07 Fakultät Konstruktions-, Produktions- und Fahrzeugtechnik

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    ROSIE : RObust Sparse ensemble for outlIEr detection and gene selection in cancer omics data
    (2022) Jensch, Antje; Lopes, Marta B.; Vinga, Susana; Radde, Nicole
    The extraction of novel information from omics data is a challenging task, in particular, since the number of features (e.g. genes) often far exceeds the number of samples. In such a setting, conventional parameter estimation leads to ill-posed optimization problems, and regularization may be required. In addition, outliers can largely impact classification accuracy. Here we introduce ROSIE, an ensemble classification approach, which combines three sparse and robust classification methods for outlier detection and feature selection and further performs a bootstrap-based validity check. Outliers of ROSIE are determined by the rank product test using outlier rankings of all three methods, and important features are selected as features commonly selected by all methods. We apply ROSIE to RNA-Seq data from The Cancer Genome Atlas (TCGA) to classify observations into Triple-Negative Breast Cancer (TNBC) and non-TNBC tissue samples. The pre-processed dataset consists of 16,600 genes and more than 1,000 samples. We demonstrate that ROSIE selects important features and outliers in a robust way. Identified outliers are concordant with the distribution of the commonly selected genes by the three methods, and results are in line with other independent studies. Furthermore, we discuss the association of some of the selected genes with the TNBC subtype in other investigations. In summary, ROSIE constitutes a robust and sparse procedure to identify outliers and important genes through binary classification. Our approach is ad hoc applicable to other datasets, fulfilling the overall goal of simultaneously identifying outliers and candidate disease biomarkers to the targeted in therapy research and personalized medicine frameworks.
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    Entwicklung einer Methode zur Analyse der Tätigkeitsverteilung in Laborumgebungen der Lebenswissenschaften
    (Stuttgart : Fraunhofer Verlag, 2022) Castor, Jörg; Spath, Dieter (Univ.-Prof. Dr.-Ing. Dr.-Ing. E.h. Dr. h.c.)
    Laborarbeit der Lebenswissenschaften verändert sich. Wichtige Treiber sind dabei die Informatisierung und Automatisierung von Laborarbeit, die fachübergreifende Zusammenarbeit und Kommunikation sowie der steigende Anteil an wissensbasierter, theoretischer Arbeit. Die Auseinandersetzung mit Forschung und Praxis der Laborarbeit in den Lebenswissenschaften zeigte einen Mangel an wissenschaftlichen Erkenntnissen und Untersuchungen zu diesem Thema. Es existiert kein wissenschaftlicher Ansatz tätigkeitsbezogene Aspekte der lebenswissenschaftlichen Forschung und ihren Arbeitsorten systematisch zu untersuchen, um ein besseres Lagebild zur Arbeit in lebenswissenschaftlichen Laborumgebungen zu erhalten. Eine fundierte gestalterische Auseinandersetzung mit den prognostizierten und wahrnehmbaren Veränderungen von Laborarbeit kann so kaum erfolgen. Zielsetzung der vorliegenden Arbeit ist daher die Entwicklung einer wissenschaftlichen Methode zur Analyse der Tätigkeitsverteilung in Laborumgebungen der Lebenswissenschaften, um Anhaltspunkte für mögliche Fehlnutzungen, Verdrängungseffekte und andere Wirkungen im Spannungsfeld von Raum und Tätigkeiten zu bekommen. Die Methode ermöglicht zudem Aussagen zur Flächeneffizienz von Laborumgebungen. Der Begriff Laborumgebung beschreibt in der Arbeit den räumlichen Zusammenhang von Laboren mit Laborbänken, Laborabzügen, Schreib-/Auswerteplätzen, Sonderlaboren, Laborlagern sowie Büros und Kommunikationsflächen. Für die Anwendung der Methode werden jeweils nass-präparative Tätigkeiten, Schreib-, Lese- und Auswertetätigkeiten sowie Kommunikationstätigkeiten gebündelt. Kommunikationstätigkeiten werden eine besondere Relevanz in der modernen Forschungsarbeit zugeschrieben. Sie sind zudem die einzigen Tätigkeiten, die an allen Arbeitsorten in Laborumgebungen vorkommen. Als weitere Anwendung lässt die Methode daher eine Beurteilung der Qualität des raumbezogenen Informationsflusses und der tätigkeitsadäquaten Nutzung der Arbeitsorte in der Laborumgebung mittels eigener Qualitätsparameter für Kommunikation zu. In der praktischen Anwendung der Methode wird deutlich, dass die wissenschaftliche Herangehensweise gerade bei Einzeluntersuchungen einen gewissen Aufwand erfordert. Die Methode zeigte aber einen guten Praxisnutzen - insbesondere bei einer vergleichenden Untersuchung wie im Anwendungsbeispiel. So wurden durch die Vergleichsmöglichkeit im Anwendungsbeispiel sowohl Vorteile der effizienten Flächennutzung einer modernen »Multi-Space« Laborumgebung sichtbar, als auch die dadurch bedingten Schwierigkeiten hinsichtlich der Verdrängung raumtypischer Arbeitsweisen in dichteren räumlichen Funktionszusammenhängen.
