@article{SchmalzlPlumhoffGilbertetal.2019, author = {Schmalzl, Jonas and Plumhoff, Piet and Gilbert, Fabian and Gohlke, Frank and Konrads, Christian and Brunner, Ulrich and Jakob, Franz and Ebert, Regina and Steinert, Andre F.}, title = {Tendon-derived stem cells from the long head of the biceps tendon}, series = {Bone \& Joint Research}, volume = {8}, journal = {Bone \& Joint Research}, number = {9}, doi = {10.1302/2046-3758.89.BJR-2018-0214.R2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200370}, pages = {414-424}, year = {2019}, abstract = {Objectives The long head of the biceps (LHB) is often resected in shoulder surgery and could therefore serve as a cell source for tissue engineering approaches in the shoulder. However, whether it represents a suitable cell source for regenerative approaches, both in the inflamed and non-inflamed states, remains unclear. In the present study, inflamed and native human LHBs were comparatively characterized for features of regeneration. Methods In total, 22 resected LHB tendons were classified into inflamed samples (n = 11) and non-inflamed samples (n = 11). Proliferation potential and specific marker gene expression of primary LHB-derived cell cultures were analyzed. Multipotentiality, including osteogenic, adipogenic, chondrogenic, and tenogenic differentiation potential of both groups were compared under respective lineage-specific culture conditions. Results Inflammation does not seem to affect the proliferation rate of the isolated tendon-derived stem cells (TDSCs) and the tenogenic marker gene expression. Cells from both groups showed an equivalent osteogenic, adipogenic, chondrogenic and tenogenic differentiation potential in histology and real-time polymerase chain reaction (RT-PCR) analysis. Conclusion These results suggest that the LHB tendon might be a suitable cell source for regenerative approaches, both in inflamed and non-inflamed states. The LHB with and without tendinitis has been characterized as a novel source of TDSCs, which might facilitate treatment of degeneration and induction of regeneration in shoulder surgery.}, language = {en} } @article{PaulsHamaratTrufasuetal.2019, author = {Pauls, Dennis and Hamarat, Yasmin and Trufasu, Luisa and Schendzielorz, Tim M. and Gramlich, Gertrud and Kahnt, J{\"o}rg and Vanselow, Jens and Schlosser, Andreas and Wegener, Christian}, title = {Drosophila carboxypeptidase D (SILVER) is a key enzyme in neuropeptide processing required to maintain locomotor activity levels and survival rate}, series = {European Journal of Neuroscience}, volume = {50}, journal = {European Journal of Neuroscience}, number = {9}, doi = {10.1111/ejn.14516}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204863}, pages = {3502-3519}, year = {2019}, abstract = {Neuropeptides are processed from larger preproproteins by a dedicated set of enzymes. The molecular and biochemical mechanisms underlying preproprotein processing and the functional importance of processing enzymes are well-characterised in mammals, but little studied outside this group. In contrast to mammals, Drosophila melanogaster lacks a gene for carboxypeptidase E (CPE ), a key enzyme for mammalian peptide processing. By combining peptidomics and neurogenetics, we addressed the role of carboxypeptidase D (dCPD ) in global neuropeptide processing and selected peptide-regulated behaviours in Drosophila . We found that a deficiency in dCPD results in C-terminally extended peptides across the peptidome, suggesting that dCPD took over CPE function in the fruit fly. dCPD is widely expressed throughout the nervous system, including peptidergic neurons in the mushroom body and neuroendocrine cells expressing adipokinetic hormone. Conditional hypomorphic mutation in the dCPD -encoding gene silver in the larva causes lethality, and leads to deficits in starvation-induced hyperactivity and appetitive gustatory preference, as well as to reduced viability and activity levels in adults. A phylogenomic analysis suggests that loss of CPE is not common to insects, but only occurred in Hymenoptera and Diptera. Our results show that dCPD is a key enzyme for neuropeptide processing and peptide-regulated behaviour in Drosophila . dCPD thus appears as a suitable target to genetically shut down total neuropeptide production in peptidergic neurons. The persistent occurrence of CPD in insect genomes may point to important further CPD functions beyond neuropeptide processing which cannot be fulfilled by CPE.}, language = {en} } @article{WajantBeilhack2019, author = {Wajant, Harald and Beilhack, Andreas}, title = {Targeting regulatory T cells by addressing tumor necrosis factor and its receptors in allogeneic hematopoietic cell transplantation and cancer}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, number = {2040}, doi = {10.3389/fimmu.2019.02040}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201578}, year = {2019}, abstract = {An intricate network of molecular and cellular actors orchestrates the delicate balance between effector immune responses and immune tolerance. The pleiotropic cytokine tumor necrosis factor-alpha (TNF) proves as a pivotal protagonist promoting but also suppressing immune responses. These opposite actions are accomplished through specialist cell types responding to TNF via TNF receptors TNFR1 and TNFR2. Recent findings highlight the importance of TNFR2 as a key regulator of activated natural FoxP3+ regulatory T cells (Tregs) in inflammatory conditions, such as acute graft-vs.