TY - GEN A1 - Moualeu-Ngangue, Dany Pascal A1 - Röblitz, Susanna A1 - Ehrig, Rainald A1 - Deuflhard, Peter T1 - Parameter Identification for a Tuberculosis Model in Cameroon N2 - A deterministic model of tuberculosis in sub-Saharan Africa in general and Cameroon in particular including lack of access to the treatment and weak diagnose capacity is designed and analyzed with respect to its transmission dynamics. The model includes 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 most sensitive parameters of the model are identified using a state-of-the-art Gauss-Newton Method. In particular, parameters representing the proportion of individuals having access to medical facilities have a large impact on the dynamics of the disease. It has been shown that an increase of these parameter values over the time can significantly reduce the disease burden in the population within the next 15 years. T3 - ZIB-Report - 13-72 KW - Tuberculosis, parameter identification, sensitivity analysis, Gauss-Newton method, Nonlinear dynamical systems. Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:0297-zib-43087 SN - 1438-0064 ER - TY - JOUR A1 - Plöntzke, Julia A1 - Berg, Mascha A1 - Ehrig, Rainald A1 - Leonhard-Marek, Sabine A1 - Müller, Kerstin-Elisabeth A1 - Röblitz, Susanna T1 - Model Based Exploration of Hypokalemia in Dairy Cows JF - Scientific Reports N2 - Hypokalemia, characterized by too low serum potassium levels, is a severe mineral disorder which can be life threatening. It is increasingly diagnosed in veterinarian healthcare and a topic of ongoing research. In this paper, we explore the different originating conditions of hypokalemia: reduced potassium intake, increased excretion, acid-base disturbances, or increased insulin, by using a dynamic mathematical model for potassium balance in non-lactating and lactating cows. Simulations are compared with literature. The results give insights into the network dynamics and point to scenarios on which experimental effort should be focused. Application of mathematical models can assist in experimental planning as well as the reduction, refinement and replacement of animal experiments. Y1 - 2022 U6 - https://doi.org/10.1038/s41598-022-22596-0 VL - 12, 19781 ER - TY - CHAP A1 - Mancini, Toni A1 - Mari, Federico A1 - Massini, Annalisa A1 - Melatti, Igor A1 - Salvo, Ivano A1 - Sinisi, Stefano A1 - Tronci, Enrico A1 - Ehrig, Rainald A1 - Röblitz, Susanna A1 - Leeners, Brigitte T1 - Computing Personalised Treatments through In Silico Clinical Trials. A Case Study on Downregulation in Assisted Reproduction T2 - Experimental Evaluation of Algorithms for Solving Problems with Combinatorial Explosion, Workshop of the Federated Logic Conference 2018 (FLoC 2018), Oxford N2 - In Silico Clinical Trials (ISCT), i.e., clinical experimental campaigns carried out by means of computer simulations, hold the promise to decrease time and cost for the safety and efficacy assessment of pharmacological treatments, reduce the need for animal and human testing, and enable precision medicine. In this paper we present a case study aiming at quantifying, by means of a multi-arm ISCT supervised by intelligent search, the potential impact of precision medicine approaches on a real pharmacological treatment, namely the downregulation phase of a complex clinical protocol for assisted reproduction. Y1 - 2018 U6 - https://doi.org/10.29007/g864 SP - 1 EP - 16 ER - TY - JOUR A1 - Weber, Marie-Christin A1 - Fischer, Lisa A1 - Damerau, Alexandra A1 - Ponomarev, Igor A1 - Pfeiffenberger, Moritz A1 - Gaber, Timo A1 - Götschel, Sebastian A1 - Lang, Jens A1 - Röblitz, Susanna A1 - Buttgereit, Frank A1 - Ehrig, Rainald A1 - Lang, Annemarie T1 - Macroscale mesenchymal condensation to study cytokine-driven cellular and matrix-related changes