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    Modeling of biocatalytic reactions: a workflow for model calibration, selection, and validation using Bayesian statistics
    (2019) Eisenkolb, Ina; Jensch, Antje; Eisenkolb, Kerstin; Kramer, Andrei; Buchholz, Patrick C. F.; Pleiss, Jürgen; Spiess, Antje; Radde, Nicole
    We present a workflow for kinetic modeling of biocatalytic reactions which combines methods from Bayesian learning and uncertainty quantification for model calibration, model selection, evaluation, and model reduction in a consistent statistical frame-work. Our workflow is particularly tailored to sparse data settings in which a considerable variability of the parameters remains after the models have been adapted to available data, a ubiquitous problem in many real-world applications. Our workflow is exemplified on an enzyme-catalyzed two-substrate reaction mechanism describing the symmetric carboligation of 3,5-dimethoxy-benzaldehyde to (R)-3,3',5,5'-tetramethoxybenzoin catalyzed by benzaldehyde lyase from Pseudomonas fluorescens. Results indicate a substrate-dependent inactivation of enzyme, which is in accordance with other recent studies.
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    Cu-doped calcium phosphate supraparticles for bone tissue regeneration
    (2024) Höppel, Anika; Bahr, Olivia; Ebert, Regina; Wittmer, Annette; Seidenstuecker, Michael; Carolina Lanzino, M.; Gbureck, Uwe; Dembski, Sofia
    Calcium phosphate (CaP) minerals have shown great promise as bone replacement materials due to their similarity to the mineral phase of natural bone. In addition to biocompatibility and osseointegration, the prevention of infection is crucial, especially due to the high concern of antibiotic resistance. In this context, a controlled drug release as well as biodegradation are important features which depend on the porosity of CaP. An increase in porosity can be achieved by using nanoparticles (NPs), which can be processed to supraparticles, combining the properties of nano- and micromaterials. In this study, Cu-doped CaP supraparticles were prepared to improve the bone substitute properties while providing antibacterial effects. In this context, a modified sol-gel process was used for the synthesis of CaP NPs, where a Ca/P molar ratio of 1.10 resulted in the formation of crystalline β-tricalcium phosphate (β-TCP) after calcination at 1000 °C. In the next step, CaP NPs with Cu 2+ (0.5-15.0 wt%) were processed into supraparticles by a spray drying method. Cu release experiments of the different Cu-doped CaP supraparticles demonstrated a long-term sustained release over 14 days. The antibacterial properties of the supraparticles were determined against Gram-positive ( Bacillus subtilis and Staphylococcus aureus ) and Gram-negative ( Escherichia coli ) bacteria, where complete antibacterial inhibition was achieved using a Cu concentration of 5.0 wt%. In addition, cell viability assays of the different CaP supraparticles with human telomerase-immortalized mesenchymal stromal cells (hMSC-TERT) exhibited high biocompatibility with particle concentrations of 0.01 mg mL -1 over 72 hours.
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    Editorial - optical microscopic and spectroscopic techniques targeting biological applications
    (2021) Micó, Vicente; Pedrini, Giancarlo; Lei, Ming; Zuo, Chao; Gao, Peng
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    Miniature low-cost γ-radiation sensor for localization of radioactively marked lymph nodes
    (2022) Behling, Merlin; Wezel, Felix; Pott, Peter P.
    Detection of metastasis spread at an early stage of disease in lymph nodes can be achieved by imaging techniques, such as PET and fluoride-marked tumor cells. Intraoperative detection of small metastasis can be problematic especially in minimally invasive surgical settings. A γ-radiation sensor can be inserted in the situs to facilitate intraoperative localization of the lymph nodes. In the minimally invasive setting, the sensor must fit through the trocar and for robot-aided interventions, a small, capsule-like device is favorable. Size reduction could be achieved by using only a few simple electronic parts packed in a single-use sensor-head also leading to a low-cost device. This paper first describes the selection of an appropriate low-cost diode, which is placed in a sensor head (Ø 12 mm) and characterized in a validation experiment. Finally, the sensor and its performance during a detection experiment with nine subjects is evaluated. The subjects had to locate a 137Cs source (138 kBq activity, 612 keV) below a wooden plate seven times. Time to accomplish this task and error rate were recorded and evaluated. The time needed by the subjects to complete each run was 95 ± 68.1 s for the first trial down to 40 ± 23.9 s for the last. All subjects managed to locate the 137Cs source precisely. Further reduction in size and a sterilizable housing are prerequisites for in vitro tests on explanted human lymph nodes and finally in vivo testing.
