mariëtte, van den Biggelaar, Maartje, Meijer, Alexander B, Mertens, Koen, Ebberink, Eduard H T M, Afd Pharmaceutics, Afd Biomol.Mass Spect. and Proteomics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics, Freato, Nadia, van Alphen, Floris P J, Boon-Spijker, Mariëtte, van den Biggelaar, Maartje, Meijer, Alexander B, Mertens, Koen, and Ebberink, Eduard H T M

Published
2021

33. Unique surface-exposed hydrophobic residues in the C1 domain of Factor VIII contribute to cofactor function and Von Willebrand Factor binding

Author

Przeradzka, Małgorzata A, Freato, Nadia, Boon-Spijker, Mariëtte, van Galen, Josse, van der Zwaan, Carmen, Mertens, Koen, van den Biggelaar, Maartje, Meijer, Alexander B, Przeradzka, Małgorzata A, Freato, Nadia, Boon-Spijker, Mariëtte, van Galen, Josse, van der Zwaan, Carmen, Mertens, Koen, van den Biggelaar, Maartje, and Meijer, Alexander B

Abstract

BACKGROUND: The identity of the amino acid regions of factor VIII (FVIII) that contribute to factor IXa (FIXa) and Von Willebrand Factor (VWF) binding has not been fully resolved. Previously, we observed that replacing the FVIII C1 domain for the one of factor V (FV) markedly reduces VWF binding and cofactor function. Compared to the FV C1 domain, this implies that the FVIII C1 domain comprises unique surface-exposed elements involved in VWF and FIXa interaction.OBJECTIVE: The aim of this study is to identify residues in the FVIII C1 domain that contribute to VWF and FIXa binding.METHODS: Structures and primary sequences of FVIII and FV were compared to identify surface-exposed residues unique to the FVIII C1 domain. The identified residues were replaced into alanine residues to identify their role in FIXa and VWF interaction. This role was assessed employing surface plasmon resonance analysis studies and enzyme kinetic assays.RESULTS: Five surface-exposed hydrophobic residues unique to the FVIII C1 domain, i.e.: F2035, F2068, F2127, V2130, I2139 were identified. Functional analysis indicated that residues F2068, V2130 and especially F2127 contribute to VWF and/or FIXa interaction. Substitution into alanine of the also surface-exposed V2125, which is spatially next to F2127, affected only VWF binding.CONCLUSION: The surface-exposed hydrophobic residues in C1 domain contribute to cofactor function and VWF binding. These findings provide novel information on the fundamental role of the C1 domain in FVIII life-cycle.

Published
2020

34. D'domain Region Arg782-Cys799 of Von Willebrand Factor contributes to Factor VIII binding

Author

Przeradzka, Małgorzata A, van Galen, Josse, Ebberink, Eduard H T M, Hoogendijk, Arie J, van der Zwaan, Carmen, Mertens, Koen, van den Biggelaar, Maartje, Meijer, Alexander B, Przeradzka, Małgorzata A, van Galen, Josse, Ebberink, Eduard H T M, Hoogendijk, Arie J, van der Zwaan, Carmen, Mertens, Koen, van den Biggelaar, Maartje, and Meijer, Alexander B

Abstract

In the complex with Von Willebrand Factor, factor VIII (FVIII) is protected from rapid clearance from the circulation. Although it has been established that the FVIII binding site resides in the N-terminal D'-D3 domains of Von Willebrand Factor, detailed information about the amino acid regions that contribute to FVIII binding is still lacking. In the present study, Hydrogen- deuterium exchange mass spectrometry was employed to gain insight into the FVIII binding region on Von Willebrand Factor. To this end, time-dependent deuterium incorporation was assessed in D'-D3 and the FVIII - D'-D3 complex. Data showed reduced deuterium incorporation in D region Arg782-Cys799 in the FVIII - D'-D3 complex compared to D'- D3. This implies that this region interacts with FVIII. Site-directed mutagenesis of the six-individual charged amino acids in Arg782-Cys799 into alanine residues followed by surface plasmon resonance analysis and solid phase binding studies revealed that replacement of Asp796 affected FVIII binding. A marked decrease in FVIII binding was observed for the D'-D3 Glu787Ala variant. The same was observed for D'-D3 variants in which Asp796 and Glu787 were replaced by Asn796 and Gln787. Site-directed mutagenesis of Leu786, which together with Glu787 and Cys789 forms a short helical region in the crystal structure of D'-D3, also had a marked impact on FVIII binding. The combined results show that amino acid region Arg782-Cys799 is part of a FVIII binding surface. Our study provides new insight into FVIII - Von Willebrand Factor complex formation and defects therein that may be associated with bleedings caused by markedly reduced levels of FVIII.

