TY - JOUR A1 - Frioux, Clémence A1 - Schaub, Torsten H. A1 - Schellhorn, Sebastian A1 - Siegel, Anne A1 - Wanko, Philipp T1 - Hybrid metabolic network completion JF - Theory and practice of logic programming N2 - Metabolic networks play a crucial role in biology since they capture all chemical reactions in an organism. While there are networks of high quality for many model organisms, networks for less studied organisms are often of poor quality and suffer from incompleteness. To this end, we introduced in previous work an answer set programming (ASP)-based approach to metabolic network completion. Although this qualitative approach allows for restoring moderately degraded networks, it fails to restore highly degraded ones. This is because it ignores quantitative constraints capturing reaction rates. To address this problem, we propose a hybrid approach to metabolic network completion that integrates our qualitative ASP approach with quantitative means for capturing reaction rates. We begin by formally reconciling existing stoichiometric and topological approaches to network completion in a unified formalism. With it, we develop a hybrid ASP encoding and rely upon the theory reasoning capacities of the ASP system dingo for solving the resulting logic program with linear constraints over reals. We empirically evaluate our approach by means of the metabolic network of Escherichia coli. Our analysis shows that our novel approach yields greatly superior results than obtainable from purely qualitative or quantitative approaches. KW - answer set programming KW - metabolic network KW - gap-filling KW - linear programming KW - hybrid solving KW - bioinformatics Y1 - 2018 U6 - https://doi.org/10.1017/S1471068418000455 SN - 1471-0684 SN - 1475-3081 VL - 19 IS - 1 SP - 83 EP - 108 PB - Cambridge University Press CY - New York ER - TY - JOUR A1 - Kuckelkorn, Ulrike A1 - Stübler, Sabine A1 - Textoris-Taube, Kathrin A1 - Kilian, Christiane A1 - Niewienda, Agathe A1 - Henklein, Petra A1 - Janek, Katharina A1 - Stumpf, Michael P. H. A1 - Mishto, Michele A1 - Liepe, Juliane T1 - Proteolytic dynamics of human 20S thymoproteasome JF - The journal of biological chemistry N2 - An efficient immunosurveillance of CD8(+) T cells in the periphery depends on positive/negative selection of thymocytes and thus on the dynamics of antigen degradation and epitope production by thymoproteasome and immunoproteasome in the thymus. Although studies in mouse systems have shown how thymoproteasome activity differs from that of immunoproteasome and strongly impacts the T cell repertoire, the proteolytic dynamics and the regulation of human thymoproteasome are unknown. By combining biochemical and computational modeling approaches, we show here that human 20S thymoproteasome and immunoproteasome differ not only in the proteolytic activity of the catalytic sites but also in the peptide transport. These differences impinge upon the quantity of peptide products rather than where the substrates are cleaved. The comparison of the two human 20S proteasome isoforms depicts different processing of antigens that are associated to tumors and autoimmune diseases. KW - proteasome KW - protein degradation KW - antigen processing KW - computational biology KW - bioinformatics KW - thymoproteasome KW - thymus KW - proteolysis Y1 - 2019 U6 - https://doi.org/10.1074/jbc.RA118.007347 SN - 1083-351X VL - 294 IS - 19 SP - 7740 EP - 7754 PB - American Society for Biochemistry and Molecular Biology CY - Bethesda ER -