TY - GEN A1 - Krippendorff, Ben-Fillippo A1 - Oyarzún, Diego A. A1 - Huisinga, Wilhelm T1 - Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Cell-level kinetic models for therapeutically relevant processes increasingly benefit the early stages of drug development. Later stages of the drug development processes, however, rely on pharmacokinetic compartment models while cell-level dynamics are typically neglected. We here present a systematic approach to integrate cell-level kinetic models and pharmacokinetic compartment models. Incorporating target dynamics into pharmacokinetic models is especially useful for the development of therapeutic antibodies because their effect and pharmacokinetics are inherently interdependent. The approach is illustrated by analysing the F(ab)-mediated inhibitory effect of therapeutic antibodies targeting the epidermal growth factor receptor. We build a multi-level model for anti-EGFR antibodies by combining a systems biology model with in vitro determined parameters and a pharmacokinetic model based on in vivo pharmacokinetic data. Using this model, we investigated in silico the impact of biochemical properties of anti-EGFR antibodies on their F(ab)-mediated inhibitory effect. The multi-level model suggests that the F(ab)-mediated inhibitory effect saturates with increasing drug-receptor affinity, thereby limiting the impact of increasing antibody affinity on improving the effect. This indicates that observed differences in the therapeutic effects of high affinity antibodies in the market and in clinical development may result mainly from Fc-mediated indirect mechanisms such as antibody-dependent cell cytotoxicity. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 958 KW - cell-level kinetics KW - pharmacokinetic models KW - therapeutic proteins KW - EGFR Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-431051 SN - 1866-8372 IS - 958 SP - 125 EP - 139 ER - TY - GEN A1 - Larhlimi, Abdelhalim A1 - David, Laszlo A1 - Selbig, Joachim A1 - Bockmayr, Alexander T1 - F2C2 BT - a fast tool for the computation of flux coupling in genome-scale metabolic networks T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Background: Flux coupling analysis (FCA) has become a useful tool in the constraint-based analysis of genome-scale metabolic networks. FCA allows detecting dependencies between reaction fluxes of metabolic networks at steady-state. On the one hand, this can help in the curation of reconstructed metabolic networks by verifying whether the coupling between reactions is in agreement with the experimental findings. On the other hand, FCA can aid in defining intervention strategies to knock out target reactions. Results: We present a new method F2C2 for FCA, which is orders of magnitude faster than previous approaches. As a consequence, FCA of genome-scale metabolic networks can now be performed in a routine manner. Conclusions: We propose F2C2 as a fast tool for the computation of flux coupling in genome-scale metabolic networks. F2C2 is freely available for non-commercial use at https://sourceforge.net/projects/f2c2/files/. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 921 KW - balance analysis KW - reconstruction KW - pathways KW - models KW - metabolic network KW - couple reaction KW - reversible reaction KW - linear programming problem KW - coupling relationship Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-432431 SN - 1866-8372 IS - 921 ER - TY - GEN A1 - Lenhard, Michael T1 - All's well that ends well BT - arresting cell proliferation in leaves T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - The transition from cell proliferation to cell expansion is critical for determining leaf size. Andriankaja et al. (2012) demonstrate that in leaves of dicotyledonous plants, a basal proliferation zone is maintained for several days before abruptly disappearing, and that chloroplast differentiation is required to trigger the onset of cell expansion. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 906 KW - arabidopsis-thaliana KW - genetic-control KW - growth KW - size KW - curvature Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-438035 SN - 1866-8372 IS - 906 SP - 9 EP - 11 ER - TY - GEN A1 - Dallmeyer, Anne A1 - Claussen, Martin A1 - Wang, Yongbo A1 - Herzschuh, Ulrike T1 - Spatial variability of Holocene changes in the annual precipitation pattern BT - a model-data synthesis for the Asian monsoon region T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - This study provides a detailed analysis of the mid-Holocene to present-day precipitation change in the Asian monsoon region. We compare for the first time results of high resolution climate model simulations with a standardised set of mid-Holocene moisture reconstructions. Changes in the simulated summer monsoon characteristics (onset, withdrawal, length and associated rainfall) and the mechanisms causing the Holocene precipitation changes are investigated. According to the model, most parts of the Indian subcontinent received more