@article{RoeblitzWeber2013, author = {R{\"o}blitz, Susanna and Weber, Marcus}, title = {Fuzzy spectral clustering by PCCA+: application to Markov state models and data classification}, volume = {7}, journal = {Advances in Data Analysis and Classification}, number = {2}, doi = {10.1007/s11634-013-0134-6}, pages = {147 -- 179}, year = {2013}, language = {en} } @article{HaackFackeldeyRoeblitzetal.2013, author = {Haack, Fiete and Fackeldey, Konstantin and R{\"o}blitz, Susanna and Scharkoi, Olga and Weber, Marcus and Schmidt, Burkhard}, title = {Adaptive spectral clustering with application to tripeptide conformation analysis}, volume = {139}, journal = {The Journal of Chemical Physics}, doi = {10.1063/1.4830409}, pages = {110 -- 194}, year = {2013}, language = {en} } @inproceedings{SchaeferPloentzkeRoeblitz2016, author = {Sch{\"a}fer, Stefan and Pl{\"o}ntzke, Julia and R{\"o}blitz, Susanna}, title = {Mathematical Modelling of Follicular Maturation in Cows and Women}, booktitle = {49. Jahrestagung der Physiologie und Pathologie der Fortpflanzung und gleichzeitig 41. Veterin{\"a}r-Humanmedizinische Gemeinschaftstagung 2016, Leipzig.}, year = {2016}, language = {en} } @inproceedings{IgdeWoelkRoeblitzetal.2015, author = {Igde, Sinaida and W{\"o}lk, Hendrik and R{\"o}blitz, Susanna and Reidelbach, Marco and Weber, Marcus and Hartmann, Laura}, title = {Identifying Multivalent Binding Kinetics of Precision Glycomacromolecules: A Kinetic Study Using kinITC}, booktitle = {M{\"u}nster Symposium on Cooperative Effects 2015 - SFB 858, at Westf{\"a}lische Wilhelms-Universit{\"a}t M{\"u}nster, 2015}, year = {2015}, abstract = {Multivalent sugar/protein interactions are well-known to proceed through different binding modes 1-5 which in turn can be described by their binding kinetics 3-5. This study provides additional insight into the association and dissociation reaction rates of complex multivalent sugar/protein interactions. Binding kinetics of recently introduced multivalent precision glycomacromolecules 6-8 to Concanavalin A (Con A) were studied by " kinetic Isothermal Titration Calorimetry " (kinITC) 9-11. The effect of multivalency is evaluated by comparing rate constants of glycomacromolecules obtaining the same and different valency of mannose ligands and by variation of the overall backbone properties, such as hydrophilic/ hydrophoboc. In addition, binding kinetics were studied using different conformations of Con A (homodimer vs.-tetramer) and thus a different protein valency. Our results show that precision glycomacromolecule/Con A binding proceeds non-cooperatively. Further, association and dissociation rates are mainly described by intermolecular complex formation. Together with the so-called functional valency, we can discriminate between " bound " and " unbound " states for macroscopic on-and off-rates, even for such complex glycooligomer/protein systems. By comparing e.g. a mono-to a divalent glycomacromolecule for their binding to dimeric Con A, we see a lower dissociation rate for the latter. As both bind monovalently to Con A, this is a strong indication for a statistical rebinding event. Further, there is a strong dependence of multivalent binding kinetics on the ligand density of glycomacromolecules as well as the Con A conformation and thus the overall on-and off-rates.}, language = {en} } @article{KlebanovSikorskiSchuetteetal.2021, author = {Klebanov, Ilja and Sikorski, Alexander and Sch{\"u}tte, Christof and R{\"o}blitz, Susanna}, title = {Objective priors in the empirical Bayes framework}, volume = {48}, journal = {Scandinavian Journal of Statistics}, number = {4}, publisher = {Wiley Online Library}, doi = {10.1111/sjos.12485}, pages = {1212 -- 1233}, year = {2021}, abstract = {When dealing with Bayesian inference the choice of the prior often remains a debatable question. Empirical Bayes methods offer a data-driven solution to this problem by estimating the prior itself from an ensemble of data. In the nonparametric case, the maximum likelihood estimate is known to overfit the data, an issue that is commonly tackled by regularization. However, the majority of regularizations are ad hoc choices which lack invariance under reparametrization of the model and result in inconsistent estimates for equivalent models. We introduce a nonparametric, transformation-invariant estimator for the prior distribution. Being defined in terms of the missing information similar to the reference prior, it can be seen as an extension of the latter to the data-driven setting. This implies a natural interpretation as a trade-off between choosing the least informative prior and incorporating the information provided by the data, a symbiosis between the objective and empirical Bayes methodologies.