Published
2020

35. D'domain Region Arg782-Cys799 of Von Willebrand Factor contributes to Factor VIII binding

Author

Afd Pharmaceutics, Afd Biomol.Mass Spect. and Proteomics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics, Przeradzka, Małgorzata A, van Galen, Josse, Ebberink, Eduard H T M, Hoogendijk, Arie J, van der Zwaan, Carmen, Mertens, Koen, van den Biggelaar, Maartje, Meijer, Alexander B, Afd Pharmaceutics, Afd Biomol.Mass Spect. and Proteomics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics, Przeradzka, Małgorzata A, van Galen, Josse, Ebberink, Eduard H T M, Hoogendijk, Arie J, van der Zwaan, Carmen, Mertens, Koen, van den Biggelaar, Maartje, and Meijer, Alexander B

Published
2020

36. Endocytosis by macrophages: Interplay of macrophage scavenger receptor-1 and LDL receptor-related protein-1

Author

Afd Pharmaceutics, Afd Biomol.Mass Spect. and Proteomics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics, Béguin, Eelke P, Przeradzka, Małgorzata A, Janssen, Esmée F J, Meems, Henriët, Sedek, Magdalena, van der Zwaan, Carmen, Mertens, Koen, van den Biggelaar, Maartje, Meijer, Alexander B, Mourik, Marjon J, Afd Pharmaceutics, Afd Biomol.Mass Spect. and Proteomics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics, Béguin, Eelke P, Przeradzka, Małgorzata A, Janssen, Esmée F J, Meems, Henriët, Sedek, Magdalena, van der Zwaan, Carmen, Mertens, Koen, van den Biggelaar, Maartje, Meijer, Alexander B, and Mourik, Marjon J

Published
2020

37. Unique surface-exposed hydrophobic residues in the C1 domain of Factor VIII contribute to cofactor function and Von Willebrand Factor binding

Author

Afd Pharmaceutics, Afd Biomol.Mass Spect. and Proteomics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics, Przeradzka, Małgorzata A, Freato, Nadia, Boon-Spijker, Mariëtte, van Galen, Josse, van der Zwaan, Carmen, Mertens, Koen, van den Biggelaar, Maartje, Meijer, Alexander B, Afd Pharmaceutics, Afd Biomol.Mass Spect. and Proteomics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics, Przeradzka, Małgorzata A, Freato, Nadia, Boon-Spijker, Mariëtte, van Galen, Josse, van der Zwaan, Carmen, Mertens, Koen, van den Biggelaar, Maartje, and Meijer, Alexander B

Published
2020

41. Low-voltage low-power CMOS-RF transceiver design

Author

Steyaert, Michiel S.J., De Muer, Bram, Leroux, Paul, Borremans, Marc, and Mertens, Koen

Subjects
Complementary metal oxide semiconductors -- Research, Transceivers -- Design and construction, Wireless communication systems -- Design and construction, Business, Computers, Electronics, Electronics and electrical industries
Abstract

Research over the last ten years has resulted in attempts toward single-chip CMOS RF circuits for Bluetooth, global positioning system, digital enhanced cordless telecommunications and cellular applications. An overview of the use of CMOS for low-cost integration of a high-end cellular RF transceiver front-end is presented. Some fundamental pitfalls and limitations of RF CMOS are discussed. To circumvent these obstacles, the choice of transceiver architecture, circuit topology design, and systematic optimization of the different transceiver blocks is necessary. Moreover, optimization of the transceiver as one single block by minimizing the number of power-hungry interface circuits is emphasized. As examples, a fully integrated cellular transceiver front-end, a low-power extremely low noise-figure low-noise amplifier, and a very efficient power amplifier are demonstrated. Index Terms--CMOS, low power, low voltage, receiver, RF, transceiver, wireless.

Published
2002

44. Insertion loop 256-268 in coagulation factor IX restricts enzymatic activity in the absence but not in the presence of factor VIII

Author

Kolkman, Joost A. and Mertens, Koen

Subjects
Blood coagulation factors -- Physiological aspects, Vitamin K -- Physiological aspects, Enzymes -- Physiological aspects, Biological sciences, Chemistry
Abstract

Insertion loop 256-268 in coagulation factor IX is discussed. It restricts enzymatic activity where factor VIII is absent. a study has shown that the loop restricts the activity of factor IXa toward synthetic and natural substrates. Complex formation of factor VIIIa cuts back on the inhibitory effect of the insertion loop on activation of FX.

Published
2000

46. Differences between Platelets Derived from Neonatal Cord Blood and Adult Peripheral Blood Assessed by Mass Spectrometry

Author

Stokhuijzen, Eva, Koornneef, Johanna M, Nota, Benjamin, van den Eshof, Bart Laurens, van Alphen, Floris Pieter Joachim, van den Biggelaar, Maartje, Van Der Zwaan, Carmen, Kuijk, Carlijn, Mertens, Koen, Fijnvandraat, Karin, Meijer, Alexander Benjamin, Afd Pharmaceutics, Pharmaceutics, Biomolecular Mass Spectrometry and Proteomics, Graduate School, ARD - Amsterdam Reproduction and Development, ACS - Amsterdam Cardiovascular Sciences, Paediatric Infectious Diseases / Rheumatology / Immunology, ACS - Pulmonary hypertension & thrombosis, Afd Pharmaceutics, Pharmaceutics, and Biomolecular Mass Spectrometry and Proteomics

