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  • Article
    Open Access
    Lymph node and pulmonary tuberculosis during upadacitinib treatment in a psoriatic arthritis patient
    (2023-07-04) Valor-Méndez, Larissa; Manger, Bernhard; Wacker, Jochen; Kleyer, Arnd; Schett, Georg
  • Article
    Open Access
    Clinical Images: Tissue remodeling in autoimmune statin-induced necrotizing autoimmune myopathy
    (2023-07-04) Valor-Méndez, Larissa; Manger, Bernhard; Knitza, Johannes; Schmidkonz, Christian; Kleyer, Arnd; Schett, Georg
  • Article
    Open Access
    A Review on Antecedents and Consequences of Leisure Reading and Writing in Children
    (2023-07-04) Birnbaum, Lisa; Kröner, Stephan
    It is desirable that children engage in reading and writing beyond school. What is known about various individual and environmental variables that may be related to children’s leisure reading and writing? And how strong is existing evidence? Our scoping review aims at mapping research on leisure reading and writing in first- to fourth-graders. Using content analysis, we extracted 135 research findings, among them only 6 on leisure writing. In most findings, leisure reading and writing were considered as consequences of variables like reading competence, motivation, and attitudes. Considerably fewer findings included leisure reading and writing as antecedents. We discuss the need for more longitudinal and experimental studies and a stronger focus on the connection between leisure reading and writing.
  • Article
    Open Access
    Dissolved oxygen isotope modelling refines metabolic state estimates of stream ecosystems with different land use background
    (Springer Nature, 2023-07-04) Piatka, David R.; Venkiteswaran, Jason J.; Uniyal, Bhumika; Kaule, Robin; Gilfedder, Benjamin; Barth, Johannes A. C.
    Dissolved oxygen (DO) is crucial for aerobic life in streams and rivers and mostly depends on photosynthesis (P), ecosystem respiration (R) and atmospheric gas exchange (G). However, climate and land use changes progressively disrupt metabolic balances in natural streams as sensitive reflectors of their catchments. Comprehensive methods for mapping fundamental ecosystem services become increasingly important in a rapidly changing environment. In this work we tested DO and its stable isotope (18O/16O) ratios as novel tools for the status of stream ecosystems. For this purpose, six diel sampling campaigns were performed at three low-order and mid-latitude European streams with different land use patterns. Modelling of diel DO and its stable isotopes combined with land use analyses showed lowest P rates at forested sites, with a minimum of 17.9 mg m−2 h−1. Due to high R rates between 230 and 341 mg m−2 h−1 five out of six study sites showed a general heterotrophic state with P:R:G ratios between 0.1:1.1:1 and 1:1.9:1. Only one site with agricultural and urban influences showed a high P rate of 417 mg m−2 h−1 with a P:R:G ratio of 1.9:1.5:1. Between all sites gross G rates varied between 148 and 298 mg m−2 h−1. In general, metabolic rates depend on the distance of sampling locations to river sources, light availability, nutrient concentrations and possible exchanges with groundwater. The presented modelling approach introduces a new and powerful tool to study effects of land use on stream health. Such approaches should be integrated into future ecological monitoring.
  • Article
    Open Access
    Inter-species cell detection - datasets on pulmonary hemosiderophages in equine, human and feline specimens
    (Springer Nature, 2023-07-04) Marzahl, Christian; Hill, Jenny; Stayt, Jason; Bienzle, Dorothee; Welker, Lutz; Wilm, Frauke; Voigt, Jörn; Aubreville, Marc; Maier, Andreas; Klopfleisch, Robert; Breininger, Katharina; Bertram, Christof A.
    Pulmonary hemorrhage (P-Hem) occurs among multiple species and can have various causes. Cytology of bronchoalveolar lavage fluid (BALF) using a 5-tier scoring system of alveolar macrophages based on their hemosiderin content is considered the most sensitive diagnostic method. We introduce a novel, fully annotated multi-species P-Hem dataset, which consists of 74 cytology whole slide images (WSIs) with equine, feline and human samples. To create this high-quality and high-quantity dataset, we developed an annotation pipeline combining human expertise with deep learning and data visualisation techniques. We applied a deep learning-based object detection approach trained on 17 expertly annotated equine WSIs, to the remaining 39 equine, 12 human and 7 feline WSIs. The resulting annotations were semi-automatically screened for errors on multiple types of specialised annotation maps and finally reviewed by a trained pathologist. Our dataset contains a total of 297,383 hemosiderophages classified into five grades. It is one of the largest publicly available WSIs datasets with respect to the number of annotations, the scanned area and the number of species covered.