}, language = {en} } @article{ReuterWeberFackeldeyetal.2018, author = {Reuter, Bernhard and Weber, Marcus and Fackeldey, Konstantin and R{\"o}blitz, Susanna and Garcia, Martin E.}, title = {Generalized Markov State Modeling Method for Nonequilibrium Biomolecular Dynamics: Exemplified on Amyloid β Conformational Dynamics Driven by an Oscillating Electric Field}, volume = {14}, journal = {Journal of Chemical Theory and Computation}, number = {7}, doi = {10.1021/acs.jctc.8b00079}, pages = {3579 -- 3594}, year = {2018}, abstract = {Markov state models (MSMs) have received an unabated increase in popularity in recent years, as they are very well suited for the identification and analysis of metastable states and related kinetics. However, the state-of-the-art Markov state modeling methods and tools enforce the fulfillment of a detailed balance condition, restricting their applicability to equilibrium MSMs. To date, they are unsuitable to deal with general dominant data structures including cyclic processes, which are essentially associated with nonequilibrium systems. To overcome this limitation, we developed a generalization of the common robust Perron Cluster Cluster Analysis (PCCA+) method, termed generalized PCCA (G-PCCA). This method handles equilibrium and nonequilibrium simulation data, utilizing Schur vectors instead of eigenvectors. G-PCCA is not limited to the detection of metastable states but enables the identification of dominant structures in a general sense, unraveling cyclic processes. This is exemplified by application of G-PCCA on nonequilibrium molecular dynamics data of the Amyloid β (1-40) peptide, periodically driven by an oscillating electric field.}, language = {en} } @misc{OmariPloentzkeRoeblitz2019, author = {Omari, Mohamed and Pl{\"o}ntzke, Julia and R{\"o}blitz, Susanna}, title = {A pharmacokinetic-pharmacodynamic model for single dose administration of Dexamethasone in dairy cows}, issn = {1438-0064}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-75043}, year = {2019}, abstract = {We present a mechanistic pharmacokinetic-pharmacodynamic model to simulate the effect of dexamethasone on the glucose metabolism in dairy cows. The coupling of the pharmacokinetic model to the pharmacodynamic model is based on mechanisms underlying homeostasis regulation by dexamethasone. In particular, the coupling takes into account the predominant role of dexamethasone in stimulating glucagon secretion, glycogenolysis and lipolysis and in impairing the sensitivity of cells to insulin. Simulating the effect of a single dose of dexamethasone on the physiological behaviour of the system shows that the adopted mechanisms are able to induce a temporary hyperglycemia and hyperinsulinemia, which captures the observed data in non-lactating cows. In lactating cows, the model simulations show that a single dose of dexamethasone reduces the lipolytic effect, owing to the reduction of glucose uptake by the mammary gland.}, language = {en} } @article{ErlekamIgdeRoeblitzetal.2019, author = {Erlekam, Franziska and Igde, Sinaida and R{\"o}blitz, Susanna and Hartmann, Laura and Weber, Marcus}, title = {Modeling of Multivalent Ligand-Receptor Binding Measured by kinITC}, volume = {7}, journal = {Computation}, number = {3}, doi = {10.3390/computation7030046}, pages = {46}, year = {2019}, abstract = {In addition to the conventional Isothermal Titration Calorimetry (ITC), kinetic ITC (kinITC) not only gains thermodynamic information, but also kinetic data from a biochemical binding process. Moreover, kinITC gives insights into reactions consisting of two separate kinetic steps, such as protein folding or sequential binding processes. The ITC method alone cannot deliver kinetic parameters, especially not for multivalent bindings. This paper describes how to solve the problem using kinITC and an invariant subspace projection. The algorithm is tested for multivalent systems with different valencies.