precipitation (up to 5 mm/day) at mid-Holocene than at present-day. This is related to a stronger Indian summer monsoon accompanied by an intensified vertically integrated moisture flux convergence. The East Asian monsoon region exhibits local inhomogeneities in the simulated annual precipitation signal. The sign of this signal depends on the balance of decreased pre-monsoon and increased monsoon precipitation at mid-Holocene compared to present-day. Hence, rainfall changes in the East Asian monsoon domain are not solely associated with modifications in the summer monsoon circulation but also depend on changes in the mid-latitudinal westerly wind system that dominates the circulation during the pre-monsoon season. The proxy-based climate reconstructions confirm the regional dissimilarities in the annual precipitation signal and agree well with the model results. Our results highlight the importance of including the pre-monsoon season in climate studies of the Asian monsoon system and point out the complex response of this system to the Holocene insolation forcing. The comparison with a coarse climate model simulation reveals that this complex response can only be resolved in high resolution simulations. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 905 KW - Asian monsoon KW - holocene KW - precipitation KW - climate modelling KW - moisture reconstructions Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-432771 SN - 1866-8372 IS - 905 ER - TY - GEN A1 - Powell, Anahid E. A1 - Lenhard, Michael T1 - Control of organ size in plants T2 - Postprints der Universität Potsdam : Mathematisch Naturwissenschaftliche Reihe N2 - The size of plant organs, such as leaves and flowers, is determined by an interaction of genotype and environmental influences. Organ growth occurs through the two successive processes of cell proliferation followed by cell expansion. A number of genes influencing either or both of these processes and thus contributing to the control of final organ size have been identified in the last decade. Although the overall picture of the genetic regulation of organ size remains fragmentary, two transcription factor/microRNA-based genetic pathways are emerging in the control of cell proliferation. However, despite this progress, fundamental questions remain unanswered, such as the problem of how the size of a growing organ could be monitored to determine the appropriate time for terminating growth. While genetic analysis will undoubtedly continue to advance our knowledge about size control in plants, a deeper understanding of this and other basic questions will require including advanced live-imaging and mathematical modeling, as impressively demonstrated by some recent examples. This should ultimately allow the comparison of the mechanisms underlying size control in plants and in animals to extract common principles and lineage-specific solutions. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 898 KW - BHLH transcription factor KW - genome-wide association KW - arabidopsis-thaliana KW - cell-proliferation KW - leaf development KW - developing leaves KW - petal growth KW - gene family KW - tor kinase KW - auxin Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-438029 SN - 1866-8372 IS - 898 ER - TY - GEN A1 - Jing, Runchun A1 - Ambrose, Michael A. A1 - Knox, Maggie R. A1 - Smykal, Petr A1 - Hybl, Miroslav A1 - Ramos, Á. A1 - Caminero, Constantino A1 - Burstin, Judith A1 - Duc, Gerard A1 - van Soest, L. J. M. A1 - Święcicki, W. K. A1 - Pereira, M. Graca A1 - Vishnyakova, Margarita A1 - Davenport, Guy F. A1 - Flavell, Andrew J. A1 - Ellis, T. H. Noel T1 - Genetic diversity in European Pisum germplasm collections T2 - Postprints der Universität Potsdam : Mathematisch Naturwissenschaftliche Reihe N2 - The distinctness of, and overlap between, pea genotypes held in several Pisum germplasm collections has been used to determine their relatedness and to test previous ideas about the genetic diversity of Pisum. Our characterisation of genetic diversity among 4,538 Pisum accessions held in 7 European Genebanks has identified sources of novel genetic variation, and both reinforces and refines previous interpretations of the overall structure of genetic diversity in Pisum. Molecular marker analysis was based upon the presence/absence of polymorphism of retrotransposon insertions scored by a high-throughput microarray and SSAP approaches. We conclude that the diversity of Pisum constitutes a broad continuum, with graded differentiation into sub-populations which display various degrees of distinctness. The most distinct genetic groups correspond to the named taxa while the cultivars and landraces of Pisum sativum can be divided into two broad types, one of which is strongly enriched for modern cultivars. The addition of germplasm sets from six European Genebanks, chosen to represent high diversity, to a single collection previously studied with these markers resulted in modest additions to the overall diversity observed, suggesting that the great majority of the total genetic diversity collected for the Pisum genus has now been described. Two interesting sources of novel genetic variation have been identified. Finally, we have proposed reference sets of core accessions with a range of sample sizes to represent Pisum diversity for the future study and exploitation by researchers and breeders. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 871 KW - germplasm collection KW - insertion polymorphism KW - retrotransposon insertion KW - broad continuum KW - SSAP marker Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-434743 SN - 1866-8372 IS - 871 SP - 367 EP - 380 ER - TY - GEN A1 - Krügel, André A1 - Vitu, Françoise A1 - Engbert, Ralf T1 - Fixation positions after skipping saccades BT - a single space makes a large difference T2 - Postprints der Universität Potsdam : Mathematisch Naturwissenschaftliche Reihe N2 - During reading, saccadic eye movements are generated to shift words into the center of the visual field for lexical processing. Recently, Krugel and Engbert (Vision Research 50:1532-1539, 2010) demonstrated that within-word fixation positions are largely shifted to the left after skipped words. However, explanations of the origin of this effect cannot be drawn from normal reading data alone. Here we show that the large effect of skipped words on the distribution of within-word fixation positions is primarily based on rather subtle differences in the low-level visual information acquired before saccades. Using arrangements of "x" letter strings, we reproduced the effect of skipped character strings in a highly controlled single-saccade task. Our results demonstrate that the effect of skipped words in reading is the signature of a general visuomotor phenomenon. Moreover, our findings extend beyond the scope of the widely accepted range-error model, which posits that within-word fixation positions in reading depend solely on the distances of target words. We expect that our results will provide critical boundary conditions for the development of visuomotor models of saccade planning during reading. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 856 KW - eye movements KW - reading KW - motor control KW - skipping Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-432887 SN - 1866-8372 IS - 856 SP - 1556 EP - 1561 ER - TY - GEN A1 - Kleessen, Sabrina A1 - Nikoloski, Zoran T1 - Dynamic regulatory on/off minimization for biological systems under internal temporal perturbations T2 - Postprints der Universität Potsdam : Mathematisch Naturwissenschaftliche Reihe N2 - Background: Flux balance analysis (FBA) together with its extension, dynamic FBA, have proven instrumental for analyzing the robustness and dynamics of metabolic networks by employing only the stoichiometry of the included reactions coupled with adequately chosen objective function. In addition, under the assumption of minimization of metabolic adjustment, dynamic FBA has recently been employed to analyze the transition between metabolic states. Results: Here, we propose a suite of novel methods for analyzing the dynamics of (internally perturbed) metabolic networks and for quantifying their robustness with limited knowledge of kinetic parameters. Following the biochemically meaningful premise that metabolite concentrations exhibit smooth temporal changes, the proposed methods rely on minimizing the significant fluctuations of metabolic profiles to predict the time-resolved metabolic state, characterized by both fluxes and concentrations. By conducting a comparative analysis with a kinetic model of the Calvin-Benson cycle and a model of plant carbohydrate metabolism, we demonstrate that the principle of regulatory on/off minimization coupled with dynamic FBA can accurately predict the changes in metabolic states. Conclusions: Our methods outperform the existing dynamic FBA-based modeling alternatives, and could help in revealing the mechanisms for maintaining robustness of dynamic processes in metabolic networks over time. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 852 KW - metabolic network KW - metabolite concentration KW - flux rate KW - flux balance analysis KW - qualitative comparative analysis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-431128 SN - 1866-8372 IS - 852 ER - TY - GEN A1 - Hische, Manuela A1 - Larhlimi, Abdelhalim A1 - Schwarz, Franziska A1 - Fischer-Rosinský, Antje A1 - Bobbert, Thomas A1 - Assmann, Anke A1 - Catchpole, Gareth S. A1 - Pfeiffer, Andreas F. H. A1 - Willmitzer, Lothar A1 - Selbig, Joachim A1 - Spranger, Joachim T1 - A distinct metabolic signature predictsdevelopment of fasting plasma glucose T2 - Postprints der Universität Potsdam : Mathematisch Naturwissenschaftliche Reihe N2 - Background High blood glucose and diabetes are amongst the conditions causing the greatest losses in years of healthy life worldwide. Therefore, numerous studies aim to identify reliable risk markers for development of impaired glucose metabolism and type 2 diabetes. However, the