-host disease (GvHD) and the tumor microenvironment. Here we review recent advances in our understanding of TNFR2 signaling in T cells and discuss how these can reconcile seemingly conflicting observations when manipulating TNF and TNFRs. As TNFR2 emerges as a new and attractive target we furthermore pinpoint strategies and potential pitfalls for therapeutic targeting of TNFR2 for cancer treatment and immune tolerance after allogeneic hematopoietic cell transplantation.}, language = {en} } @article{JochmannElkenaniMohamedetal.2019, author = {Jochmann, Svenja and Elkenani, Manar and Mohamed, Belal A. and Buchholz, Eric and Lbik, Dawid and Binder, Lutz and Lorenz, Kristina and Shah, Ajay M. and Hasenfuß, Gerd and Toischer, Karl and Schnelle, Moritz}, title = {Assessing the role of extracellular signal-regulated kinases 1 and 2 in volume overload-induced cardiac remodelling}, series = {ESC Heart Failure}, volume = {6}, journal = {ESC Heart Failure}, number = {5}, doi = {10.1002/ehf2.12497}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212735}, pages = {1015 -- 1026}, year = {2019}, abstract = {Aims Volume overload (VO) and pressure overload (PO) induce differential cardiac remodelling responses including distinct signalling pathways. Extracellular signal-regulated kinases 1 and 2 (ERK1/2), key signalling components in the mitogen-activated protein kinase (MAPK) pathways, modulate cardiac remodelling during pressure overload (PO). This study aimed to assess their role in VO-induced cardiac remodelling as this was unknown. Methods and results Aortocaval fistula (Shunt) surgery was performed in mice to induce cardiac VO. Two weeks of Shunt caused a significant reduction of cardiac ERK1/2 activation in wild type (WT) mice as indicated by decreased phosphorylation of the TEY (Thr-Glu-Tyr) motif (-28\% as compared with Sham controls, P < 0.05). Phosphorylation of other MAPKs was unaffected. For further assessment, transgenic mice with cardiomyocyte-specific ERK2 overexpression (ERK2tg) were studied. At baseline, cardiac ERK1/2 phosphorylation in ERK2tg mice remained unchanged compared with WT littermates, and no overt cardiac phenotype was observed; however, cardiac expression of the atrial natriuretic peptide was increased on messenger RNA (3.6-fold, P < 0.05) and protein level (3.1-fold, P < 0.05). Following Shunt, left ventricular dilation and hypertrophy were similar in ERK2tg mice and WT littermates. Left ventricular function was maintained, and changes in gene expression indicated reactivation of the foetal gene program in both genotypes. No differences in cardiac fibrosis and kinase activation was found amongst all experimental groups, whereas apoptosis was similarly increased through Shunt in ERK2tg and WT mice. Conclusions VO-induced eccentric hypertrophy is associated with reduced cardiac ERK1/2 activation in vivo. Cardiomyocyte-specific overexpression of ERK2, however, does not alter cardiac remodelling during VO. Future studies need to define the pathophysiological relevance of decreased ERK1/2 signalling during VO.}, language = {en} } @article{ReulChristHarteltetal.2019, author = {Reul, Christian and Christ, Dennis and Hartelt, Alexander and Balbach, Nico and Wehner, Maximilian and Springmann, Uwe and Wick, Christoph and Grundig, Christine and B{\"u}ttner, Andreas and Puppe, Frank}, title = {OCR4all—An open-source tool providing a (semi-)automatic OCR workflow for historical printings}, series = {Applied Sciences}, volume = {9}, journal = {Applied Sciences}, number = {22}, issn = {2076-3417}, doi = {10.3390/app9224853}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193103}, pages = {4853}, year = {2019}, abstract = {Optical Character Recognition (OCR) on historical printings is a challenging task mainly due to the complexity of the layout and the highly variant typography. Nevertheless, in the last few years, great progress has been made in the area of historical OCR, resulting in several powerful open-source tools for preprocessing, layout analysis and segmentation, character recognition, and post-processing. The drawback of these tools often is their limited applicability by non-technical users like humanist scholars and in particular the combined use of several tools in a workflow. In this paper, we present an open-source OCR software called OCR4all, which combines state-of-the-art OCR components and continuous model training into a comprehensive workflow. While a variety of materials can already be processed fully automatically, books with more complex layouts require manual intervention by the users. This is mostly due to the fact that the required ground truth for training stronger mixed models (for segmentation, as well as text recognition) is not available, yet, neither in the desired quantity nor quality. To deal with this issue in the short run, OCR4all offers a comfortable GUI that allows error corrections not only in the final output, but already in early stages to minimize error propagations. In the long run, this constant manual correction produces large quantities of valuable, high quality training material, which can be used to improve fully automatic approaches. Further on, extensive configuration capabilities are provided to set the degree of automation of