  • Article
    Open Access
    Seeing structural evolution of organic molecular nano-crystallites using 4D scanning confocal electron diffraction (4D-SCED)
    (2023-07-04) Wu, Mingjian; Harreiß, Christina; Ophus, Colin; Johnson, Manuel; Fink, Rainer H.; Spiecker, Erdmann
    Direct observation of organic molecular nanocrystals and their evolution using electron microscopy is extremely challenging, due to their radiation sensitivity and complex structure. Here, we introduce 4D-scanning confocal electron diffraction (4D-SCED), which enables direct in situ observation of bulk heterojunction (BHJ) thin films. 4D-SCED combines confocal electron optic setup with a pixelated detector to record focused spot-like diffraction patterns with high angular resolution, using an order of magnitude lower dose than previous methods. We apply it to study an active layer in organic solar cells, namely DRCN5T:PC71BM BHJ thin films. Structural details of DRCN5T nano-crystallites oriented both in- and out-of-plane are imaged at ~5 nm resolution and dose budget of ~5 e−/Å2. We use in situ annealing to observe the growth of the donor crystals, evolution of the crystal orientation, and progressive enrichment of PC71BM at interfaces. This highly dose-efficient method opens more possibilities for studying beam sensitive soft materials.
  • Article
    Open Access
    Teaming up main group metals with metallic iron to boost hydrogenation catalysis
    (2023-07-04) Färber, Christian; Stegner, Philipp; Zenneck, Ulrich; Knüpfer, Christian; Bendt, Georg; Schulz, Stephan; Harder, Sjoerd
    Hydrogenation of unsaturated bonds is a key step in both the fine and petrochemical industries. Homogeneous and heterogeneous catalysts are historically based on noble group 9 and 10 metals. Increasing awareness of sustainability drives the replacement of costly, and often harmful, precious metals by abundant 3d-metals or even main group metals. Although not as efficient as noble transition metals, metallic barium was recently found to be a versatile hydrogenation catalyst. Here we show that addition of finely divided Fe0, which itself is a poor hydrogenation catalyst, boosts activities of Ba0 by several orders of magnitude, enabling rapid hydrogenation of alkynes, imines, challenging multi-substituted alkenes and non-activated arenes. Metallic Fe0 also boosts the activity of soluble early main group metal hydride catalysts, or precursors thereto. This synergy originates from cooperativity between a homogeneous, highly reactive, polar main group metal hydride complex and a heterogeneous Fe0 surface that is responsible for substrate activation.
  • Article
    Open Access
    Smartphone-Based Colorimetric Analysis of Urine Test Strips for At-Home Prenatal Care
    (2023-07-04) Flaucher, Madeleine; Nissen, Michael; Jaeger, Katharina M.; Titzmann, Adriana; Pontones, Constanza; Huebner, Hanna; Fasching, Peter A.; Beckmann, Matthias W.; Gradl, Stefan; Eskofier, Bjoern M.
    Objective: Clinical urine tests are a key component of prenatal care. As of now, urine test strips are evaluated through a time consuming, often error-prone and operator-dependent visual color comparison of test strips and reference cards by medical staff. Methods and procedures: This work presents an automated pipeline for urinalysis with urine test strips using smartphone camera images in home environments, combining several image processing and color combination techniques. Our approach is applicable to off-the-shelf test strips in home conditions with no additional hardware required. For development and evaluation of our pipeline we collected image data from two sources: i) A user study (26 participants, 150 images) and ii) a lab study (135 images). Results: We trained a region-based convolutional neural network that is able to detect the urine test strip location and orientation in images with a wide variety of light conditions, backgrounds and perspectives with an accuracy of 85.5%. The reference card can be robustly detected through a feature matching approach in 98.6% of the images. Color comparison by Hue channel (0.81 F1-Score), Matching factor (0.80 F1-Score) and Euclidean distance (0.70 F1-Score) were evaluated to determine the urinalysis results. Conclusion: We show that an automated smartphone-based colorimetric analysis of urine test strips in a home environment is feasible. It facilitates examinations and provides the possibility to shift care into an at-home environment. Clinical impact: The findings demonstrate that routine urine examinations can be transferred into the home environment using a smartphone. Simultaneously, human error is avoided, accuracy is increased and medical staff is relieved.