during cartilage degradation JF - Biofabrication N2 - 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. Y1 - 2020 U6 - https://doi.org/10.1088/1758-5090/aba08f VL - 12 IS - 4 ER - TY - JOUR A1 - Fischer, Sophie A1 - Ehrig, Rainald A1 - Schäfer, Stefan A1 - Tronci, Enrico A1 - Mancini, Toni A1 - Egli, Marcel A1 - Ille, Fabian A1 - Krüger, Tillmann H. C. A1 - Leeners, Brigitte A1 - Röblitz, Susanna T1 - Mathematical Modelling and Simulation Provides Evidence for New Strategies of Ovarian Stimulation JF - Frontiers in Endocrinology N2 - 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. Y1 - 2021 U6 - https://doi.org/10.3389/fendo.2021.613048 VL - 12 ER - TY - JOUR A1 - Lang, Annemarie A1 - Volkamer, Andrea A1 - Behm, Laura A1 - Röblitz, Susanna A1 - Ehrig, Rainald A1 - Schneider, Marlon A1 - Geris, Lisbet A1 - Wichard, Joerg A1 - Buttgereit, Frank T1 - In silico Methods - Computational Alternatives to Animal Testing JF - ALTEX N2 - 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 Charité-Universitätsmedizin 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. Y1 - 2018 U6 - https://doi.org/10.14573/altex.1712031 VL - 35 IS - 1 SP - 126 EP - 128 ER - TY - JOUR A1 - Weber, Marie-Christin A1 - Fischer, Lisa A1 - Damerau, Alexandra A1 - Ponomarev, Igor A1 - Pfeiffenberger, Moritz A1 - Gaber, Timo A1 - Götschel, Sebastian A1 - Lang, Jens A1 - Röblitz, Susanna A1 - Buttgereit, Frank A1 - Ehrig, Rainald A1 - Lang, Annemarie T1 - In vitro and in silico modeling of cellular and matrix-related changes during the early phase of osteoarthritis JF - BioRxiv N2 - 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. Y1 - 2019 U6 - https://doi.org/10.1101/725317 ER - TY - JOUR A1 - Lang, Annemarie A1 - Fischer, Lisa A1 - Weber, Marie-Christin A1 - Gaber, Timo A1 - Ehrig, Rainald A1 - Röblitz, Susanna A1 - Buttgereit, Frank T1 - Combining in vitro simulation and in silico modelling towards a sophisticated human osteoarthritis model JF - Osteoarthritis and Cartilage N2 - 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. Y1 - 2019 U6 - https://doi.org/10.1016/j.joca.2019.02.277 VL - 27 SP - S183 ER - TY - JOUR A1 - Moualeu-Ngangue, Dany Pascal A1 - Röblitz, Susanna A1 - Ehrig, Rainald A1 - Deuflhard, Peter T1 - Parameter Identification in a Tuberculosis Model for Cameroon JF - PLOS ONE N2 - 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. Y1 - 2015 U6 - https://doi.org/10.1371/journal.pone.0120607 ER - TY - CHAP A1 - Ehrig, Rainald A1 - Dierkes, Thomas A1 - Schäfer, Stefan A1 - Röblitz, Susanna A1 - Tronci, Enrico A1 - Mancini, Toni A1 - Salvo, Ivano A1 - Alimguzhin, Vadim A1 - Mari, Federico A1 - Melatti, Igor A1 - Massini, Annalisa A1 - Krüger, Tillmann H. C. A1 - Egli, Marcel A1 - Ille, Fabian A1 - Leeners, Brigitte T1 - An integrative approach for model driven computation of treatments in reproductive medicine T2 - BIOMAT - Proceedings of the 15th International Symposium on Mathematical and Computational Biology, Rorkee, India Y1 - 2016 ER - TY - CHAP A1 - Mancini, Toni A1 - Salvo, Ivano A1 - Mari, Federico A1 - Melatti, Igor A1 - Massini, Annalisa A1 - Sinisi, Stefano A1 - Tronci, Enrico A1 - Davi, Francesco A1 - Dierkes, Thomas A1 - Ehrig, Rainald A1 - Röblitz, Susanna A1 - Leeners, Brigitte A1 - Krüger, Tillmann H. C. A1 - Egli, Marcel A1 - Ille, Fabian T1 - Patient-Specific Models from Inter-Patient Biological Models and Clinical Records T2 - Proceedings of the 14th Conference on Formal Methods in Computer-Aided Design (FMCAD 2014) Y1 - 2014 SP - 207 EP - 214 ER - TY - JOUR A1 - Stötzel, Claudia A1 - Ehrig, Rainald A1 - Boer, H. Marike T. A1 - Plöntzke, Julia A1 - Röblitz, Susanna T1 - Exploration of different wave patterns in a model of the bovine estrous cycle by Fourier analysis JF - BIOMAT - Proceedings of the 14th International