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    Rapid sampling of Escherichia coli after changing oxygen conditions reveals transcriptional dynamics
    (2017) Wulffen, Joachim von; Ulmer, Andreas; Jäger, Günter; Sawodny, Oliver; Feuer, Ronny
    Escherichia coli is able to shift between anaerobic and aerobic metabolism by adapting its gene expression, e.g., of metabolic genes, to the new environment. The dynamics of gene expression that result from environmental shifts are limited, amongst others, by the time needed for regulation and transcription elongation. In this study, we examined gene expression dynamics after an anaerobic-to-aerobic shift on a short time scale (0.5, 1, 2, 5, and 10 min) by RNA sequencing with emphasis on delay times and transcriptional elongation rates (TER). Transient expression patterns and timing of differential expression, characterized by delay and elongation, were identified as key features of the dataset. Gene ontology enrichment analysis revealed early upregulation of respiratory and iron-related gene sets. We inferred specific TERs of 89 operons with a mean TER of 42.0 nt/s and mean delay time of 22.4 s. TERs correlate with sequence features, such as codon bias, whereas delay times correlate with the involvement of regulators. The presented data illustrate that at very short times after a shift in oxygenation, extensional changes of the transcriptome, such as temporary responses, can be observed. Besides regulation, TERs contribute to the dynamics of gene expression.
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    Basic regulatory principles of Escherichia coli's electron transport chain for varying oxygen conditions
    (2014) Henkel, Sebastian; Beek, Alexander ter; Steinsiek, Sonja; Stagge, Stefan; Bettenbrock, Katja; Teixeira de Mattos, M. Joost; Sauter, Thomas; Sawodny, Oliver; Ederer, Michael
    For adaptation between anaerobic, micro-aerobic and aerobic conditions Escherichia coli's metabolism and in particular its electron transport chain (ETC) is highly regulated. Although it is known that the global transcriptional regulators FNR and ArcA are involved in oxygen response it is unclear how they interplay in the regulation of ETC enzymes under micro-aerobic chemostat conditions. Also, there are diverse results which and how quinones (oxidised/reduced, ubiquinone/other quinones) are controlling the ArcBA two-component system. In the following a mathematical model of the E. coli ETC linked to basic modules for substrate uptake, fermentation product excretion and biomass formation is introduced. The kinetic modelling focusses on regulatory principles of the ETC for varying oxygen conditions in glucose-limited continuous cultures. The model is based on the balance of electron donation (glucose) and acceptance (oxygen or other acceptors). Also, it is able to account for different chemostat conditions due to changed substrate concentrations and dilution rates. The parameter identification process is divided into an estimation and a validation step based on previously published and new experimental data. The model shows that experimentally observed, qualitatively different behaviour of the ubiquinone redox state and the ArcA activity profile in the micro-aerobic range for different experimental conditions can emerge from a single network structure. The network structure features a strong feed-forward effect from the FNR regulatory system to the ArcBA regulatory system via a common control of the dehydrogenases of the ETC. The model supports the hypothesis that ubiquinone but not ubiquinol plays a key role in determining the activity of ArcBA in a glucose-limited chemostat at micro-aerobic conditions.
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    Implementation and validation of the extended Hill-type muscle model with robust routing capabilities in LS-DYNA for active human body models
    (2017) Kleinbach, Christian; Martynenko, Oleksandr; Promies, Janik; Häufle, Daniel F. B.; Fehr, Jörg; Schmitt, Syn
    In the state of the art finite element AHBMs for car crash analysis in the LS-DYNA software material named *MAT_MUSCLE (*MAT_156) is used for active muscles modeling. It has three elements in parallel configuration, which has several major drawbacks: restraint approximation of the physical reality, complicated parameterization and absence of the integrated activation dynamics. This study presents implementation of the extended four element Hill-type muscle model with serial damping and eccentric force-velocity relation including Ca2+ dependent activation dynamics and internal method for physiological muscle routing.
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    A rapid method for the extraction and analysis of carotenoids and other hydrophobic substances suitable for systems biology studies with photosynthetic bacteria
    (2013) Bóna-Lovász, Judit; Bóna, Aron; Ederer, Michael; Sawodny, Oliver; Ghosh, Robin
    A simple, rapid, and inexpensive extraction method for carotenoids and other non-polar compounds present in phototrophic bacteria has been developed. The method, which has been extensively tested on the phototrophic purple non-sulphur bacterium Rhodospirillum rubrum, is suitable for extracting large numbers of samples, which is common in systems biology studies, and yields material suitable for subsequent analysis using HPLC and mass spectroscopy. The procedure is particularly suitable for carotenoids and other terpenoids, including quinones, bacteriochlorophyll a and bacteriopheophytin a, and is also useful for the analysis of polar phospholipids. The extraction procedure requires only a single step extraction with a hexane/methanol/water mixture, followed by HPLC using a Spherisorb C18 column, with a mobile phase consisting of acetone-water and a non-linear gradient of 50%-100% acetone. The method was employed for examining the carotenoid composition observed during microaerophilic growth of R. rubrum strains, and was able to determine 18 carotenoids, 4 isoprenoid-quinones, bacteriochlorophyll a and bacteriopheophytin a as well as four different phosphatidylglycerol species of different acyl chain compositions. The analytical procedure was used to examine the dynamics of carotenoid biosynthesis in the major and minor pathways operating simultaneously in a carotenoid biosynthesis mutant of R. rubrum.