  • Article
    Open Access
    Neural network based successor representations to form cognitive maps of space and language
    (Springer Nature, 2023-07-04) Stoewer, Paul; Schlieker, Christian; Schilling, Achim; Metzner, Claus; Maier, Andreas; Krauss, Patrick
    How does the mind organize thoughts? The hippocampal-entorhinal complex is thought to support domain-general representation and processing of structural knowledge of arbitrary state, feature and concept spaces. In particular, it enables the formation of cognitive maps, and navigation on these maps, thereby broadly contributing to cognition. It has been proposed that the concept of multi-scale successor representations provides an explanation of the underlying computations performed by place and grid cells. Here, we present a neural network based approach to learn such representations, and its application to different scenarios: a spatial exploration task based on supervised learning, a spatial navigation task based on reinforcement learning, and a non-spatial task where linguistic constructions have to be inferred by observing sample sentences. In all scenarios, the neural network correctly learns and approximates the underlying structure by building successor representations. Furthermore, the resulting neural firing patterns are strikingly similar to experimentally observed place and grid cell firing patterns. We conclude that cognitive maps and neural network-based successor representations of structured knowledge provide a promising way to overcome some of the short comings of deep learning towards artificial general intelligence.
  • Article
    Open Access
    Extramedullary plasmacytoma: Tumor occurrence and therapeutic concepts—A follow-up
    (2023-07-04) Holler, Adrian; Cicha, Iwona; Eckstein, Markus; Haderlein, Marlen; Pöttler, Marina; Rappl, Anja; Iro, Heinrich; Alexiou, Christoph
    Background Extramedullary plasmacytoma (EMP) is a solitary tumor consisting of neoplastic plasma cells, with very little to no bone marrow involvement. EMPs are usually located in the head and neck region, but can also occur along the digestive tract, in lungs, or extremities. Methods Following our publication on EMP, which appeared in 1999 (Cancer 85:2305–14), we conducted a literature search for EMP-related reports published between 1999 and 2021. The documented cases, as well as 14 of our own patients from the ENT Clinic Erlangen, were extensively analyzed. Results Between 1998 and 2021, 1134 patients with EMP were reported, for whom information about the tumor localization was available. Among those, 62.4% had EMP in the head and neck area and 37.6% in other body regions. Data on therapy were reported in 897 patients, including 34.3% who received radiation, 28.1% surgery, 22.6% a combination of surgery and radiation, and 15.9% another therapy. In 76.9% patients no recurrence or transformation to multiple myeloma (MM) was reported, 12.8% showed local recurrence and 10.2% developed MM. Radiotherapy alone was associated with a tendency for increased occurrence of MM. In patients with EMP of head and neck area, combination therapy (surgery and radiation) resulted in a 5-year overall survival rate of 98.3%, surgery alone of 92.4%, and radiotherapy of 92.7%. Conclusions Collectively, our analyses indicate that surgical resection alone can achieve long-term tumor control in patients with EMP, if the tumor can be removed within safe limits without causing serious functional impairment. However, if this is not certain, either radiation or a combination of surgery and radiation therapy is suggested as an effective means of local tumor control.
  • Article
    Open Access
    Chromatic discrimination measures in mature observers depend on the response window
    (2023-07-04) Fars, Julien; Fernandes, Thiago P.; Huchzermeyer, Cord; Kremers, Jan; Paramei, Galina V.
    Our past anecdotal evidence prompted that a longer response window (RW) in the Trivector test (Cambridge Colour Test) improved mature observers’ estimates of chromatic discrimination. Here, we systematically explored whether RW variation affects chromatic discrimination thresholds measured by the length of Protan, Deutan and Tritan vectors. We employed the Trivector test with three RWs: 3 s, 5 s, and 8 s. Data of 30 healthy normal trichromats were stratified as age groups: ‘young’ (20–29 years), ‘middle-aged’ (31–48 years), and ‘mature’ (57–64 years). We found that for the ‘young’ and ‘middle-aged’, the thresholds were comparable at all tested RWs. However, the RW effect was apparent for the ‘mature’ observers: their Protan and Tritan thresholds decreased at 8-s RW compared to 3-s RW; moreover, their Tritan threshold decreased at 5-s RW compared to 3-s RW. Elevated discrimination thresholds at shorter RWs imply that for accurate performance, older observers require longer stimulus exposure and are indicative of ageing effects manifested by an increase in critical processing duration. Acknowledging low numbers in our ‘middle-aged’ and ‘mature’ samples, we consider our study as pilot. Nonetheless, our findings encourage us to advocate a RW extension in the Trivector protocol for testing mature observers, to ensure veridical measures of their chromatic discrimination by disentangling these from other ageing effects—slowing down of both motor responses and visual processing.