the workflow and to make adaptations to the carefully selected default parameters for specific printings, if necessary. During experiments, the fully automated application on 19th Century novels showed that OCR4all can considerably outperform the commercial state-of-the-art tool ABBYY Finereader on moderate layouts if suitably pretrained mixed OCR models are available. Furthermore, on very complex early printed books, even users with minimal or no experience were able to capture the text with manageable effort and great quality, achieving excellent Character Error Rates (CERs) below 0.5\%. The architecture of OCR4all allows the easy integration (or substitution) of newly developed tools for its main components by standardized interfaces like PageXML, thus aiming at continual higher automation for historical printings.}, language = {en} } @article{DjebkoPuppeKayal2019, author = {Djebko, Kirill and Puppe, Frank and Kayal, Hakan}, title = {Model-based fault detection and diagnosis for spacecraft with an application for the SONATE triple cube nano-satellite}, series = {Aerospace}, volume = {6}, journal = {Aerospace}, number = {10}, issn = {2226-4310}, doi = {10.3390/aerospace6100105}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-198836}, pages = {105}, year = {2019}, abstract = {The correct behavior of spacecraft components is the foundation of unhindered mission operation. However, no technical system is free of wear and degradation. A malfunction of one single component might significantly alter the behavior of the whole spacecraft and may even lead to a complete mission failure. Therefore, abnormal component behavior must be detected early in order to be able to perform counter measures. A dedicated fault detection system can be employed, as opposed to classical health monitoring, performed by human operators, to decrease the response time to a malfunction. In this paper, we present a generic model-based diagnosis system, which detects faults by analyzing the spacecraft's housekeeping data. The observed behavior of the spacecraft components, given by the housekeeping data is compared to their expected behavior, obtained through simulation. Each discrepancy between the observed and the expected behavior of a component generates a so-called symptom. Given the symptoms, the diagnoses are derived by computing sets of components whose malfunction might cause the observed discrepancies. We demonstrate the applicability of the diagnosis system by using modified housekeeping data of the qualification model of an actual spacecraft and outline the advantages and drawbacks of our approach.}, language = {en} } @article{DietrichKrebsLimanetal.2019, author = {Dietrich, Georg and Krebs, Jonathan and Liman, Leon and Fette, Georg and Ertl, Maximilian and Kaspar, Mathias and St{\"o}rk, Stefan and Puppe, Frank}, title = {Replicating medication trend studies using ad hoc information extraction in a clinical data warehouse}, series = {BMC Medical Informatics and Decision Making}, volume = {19}, journal = {BMC Medical Informatics and Decision Making}, doi = {10.1186/s12911-018-0729-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200409}, pages = {15}, year = {2019}, abstract = {Background Medication trend studies show the changes of medication over the years and may be replicated using a clinical Data Warehouse (CDW). Even nowadays, a lot of the patient information, like medication data, in the EHR is stored in the format of free text. As the conventional approach of information extraction (IE) demands a high developmental effort, we used ad hoc IE instead. This technique queries information and extracts it on the fly from texts contained in the CDW. Methods We present a generalizable approach of ad hoc IE for pharmacotherapy (medications and their daily dosage) presented in hospital discharge letters. We added import and query features to the CDW system, like error tolerant queries to deal with misspellings and proximity search for the extraction of the daily dosage. During the data integration process in the CDW, negated, historical and non-patient context data are filtered. For the replication studies, we used a drug list grouped by ATC (Anatomical Therapeutic Chemical Classification System) codes as input for queries to the CDW. Results We achieve an F1 score of 0.983 (precision 0.997, recall 0.970) for extracting medication from discharge letters and an F1 score of 0.974 (precision 0.977, recall 0.972) for extracting the dosage. We replicated three published medical trend studies for hypertension, atrial fibrillation and chronic kidney disease. Overall, 93\% of the main findings could be replicated, 68\% of sub-findings, and 75\% of all findings. One study could be completely replicated with all main and sub-findings. Conclusion A novel approach for ad hoc IE is presented. It is very suitable for basic medical texts like discharge letters and finding reports. Ad hoc IE is by definition more limited than conventional IE and does not claim to replace it, but it substantially exceeds the search capabilities of many CDWs and it is convenient to conduct replication studies fast and with high quality.