Subjects
Adult, Blood Platelets, Male, Proteomics, 0301 basic medicine, Platelet Aggregation, proteome, Integrin, 030204 cardiovascular system & hematology, Biochemistry, Umbilical cord, Flow cytometry, 03 medical and health sciences, Thromboxane A2, chemistry.chemical_compound, 0302 clinical medicine, medicine, Humans, Receptor, PAR-1, Platelet, Receptor, mass spectrometry, chemistry.chemical_classification, medicine.diagnostic_test, biology, Chemistry, Infant, Newborn, General Chemistry, Middle Aged, Fetal Blood, Platelet Activation, Molecular biology, 030104 developmental biology, medicine.anatomical_structure, Cord blood, platelets, cord blood, biology.protein, Female, Receptors, Thrombin, Collagen, Transcriptome, Glycoprotein
Abstract

It has been proposed that differences may exist between umbilical cord blood (CB) platelets and adult peripheral blood (APB) platelets, including altered protein levels of the main platelet integrins. We have now compared the protein expression profiles of CB and APB platelets employing a label-free comparative proteomics approach. Aggregation studies showed that CB platelets effectively aggregate in the presence of thromboxane A2 analogue, collagen, and peptide agonists of the proteinase-activated receptors 1 and 4. In agreement with previous studies, higher concentrations of the agonists were required to initiate aggregation in the CB platelets. Mass spectrometry analysis revealed no significant difference in the expression levels of critical platelet receptors like glycoprotein (GP)Ib, GPV, GPIX, and integrin αIIbβ3. This was confirmed using flow cytometry-based approaches. Gene ontology enrichment analysis revealed that elevated proteins in CB platelets were in particular enriched in proteins contributing to mitochondrial energy metabolism processes. The reduced proteins were enriched in proteins involved in, among others, platelet degranulation and activation. In conclusion, this study reveals that the CB and APB platelets are distinct. In particular, changes were observed for proteins that belong to metabolic and energy generation processes and not for the critical adhesive platelet integrins and glycoproteins.

Published
2017

47. Cellular uptake of coagulation factor VIII: Elusive role of the membrane-binding spikes in the C1 domain

Author

Castro-Núñez, Lydia, Koornneef, Johanna M, Rondaij, Mariska G, Bloem, Esther, Zwaan, Carmen van der, Mertens, Koen, Meijer, Sander, Meems, Henriet, Pharmaceutics, Afd Pharmaceutics, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Pharmaceutics, Afd Pharmaceutics, Afd Biomol.Mass Spect. and Proteomics, and Biomolecular Mass Spectrometry and Proteomics

Subjects
Models, Molecular, 0301 basic medicine, receptor-mediated endocytosis, congenital, hereditary, and neonatal diseases and abnormalities, animal diseases, media_common.quotation_subject, Cell, Endocytosis, Biochemistry, Epitope, Cell Line, Flow cytometry, α2-macroglobulin, 03 medical and health sciences, Protein Domains, Von Willebrand factor, hemic and lymphatic diseases, medicine, Humans, Internalization, low density lipoprotein receptor related protein 1, media_common, Factor VIII, biology, medicine.diagnostic_test, Chemistry, Cell Membrane, Factor V, Cell Biology, Receptor-mediated endocytosis, LRP1, Cell biology, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Low Density Lipoprotein Receptor-Related Protein-1, Protein Binding
Abstract

Low density lipoprotein receptor-related protein 1 (LRP1) is involved in the catabolism of many ligands, including factor VIII (FVIII) and alpha-2-macroglobulin (α2M). Transfer of FVIII to LRP1 is currently believed to be preceded by pre-concentration on the cell surface, by interacting with a so far unidentified component. In the present study, we used confocal microscopy and flow cytometry to compare endocytosis of FVIII and α2M using U87MG cells. The results show that α2M is rapidly internalized and does not compete for LRP1 mediated internalization of FVIII. FVIII endocytosis did not occur in the presence of receptor-associated-protein (RAP), but FVIII remained visible as a striated fluorescent pattern at the cell borders. In the presence of Von Willebrand Factor (VWF), no FVIII was observed on or within the cells, suggesting that VWF blocks interaction with both cell surface and LRP1. The same dual inhibition has previously been observed for FVIII C1 domain directed monoclonal antibody KM33. Elimination of the KM33 epitope by replacing FVIII C1 residues 2091-2095 and 2155-2160 for the homologues from factor V (FV), however, did not impair FVIII endocytosis. These membrane spikes alone were insufficient for cellular uptake, because FV was neither internalized by U87MG cells nor capable of effectively competing for FVIII endocytosis. These results show that FVIII endocytosis is driven by interaction with LRP1, but at the same time involves the spikes in the C1 domain that have been implicated in lipid binding.

Published
2017

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