  • Article
    Open Access
    Endometriosis in women undergoing ovarian tissue transplantation due to premature menopause after gonadotoxic treatment or spontaneous premature ovarian failure
    (2023-07-04) Lotz, Laura; Dietl, Anna; Hoffmann, Inge; Müller, Anrdreas; Burghaus, Stefanie; Beckmann, Matthias Wilhelm; Dittrich, Ralf
    Introduction Cryopreservation of ovarian tissue with subsequent transplantation is an efficient option for restoring fertility in women at risk of premature ovarian failure. The association between infertility and endometriosis is well recognized. Although endometriosis usually ends with the onset of natural or iatrogen menopause due to declining estrogen levels, endometriosis can in rare cases occur after menopause. This study aims to investigate women with premature menopause who were diagnosed with endometriosis during laparoscopy for ovarian tissue transplantation, and to address the questions of how endometriotic lesions after cytotoxic treatment and premature menopause might be explained, whether endometriosis affects pregnancy rates, and whether there is an association between endometriosis and the original cancer. Material and Methods Seventeen patients who had undergone ovarian tissue transplantation to restore their fertility and who were diagnosed with endometriosis during transplantation were included in this retrospective study. The endometriosis foci were completely removed and ovarian tissue was transplanted into the pelvic peritoneum. Preexisting conditions, use of hormonal preparations, endometriosis stage pain assessment, as well as pregnancy and live birth rate were evaluated. Results The mean age of the patients was 29.5 ± 6.3 years (range 14–39) at the time of ovarian tissue harvest and 34.6 ± 4.3 years (range 28–40) at transplantation. Prior to transplantation, four patients had taken hormone replacement therapy, four women oral contraceptives and two patients’ tamoxifen. Twelve women had stage I endometriosis and five stage II endometrioses according to the rASRM classification. Four patients reported dysmenorrhea. None of the women complained of general pelvic pain or dyspareunia. The pregnancy rate in the study population was 41.2%, with a live birth rate of 35.3%. The pregnancies occurred in three cases after spontaneous conception, in four women after a natural cycle IVF/ICSI. Conclusions This study highlights the under-researched association between endometriosis in women entering premature or early menopause either after gonadotoxic treatment or due to primary ovarian insufficiency. As more and more patients seek to have their cryopreserved ovarian tissue transplanted to fulfill their desire to have children, specialists will inevitably encounter women with this condition.
  • Article
    Open Access
    3D printed gelatin/decellularized bone composite scaffolds for bone tissue engineering: Fabrication, characterization and cytocompatibility study
    (2023-07-04) Kara, Aylin; Distler, Thomas; Polley, Christian; Schneidereit, Dominik; Seitz, Hermann; Friedrich, Oliver; Tihminlioglu, Funda; Boccaccini, Aldo R.
    Three-dimensional (3D) printing technology enables the design of personalized scaffolds with tunable pore size and composition. Combining decellularization and 3D printing techniques provides the opportunity to fabricate scaffolds with high potential to mimic native tissue. The aim of this study is to produce novel decellularized bone extracellular matrix (dbECM)-reinforced composite-scaffold that can be used as a biomaterial for bone tissue engineering. Decellularized bone particles (dbPTs, ∼100 ​μm diameter) were obtained from rabbit femur and used as a reinforcement agent by mixing with gelatin (GEL) in different concentrations. 3D scaffolds were fabricated by using an extrusion-based bioprinter and crosslinking with microbial transglutaminase (mTG) enzyme, followed by freeze-drying to obtain porous structures. Fabricated 3D scaffolds were characterized morphologically, mechanically, and chemically. Furthermore, MC3T3-E1 mouse pre-osteoblast cells were seeded on the dbPTs reinforced GEL scaffolds (GEL/dbPTs) and cultured for 21 days to assess cytocompatibility and cell attachment. We demonstrate the 3D-printability of dbPTs-reinforced GEL hydrogels and the achievement of homogenous distribution of the dbPTs in the whole scaffold structure, as well as bioactivity and cytocompatibility of GEL/dbPTs scaffolds. It was shown that Young's modulus and degradation rate of scaffolds were enhanced with increasing dbPTs content. Multiphoton microscopy imaging displayed the interaction of cells with dbPTs, indicating attachment and proliferation of cells around the particles as well as into the GEL-particle hydrogels. Our results demonstrate that GEL/dbPTs hydrogel formulations have potential for bone tissue engineering.