Symposium on Mathematical and Computational Biology, Bedlewo, Poland N2 - Cows typically have different numbers of follicular waves during their hormonal cycle. Understanding the underlying regulations leads to insights into the reasons for declined fertility, a phenomenon that has been observed during the last decades. We present a systematic approach based on Fourier analysis to examine how parameter changes in a model of the bovine estrous cycle lead to different wave patterns. Even without any biological considerations, this allows to detect the responsible model parameters that control the type of periodicity of the solution, thus supporting experimental planning of animal scientists. Y1 - 2014 ER - TY - JOUR A1 - Hengartner, Michael A1 - Krüger, Tillmann H. C. A1 - Geraedts, Kirsten A1 - Tronci, Enrico A1 - Mancini, Toni A1 - Ille, Fabian A1 - Egli, Marcel A1 - Röblitz, Susanna A1 - Ehrig, Rainald A1 - Saleh, Lanja A1 - Spanaus, Katharina A1 - Schippert, Cordula A1 - Zhang, Yuanyuan A1 - Leeners, Brigitte T1 - Negative affect is unrelated to fluctuations in hormone levels across the menstrual cycle: evidence from a multisite observational study across two successive cycles JF - Journal of Psychosomatic Research Y1 - 2017 U6 - https://doi.org/10.1016/j.jpsychores.2017.05.018 VL - 99 SP - 21 EP - 27 ER - TY - GEN A1 - Ehrig, Rainald A1 - Dierkes, Thomas A1 - Schäfer, Stefan A1 - Röblitz, Susanna A1 - Tronci, Enrico A1 - Mancini, Toni A1 - Salvo, Ivano A1 - Alimguzhin, Vadim A1 - Mari, Federico A1 - Melatti, Igor A1 - Massini, Annalisa A1 - Krüger, Tillmann H. C. A1 - Egli, Marcel A1 - Ille, Fabian A1 - Leeners, Brigitte T1 - An Integrative Approach for Model Driven Computation of Treatments in Reproductive Medicine N2 - We present an overview of the current status of the European collaborative project PAEON. The challenge of PAEON is to provide specialists in reproduc- tive medicine with a computerised model of the menstrual cycle under normal and various pathological conditions, which will allow them to get further in- sight in fertility dynamics. This model also enables the simulation of treatment protocols, which were used within in vitro fertilization. By the definition of virtual patients through biologically admissible parametrizations our approach allows not only the evaluation of a given treatment strategy in silico, but also the design and optimization of such protocols. Once a protocol is formalized in the virtual hospital, the success can be controlled by a treatment execution monitor, which works then as a clinical decision support system. All these tools will be combined in a virtual hospital environment, enabling the access to the PAEON services through the web. T3 - ZIB-Report - 16-04 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:0297-zib-57103 SN - 1438-0064 ER - TY - GEN A1 - Stötzel, Claudia A1 - Ehrig, Rainald A1 - Boer, H. Marike T. A1 - Plöntzke, Julia A1 - Röblitz, Susanna T1 - Exploration of different wave patterns in a model of the bovine estrous cycle by Fourier analysis N2 - Cows typically have different numbers of follicular waves during their hormonal cycle. Understanding the underlying regulations leads to insights into the reasons for declined fertility, a phenomenon that has been observed during the last decades. We present a systematic approach based on Fourier analysis to examine how parameter changes in a model of the bovine estrous cycle lead to different wave patterns. Even without any biological considerations, this allows to detect the responsible model parameters that control the type of periodicity of the solution, thus supporting experimental planning of animal scientists. T3 - ZIB-Report - 16-02 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:0297-zib-57039 SN - 1438-0064 ER -