}, language = {en} } @article{OmariLangePloentzkeetal.2020, author = {Omari, Mohamed and Lange, Alexander and Pl{\"o}ntzke, Julia and R{\"o}blitz, Susanna}, title = {Model-based exploration of the impact of glucose metabolism on the estrous cycle dynamics in dairy cows}, volume = {15}, journal = {Biology Direct}, doi = {10.1186/s13062-019-0256-7}, year = {2020}, language = {en} } @article{WeberFischerDamerauetal.2020, author = {Weber, Marie-Christin and Fischer, Lisa and Damerau, Alexandra and Ponomarev, Igor and Pfeiffenberger, Moritz and Gaber, Timo and G{\"o}tschel, Sebastian and Lang, Jens and R{\"o}blitz, Susanna and Buttgereit, Frank and Ehrig, Rainald and Lang, Annemarie}, title = {Macroscale mesenchymal condensation to study cytokine-driven cellular and matrix-related changes during cartilage degradation}, volume = {12}, journal = {Biofabrication}, number = {4}, doi = {10.1088/1758-5090/aba08f}, year = {2020}, abstract = {Understanding the pathophysiological processes of cartilage degradation requires adequate model systems to develop therapeutic strategies towards osteoarthritis (OA). Although different in vitro or in vivo models have been described, further comprehensive approaches are needed to study specific disease aspects. This study aimed to combine in vitro and in silico modeling based on a tissue-engineering approach using mesenchymal condensation to mimic cytokine-induced cellular and matrix-related changes during cartilage degradation. Thus, scaffold-free cartilage-like constructs (SFCCs) were produced based on self-organization of mesenchymal stromal cells (mesenchymal condensation) and i) characterized regarding their cellular and matrix composition or secondly ii) treated with interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) for 3 weeks to simulate OA-related matrix degradation. In addition, an existing mathematical model based on partial differential equations was optimized and transferred to the underlying settings to simulate distribution of IL-1β, type II collagen degradation and cell number reduction. By combining in vitro and in silico methods, we aim to develop a valid, efficient alternative approach to examine and predict disease progression and effects of new therapeutics.}, language = {en} } @article{FischerEhrigSchaeferetal.2021, author = {Fischer, Sophie and Ehrig, Rainald and Sch{\"a}fer, Stefan and Tronci, Enrico and Mancini, Toni and Egli, Marcel and Ille, Fabian and Kr{\"u}ger, Tillmann H. C. and Leeners, Brigitte and R{\"o}blitz, Susanna}, title = {Mathematical Modelling and Simulation Provides Evidence for New Strategies of Ovarian Stimulation}, volume = {12}, journal = {Frontiers in Endocrinology}, doi = {10.3389/fendo.2021.613048}, year = {2021}, abstract = {New approaches to ovarian stimulation protocols, such as luteal start, random start or double stimulation, allow for flexibility in ovarian stimulation at different phases of the menstrual cycle which is especially useful when time for assisted reproductive technology is limited, e.g. for emergency fertility preservation in cancer patients. It has been proposed that the success of these methods is based on the continuous growth of multiple cohorts ("waves") of follicles throughout the menstrual cycle which leads to the availability of ovarian follicles for ovarian controlled stimulation at several time points. Though several preliminary studies have been published, their scientific evidence has not been considered as being strong enough to integrate these results into routine clinical practice. This work aims at adding further scientific evidence about the efficiency of variable-start protocols and underpinning the theory of follicular waves by using mathematical modelling and numerical simulations. For this purpose, we have modified and coupled two previously published models, one describing the time course of hormones and one describing competitive follicular growth in a normal menstrual cycle. The coupled model is used to test stimulation protocols in silico. Simulation results show the occurrence of follicles in a wave-like manner during a normal menstrual cycle and qualitatively predict the outcome of ovarian stimulation initiated at different time points of the menstrual cycle.