  • Article
    Open Access
    Self-assembled monolayers enhance the efficiency of Pt single atom co-catalysts in photocatalytic H2 generation
    (2023-07-04) Wang, Yue; Hwang, Imgon; Wu, Zhenni; Schmuki, Patrik
    Single atom (SA) catalysis, over the last 10 years, has become a forefront in heterogeneous catalysis, electrocatalysis, and most recently also in photocatalysis. Pt SAs on titania have been reported to be a highly effective co-catalyst in photocatalytic H2 generation. Most recently, for the synthesis of SA loading on titania surfaces, some simple immersion techniques have been described. Here we introduce a so far unexplored but evidently very effective approach to enhance the effectivity of Pt SA co-catalysts on anodic TiO2 layers. For this, we first decorate TiO2 surfaces with a partial coverage of headgroups of silane self-assembled monolayers (SAMs) and then deposit Pt SAs on this SAM modified surface. We observe a significantly enhanced photocatalytic activity for H2 generation using this sensitization of the surface with a modified SAM.
  • Article
    Open Access
    High-resolution label-free mapping of murine kidney vasculature by raster-scanning optoacoustic mesoscopy: an ex vivo study
    (Springer, 2023-07-04) Goebel, Colin A.; Brown, Emma; Fahlbusch, Fabian B.; Wagner, Alexandra L.; Buehler, Adrian; Raupach, Thomas; Hohmann, Martin; Späth, Moritz; Burton, Neal; Woelfle, Joachim; Schmidt, Michael; Hartner, Andrea; Regensburger, Adrian P.; Knieling, Ferdinand
    Background Chronic kidney disease (CKD) is a global burden affecting both children and adults. Novel imaging modalities hold great promise to visualize and quantify structural, functional, and molecular organ damage. The aim of the study was to visualize and quantify murine renal vasculature using label-free raster scanning optoacoustic mesoscopy (RSOM) in explanted organs from mice with renal injury. Material and methods For the experiments, freshly bisected kidneys of alpha 8 integrin knock-out (KO) and wildtype mice (WT) were used. A total of n=7 female (n=4 KO, n=3 WT) and n=6 male animals (n=2 KO, n=4 WT) aged 6 weeks were examined with RSOM optoacoustic imaging systems (RSOM Explorer P50 at SWL 532nm and/or ms-P50 imaging system at 532 nm, 555 nm, 579 nm, and 606 nm). Images were reconstructed using a dedicated software, analyzed for size and vascular area and compared to standard histologic sections. Results RSOM enabled mapping of murine kidney size and vascular area, revealing differences between kidney sizes of male (m) and female (f) mice (merged frequencies (MF) f vs. m: 52.42±6.24 mm2 vs. 69.18±15.96 mm2, p=0.0156) and absolute vascular area (MF f vs. m: 35.67±4.22 mm2 vs. 49.07±13.48 mm2, p=0.0036). Without respect to sex, the absolute kidney area was found to be smaller in knock-out (KO) than in wildtype (WT) mice (WT vs. KO: MF: p=0.0255) and showed a similar trend for the relative vessel area (WT vs. KO: MF p=0.0031). Also the absolute vessel areas of KO compared to WT were found significantly different (MF p=0.0089). A significant decrease in absolute vessel area was found in KO compared to WT male mice (MF WT vs. KO: 54.37±9.35 mm2 vs. 34.93±13.82 mm2, p=0.0232). In addition, multispectral RSOM allowed visualization of oxygenated and deoxygenated parenchymal regions by spectral unmixing. Conclusion This study demonstrates the capability of RSOM for label-free visualization of differences in vascular morphology in ex vivo murine renal tissue at high resolution. Due to its scalability optoacoustic imaging provides an emerging modality with potential for further preclinical and clinical imaging applications.