molecular basis of impaired glucose metabolism is so far insufficiently understood. The development of so called 'omics' approaches in the recent years promises to identify molecular markers and to further understand the molecular basis of impaired glucose metabolism and type 2 diabetes. Although univariate statistical approaches are often applied, we demonstrate here that the application of multivariate statistical approaches is highly recommended to fully capture the complexity of data gained using high-throughput methods. Methods We took blood plasma samples from 172 subjects who participated in the prospective Metabolic Syndrome Berlin Potsdam follow-up study (MESY-BEPO Follow-up). We analysed these samples using Gas Chromatography coupled with Mass Spectrometry (GC-MS), and measured 286 metabolites. Furthermore, fasting glucose levels were measured using standard methods at baseline, and after an average of six years. We did correlation analysis and built linear regression models as well as Random Forest regression models to identify metabolites that predict the development of fasting glucose in our cohort. Results We found a metabolic pattern consisting of nine metabolites that predicted fasting glucose development with an accuracy of 0.47 in tenfold cross-validation using Random Forest regression. We also showed that adding established risk markers did not improve the model accuracy. However, external validation is eventually desirable. Although not all metabolites belonging to the final pattern are identified yet, the pattern directs attention to amino acid metabolism, energy metabolism and redox homeostasis. Conclusions We demonstrate that metabolites identified using a high-throughput method (GC-MS) perform well in predicting the development of fasting plasma glucose over several years. Notably, not single, but a complex pattern of metabolites propels the prediction and therefore reflects the complexity of the underlying molecular mechanisms. This result could only be captured by application of multivariate statistical approaches. Therefore, we highly recommend the usage of statistical methods that seize the complexity of the information given by high-throughput methods. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 850 KW - prediction KW - fasting glucose KW - type 2 diabetes KW - metabolomics KW - plasma KW - random forest KW - metabolite KW - regression KW - biomarker Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-427400 SN - 1866-8372 IS - 850 ER - TY - GEN A1 - Hoppe, Sebastian A1 - Bier, Frank Fabian A1 - von Nickisch-Rosenegk, Markus T1 - Microarray-based method for screening of immunogenic proteins from bacteria T2 - Postprints der Universität Potsdam Mathematisch-Naturwissenschaftliche Reihe N2 - Background: Detection of immunogenic proteins remains an important task for life sciences as it nourishes the understanding of pathogenicity, illuminates new potential vaccine candidates and broadens the spectrum of biomarkers applicable in diagnostic tools. Traditionally, immunoscreenings of expression libraries via polyclonal sera on nitrocellulose membranes or screenings of whole proteome lysates in 2-D gel electrophoresis are performed. However, these methods feature some rather inconvenient disadvantages. Screening of expression libraries to expose novel antigens from bacteria often lead to an abundance of false positive signals owing to the high cross reactivity of polyclonal antibodies towards the proteins of the expression host. A method is presented that overcomes many disadvantages of the old procedures. Results: Four proteins that have previously been described as immunogenic have successfully been assessed immunogenic abilities with our method. One protein with no known immunogenic behaviour before suggested potential immunogenicity. We incorporated a fusion tag prior to our genes of interest and attached the expressed fusion proteins covalently on microarrays. This enhances the specific binding of the proteins compared to nitrocellulose. Thus, it helps to reduce the number of false positives significantly. It enables us to screen for immunogenic proteins in a shorter time, with more samples and statistical reliability. We validated our method by employing several known genes from Campylobacter jejuni NCTC 11168. Conclusions: The method presented offers a new approach for screening of bacterial expression libraries to illuminate novel proteins with immunogenic features. It could provide a powerful and attractive alternative to existing methods and help to detect and identify vaccine candidates, biomarkers and potential virulence-associated factors with immunogenic behaviour furthering the knowledge of virulence and pathogenicity of studied bacteria. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 726 KW - expression library KW - immunogenic protein KW - false positive signal KW - polyclonal seron KW - standard western blot Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-429815 SN - 1866-8372 IS - 726 ER -