}, language = {en} } @misc{SchwiegerSiebertRoeblitz2018, author = {Schwieger, Robert and Siebert, Heike and R{\"o}blitz, Susanna}, title = {Correspondence of Trap Spaces in Different Models of Bioregulatory Networks}, issn = {1438-0064}, doi = {https://doi.org/10.1137/17M1155302}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-67121}, year = {2018}, abstract = {Mathematical models for bioregulatory networks can be based on different formalisms, depending on the quality of available data and the research question to be answered. Discrete boolean models can be constructed based on qualitative data, which are frequently available. On the other hand, continuous models in terms of ordinary differential equations (ODEs) can incorporate time-series data and give more detailed insight into the dynamics of the underlying system. A few years ago, a method based on multivariate polynomial interpolation and Hill functions has been developed for an automatic conversion of boolean models to systems of ordinary differential equations. This method is frequently used by modellers in systems biology today, but there are only a few results available about the conservation of mathematical structures and properties across the formalisms. Here, we consider subsets of the phase space where some components stay fixed, called trap spaces, and demonstrate how boolean trap spaces can be linked to invariant sets in the continuous state space. This knowledge is of practical relevance since finding trap spaces in the boolean setting, which is relatively easy, allows for the construction of reduced ODE models.}, language = {en} } @article{LangVolkamerBehmetal.2018, author = {Lang, Annemarie and Volkamer, Andrea and Behm, Laura and R{\"o}blitz, Susanna and Ehrig, Rainald and Schneider, Marlon and Geris, Lisbet and Wichard, Joerg and Buttgereit, Frank}, title = {In silico Methods - Computational Alternatives to Animal Testing}, volume = {35}, journal = {ALTEX}, number = {1}, doi = {10.14573/altex.1712031}, pages = {126 -- 128}, year = {2018}, abstract = {A seminar and interactive workshop on "In silico Methods - Computational Alternatives to Animal Testing" was held in Berlin, Germany, organized by Annemarie Lang, Frank Butt- gereit and Andrea Volkamer at the Charit{\´e}-Universit{\"a}tsmedizin Berlin, on August 17-18, 2017. During the half-day seminar, the variety and applications of in silico methods as alternatives to animal testing were presented with room for scientific discus- sions with experts from academia, industry and the German fed- eral ministry (Fig. 1). Talks on computational systems biology were followed by detailed information on predictive toxicology in order to display the diversity of in silico methods and the potential to embrace them in current approaches (Hartung and Hoffmann, 2009; Luechtefeld and Hartung, 2017). The follow- ing interactive one-day Design Thinking Workshop was aimed at experts, interested researchers and PhD-students interested in the use of in silico as alternative methods to promote the 3Rs (Fig. 2). Forty participants took part in the seminar while the workshop was restricted to sixteen participants.}, language = {en} } @misc{OmariLangePloentzkeetal.2019, author = {Omari, Mohamed and Lange, Alexander and Pl{\"o}ntzke, Julia and R{\"o}blitz, Susanna}, title = {A Mathematical Model for the Influence of Glucose-Insulin Dynamics on the Estrous Cycle in Dairy Cows}, issn = {1438-0064}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-73475}, year = {2019}, abstract = {Nutrition plays a crucial role in regulating reproductive hormones and follicular development in cattle. This is visible particularly during the time of negative energy balance at the onset of milk production after calving. Here, elongated periods of anovulation have been observed, resulting from alterations in luteiniz- ing hormone concentrations, likely caused by lower glucose and insulin concen- trations in the blood. The mechanisms that result in a reduced fertility are not completely understood, although a close relationship to the glucose-insulin metabolism is widely supported. Following this idea, a mathematical model of the hormonal network combining reproductive hormones and hormones that are coupled to the glucose compartments within the body of the cow was developed. The model is built on ordinary differential equations and relies on previously introduced models on the bovine estrous cycle and the glucose-insulin dynam- ics. Necessary modifications and coupling mechanisms are thoroughly discussed. Depending on the composition and the amount of food, in particular the glu- cose content in the dry matter, the model quantifies reproductive hormones and follicular development over time. Simulation results for different nutritional regimes in lactating and non-lactating dairy cows are examined and compared with experimental studies. Regarding its applicability, this work is an early attempt towards developing in silico feeding strategies and may eventually help refining and reducing animal experiments.