}, language = {en} } @article{LodaKrebsDanhofetal.2019, author = {Loda, Sophia and Krebs, Jonathan and Danhof, Sophia and Schreder, Martin and Solimando, Antonio G. and Strifler, Susanne and Rasche, Leo and Kort{\"u}m, Martin and Kerscher, Alexander and Knop, Stefan and Puppe, Frank and Einsele, Hermann and Bittrich, Max}, title = {Exploration of artificial intelligence use with ARIES in multiple myeloma research}, series = {Journal of Clinical Medicine}, volume = {8}, journal = {Journal of Clinical Medicine}, number = {7}, issn = {2077-0383}, doi = {10.3390/jcm8070999}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197231}, pages = {999}, year = {2019}, abstract = {Background: Natural language processing (NLP) is a powerful tool supporting the generation of Real-World Evidence (RWE). There is no NLP system that enables the extensive querying of parameters specific to multiple myeloma (MM) out of unstructured medical reports. We therefore created a MM-specific ontology to accelerate the information extraction (IE) out of unstructured text. Methods: Our MM ontology consists of extensive MM-specific and hierarchically structured attributes and values. We implemented "A Rule-based Information Extraction System" (ARIES) that uses this ontology. We evaluated ARIES on 200 randomly selected medical reports of patients diagnosed with MM. Results: Our system achieved a high F1-Score of 0.92 on the evaluation dataset with a precision of 0.87 and recall of 0.98. Conclusions: Our rule-based IE system enables the comprehensive querying of medical reports. The IE accelerates the extraction of data and enables clinicians to faster generate RWE on hematological issues. RWE helps clinicians to make decisions in an evidence-based manner. Our tool easily accelerates the integration of research evidence into everyday clinical practice.}, language = {en} } @article{LopezArreguinMontenegro2019, author = {Lopez-Arreguin, A. J. R. and Montenegro, S.}, title = {Improving engineering models of terramechanics for planetary exploration}, series = {Results in Engineering}, volume = {3}, journal = {Results in Engineering}, doi = {10.1016/j.rineng.2019.100027}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202490}, pages = {100027}, year = {2019}, abstract = {This short letter proposes more consolidated explicit solutions for the forces and torques acting on typical rover wheels, that can be used as a method to determine their average mobility characteristics in planetary soils. The closed loop solutions stand in one of the verified methods, but at difference of the previous, observables are decoupled requiring a less amount of physical parameters to measure. As a result, we show that with knowledge of terrain properties, wheel driving performance rely in a single observable only. Because of their generality, the formulated equations established here can have further implications in autonomy and control of rovers or planetary soil characterization.}, language = {en} } @article{GomesWestermannSauerweinetal.2019, author = {Gomes, Sara F. Martins and Westermann, Alexander J. and Sauerwein, Till and Hertlein, Tobias and F{\"o}rstner, Konrad U. and Ohlsen, Knut and Metzger, Marco and Shusta, Eric V. and Kim, Brandon J. and Appelt-Menzel, Antje and Schubert-Unkmeir, Alexandra}, title = {Induced pluripotent stem cell-derived brain endothelial cells as a cellular model to study Neisseria meningitidis infection}, series = {Frontiers in Microbiology}, volume = {10}, journal = {Frontiers in Microbiology}, number = {1181}, doi = {10.3389/fmicb.2019.01181}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201562}, year = {2019}, abstract = {Meningococcal meningitis is a severe central nervous system infection that occurs when Neisseria meningitidis (Nm) penetrates brain endothelial cells (BECs) of the meningeal blood-cerebrospinal fluid barrier. As a human-specific pathogen, in vivo models are greatly limited and pose a significant challenge. In vitro cell models have been developed, however, most lack critical BEC phenotypes limiting their usefulness. Human BECs generated from induced pluripotent stem cells (iPSCs) retain BEC properties and offer the prospect of modeling the human-specific Nm interaction with BECs. Here, we exploit iPSC-BECs as a novel cellular model to study Nm host-pathogen interactions, and provide an overview of host responses to Nm infection. Using iPSC-BECs, we first confirmed that multiple Nm strains and mutants follow similar phenotypes to previously described models. The recruitment of the recently published pilus adhesin receptor CD147 underneath meningococcal microcolonies could be verified in iPSC-BECs. Nm was also observed to significantly increase the expression of pro-inflammatory and neutrophil-specific chemokines IL6, CXCL1, CXCL2, CXCL8, and CCL20, and the secretion of IFN-γ and RANTES. For the first time, we directly observe that Nm disrupts the three tight junction proteins ZO-1, Occludin, and Claudin-5, which become frayed and/or discontinuous in BECs upon Nm challenge. In accordance with tight junction loss, a sharp loss in trans-endothelial electrical resistance, and an increase in sodium fluorescein permeability and in bacterial transmigration, was observed. Finally, we established RNA-Seq of sorted, infected iPSC-BECs, providing expression data of Nm-responsive host genes. Altogether, this model provides novel insights into Nm pathogenesis, including an impact of Nm on barrier properties and tight junction complexes, and suggests that the paracellular route may contribute to Nm traversal of BECs.}, language = {en} }