}, language = {en} } @article{WeberFischerDamerauetal.2019, author = {Weber, Marie-Christin and Fischer, Lisa and Damerau, Alexandra and Ponomarev, Igor and Pfeiffenberger, Moritz and Gaber, Timo and G{\"o}tschel, Sebastian and Lang, Jens and R{\"o}blitz, Susanna and Buttgereit, Frank and Ehrig, Rainald and Lang, Annemarie}, title = {In vitro and in silico modeling of cellular and matrix-related changes during the early phase of osteoarthritis}, journal = {BioRxiv}, doi = {10.1101/725317}, year = {2019}, abstract = {Understanding the pathophysiological processes of osteoarthritis (OA) require adequate model systems. Although different in vitro or in vivo models have been described, further comprehensive approaches are needed to study specific parts of the disease. This study aimed to combine in vitro and in silico modeling to describe cellular and matrix-related changes during the early phase of OA. We developed an in vitro OA model based on scaffold-free cartilage-like constructs (SFCCs), which was mathematically modeled using a partial differential equation (PDE) system to resemble the processes during the onset of OA. SFCCs were produced from mesenchymal stromal cells and analyzed weekly by histology and qPCR to characterize the cellular and matrix-related composition. To simulate the early phase of OA, SFCCs were treated with interleukin-1β (IL-1β), tumor necrosis factor α (TNFα) and examined after 3 weeks or cultivated another 3 weeks without inflammatory cytokines to validate the regeneration potential. Mathematical modeling was performed in parallel to the in vitro experiments. SFCCs expressed cartilage-specific markers, and after stimulation an increased expression of inflammatory markers, matrix degrading enzymes, a loss of collagen II (Col-2) and a reduced cell density was observed which could be partially reversed by retraction of stimulation. Based on the PDEs, the distribution processes within the SFCCs, including those of IL-1β, Col-2 degradation and cell number reduction was simulated. By combining in vitro and in silico methods, we aimed to develop a valid, efficient alternative approach to examine and predict disease progression and new therapeutic strategies.}, language = {en} } @article{LangFischerWeberetal.2019, author = {Lang, Annemarie and Fischer, Lisa and Weber, Marie-Christin and Gaber, Timo and Ehrig, Rainald and R{\"o}blitz, Susanna and Buttgereit, Frank}, title = {Combining in vitro simulation and in silico modelling towards a sophisticated human osteoarthritis model}, volume = {27}, journal = {Osteoarthritis and Cartilage}, doi = {10.1016/j.joca.2019.02.277}, pages = {S183}, year = {2019}, abstract = {Our project aimed at building an in silico model based on our recently developed in vitro osteoarthritis (OA) model seeking for refinement of the model to enhance validity and translatability towards the more sophisticated simulation of OA. In detail, the previously 3D in vitro model is based on 3D chondrogenic constructs generated solely from human bone marrow derived mesenchymal stromal cells (hMSCs). Besides studying the normal state of the model over 3 weeks, the in vitro model was treated with interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNFα) to mimic an OA-like environment.}, language = {en} } @article{BoerStoetzelRoeblitzetal.2011, author = {Boer, H. Marike T. and St{\"o}tzel, Claudia and R{\"o}blitz, Susanna and Deuflhard, Peter and Veerkamp, Roel F. and Woelders, Henri}, title = {A simple mathematical model of the bovine estrous cycle}, volume = {278}, journal = {Journal of Theoretical Biology}, number = {1}, doi = {10.1016/j.jtbi.2011.02.021}, pages = {20 -- 31}, year = {2011}, language = {en} } @article{BoerRoeblitzStoetzeletal.2011, author = {Boer, H. Marike T. and R{\"o}blitz, Susanna and St{\"o}tzel, Claudia and Veerkamp, Roel F. and Kemp, Bas and Woelders, Henri}, title = {Mechanisms regulating follicle wave patterns in the bovine estrous cycle investigated with a mathematical model}, volume = {94}, journal = {Journal of Dairy Science}, number = {12}, doi = {10.3168/jds.2011-4400}, pages = {5987 -- 6000}, year = {2011}, language = {en} } @incollection{BoerStoetzelRoeblitzetal.2012, author = {Boer, H. Marike T. and St{\"o}tzel, Claudia and R{\"o}blitz, Susanna and Woelders, Henri}, title = {A differential equation model to investigate the dynamics of the bovine estrous cycle}, volume = {736}, booktitle = {Advances in Systems Biology}, doi = {10.1007/978-1-4419-7210-1_35}, pages = {597 -- 606}, year = {2012}, language = {en} } @book{DeuflhardRoeblitz2015, author = {Deuflhard, Peter and R{\"o}blitz, Susanna}, title = {A guide to numerical modelling in systems biology}, volume = {12}, publisher = {Springer}, isbn = {978-3-319-20058-3}, doi = {10.1007/978-3-319-20059-0}, year = {2015}, language = {en} } @misc{StoetzelRoeblitzSiebert2015, author = {St{\"o}tzel, Claudia and R{\"o}blitz, Susanna and Siebert, Heike}, title = {Complementing ODE-based System Analysis Using Boolean Networks Derived from an Euler-like Transformation}, issn = {1438-0064}, doi = {10.1371/journal.pone.0140954}, url = {http://nbn-resolving.de/urn:nbn:de:0297-zib-56164}, year = {2015}, abstract = {In this paper, we present a systematic transition scheme for a large class of ordinary differential equations (ODEs) into Boolean networks. Our transition scheme can be applied to any system of ODEs whose right hand sides can be written as sums and products of monotone functions. It performs an Euler-like step which uses the signs of the right hand sides to obtain the Boolean update functions for every variable of the corresponding discrete model. The discrete model can, on one hand, be considered as another representation of the biological system or, alternatively, it can be used to further the analysis of the original ODE model. Since the generic transformation method does not guarantee any property conservation, a subsequent validation step is required. Depending on the purpose of the model this step can be based on experimental data or ODE simulations and characteristics. Analysis of the resulting Boolean model, both on its own and in comparison with the ODE model, then allows to investigate system properties not accessible in a purely continuous setting. The method is exemplarily applied to a previously published model of the bovine estrous cycle, which leads to new insights regarding the regulation among the components, and also indicates strongly that the system is tailored to generate stable oscillations.}, language = {en} } @article{MoualeuNgangueRoeblitzEhrigetal.2015, author = {Moualeu-Ngangue, Dany Pascal and R{\"o}blitz, Susanna and Ehrig, Rainald and Deuflhard, Peter}, title = {Parameter Identification in a Tuberculosis Model for Cameroon}, journal = {PLOS ONE}, doi = {10.1371/journal.pone.0120607}, year = {2015}, abstract = {A deterministic model of tuberculosis in Cameroon is designed and analyzed with respect to its transmission dynamics. The model includes lack of access to treatment and weak diagnosis capacity as well as both frequency- and density-dependent transmissions. It is shown that the model is mathematically well-posed and epidemiologically reasonable. Solutions are non-negative and bounded whenever the initial values are non-negative. A sensitivity analysis of model parameters is performed and the most sensitive ones are identified by means of a state-of-the-art Gauss-Newton method. In particular, parameters representing the proportion of individuals having access to medical facilities are seen to have a large impact on the dynamics of the disease. The model predicts that a gradual increase of these parameters could significantly reduce the disease burden on the population within the next 15 years.}, language = {en} } @inproceedings{EhrigDierkesSchaeferetal.2016, author = {Ehrig, Rainald and Dierkes, Thomas and Sch{\"a}fer, Stefan and R{\"o}blitz, Susanna and Tronci, Enrico and Mancini, Toni and Salvo, Ivano and Alimguzhin, Vadim and Mari, Federico and Melatti, Igor and Massini, Annalisa and Kr{\"u}ger, Tillmann H. C. and Egli, Marcel and Ille, Fabian and Leeners, Brigitte}, title = {An integrative approach for model driven computation of treatments in reproductive medicine}, booktitle = {BIOMAT - Proceedings of the 15th International Symposium on Mathematical and Computational Biology, Rorkee, India}, year = {2016}, language = {en} }