  • Article
    Open Access
    QAMaster: A new software framework for phantom-based computed tomography quality assurance
    (2023-07-03) Karius, Andre; Bert, Christoph
    The regular evaluation of imaging performance of computed tomography (CT) scanners is essential for CT quality assurance. For automation of this process, the software QAMaster was developed at the Universitätsklinikum Erlangen, which provides based on CT scans of the CatPhan® 504 (The Phantom Laboratory, Salem, USA) automated image quality analysis and documentation by evaluating CT number accuracy, spatial linearity, uniformity, contrast-noise-ratio, spatial resolution, noise, and slice thickness. Dose assessment is supported by calculations of the weighted computed tomography dose index (CTDIw) and weighted cone beam dose index (CBDIw). QAMaster was tested with CatPhan® 504 scans and compared to manual evaluations of these scans, whereby high consistency of the respective results was observed. The CT numbers, spatial linearity, uniformity, contrast-noise-ratio, noise, and slice thickness deviated by only (0.13 ± 0.25) HU, (0.02 ± 0.05) mm, (−0.01 ± 0.03)%, 0.8 ± 1.8, (0.131 ± 0.05) HU, and (0.004 ± 0.005) mm between both evaluations, respectively. The QAMaster results for spatial resolution did not differ significantly (p = 0.34) from the CatPhan® 504 based manual resolution assessment. Dose computations were fully consistent between QAMaster and manual calculations. Thus, QAMaster proved to be a comprehensive and functional software for performing an automated CT quality assurance routine. QAMaster will be open-source after its release.
  • Article
    Open Access
    Detailed in vitro analyses of the impact of multimodal cancer therapy with hyperthermia and radiotherapy on the immune phenotype of human glioblastoma cells
    (Taylor & Francis, 2023-07-03) Stoll, Eileen; Hader, Michael; Rückert, Michael; Weissmann, Thomas; Lettmaier, Sebastian; Putz, Florian; Hecht, Markus; Fietkau, Rainer; Rosin, Andreas; Frey, Benjamin; Gaipl, Udo
    Purpose Improvements of heat-delivery systems have led to hyperthermia (HT) being increasingly recognized as an adjunct treatment modality also for brain tumors. But how HT affects the immune phenotype of glioblastoma cells is only scarcely known. Materials and Methods We therefore investigated the effect of in vitro HT, radiotherapy (RT), and the combination of both (RHT) on cell death modalities, immune checkpoint molecule (ICM) expression and release of the danger signal HSP70 of two human glioblastoma cell lines (U87 and U251) by using multicolor flow cytometry and ELISA. Hyperthermia was performed once or twice for 60-minute sessions reaching temperatures of 39 °C, 41 °C, and 44 °C, respectively. RT was administered with 5 x 2 Gy. Results A hyperthermia chamber for cell culture t-flasks regulating the temperature via a contact sensor was developed. While the glioblastoma cells were rather radioresistant, particularly in U251 cells, the combination of RT with HT significantly increased the percentage of apoptotic and necrotic cells for all temperatures examined and for both, single and double HT application. In line with that, an increased release of HSP 70 was seen only in U251 cells, mainly following treatment with HT at temperatures of 44 °C alone or in combination with RT. In contrast, immune suppressive (PD-L1, PD-L2, HVEM) and immune stimulatory (ICOS-L, CD137-L and Ox40-L) ICMs were significantly increased mostly on U87 cells, and particularly after RHT with 41 °C. Conclusions Individual assessment of the glioblastoma immune cell phenotype with regard to the planned treatment is mandatory to optimize multimodal radio-immunotherapy protocols including HT.
  • Article
    Open Access
    Dynamic changes in O-GlcNAcylation regulate osteoclast differentiation and bone loss via nucleoporin 153
    (Springer Nature, 2023-07-03) Li, Yi-Nan; Chen, Chih-Wei; Trinh-Minh, Thuong; Zhu, Honglin; Matei, Alexandru-Emil; Györfi, Andrea-Hermina; Kuwert, Frederic; Hubel, Philipp; Ding, Xiao; Manh, Cuong Tran; Xu, Xiaohan; Liebel, Christoph; Fedorchenko, Vladyslav; Liang, Ruifang; Huang, Kaiyue; Pfannstiel, Jens; Huang, Min-Chuan; Lin, Neng-Yu; Ramming, Andreas; Schett, Georg; Distler, Jörg H. W.
    Bone mass is maintained by the balance between osteoclast-induced bone resorption and osteoblast-triggered bone formation. In inflammatory arthritis such as rheumatoid arthritis (RA), however, increased osteoclast differentiation and activity skew this balance resulting in progressive bone loss. O-GlcNAcylation is a posttranslational modification with attachment of a single O-linked β-D-N-acetylglucosamine (O-GlcNAc) residue to serine or threonine residues of target proteins. Although O-GlcNAcylation is one of the most common protein modifications, its role in bone homeostasis has not been systematically investigated. We demonstrate that dynamic changes in O-GlcNAcylation are required for osteoclastogenesis. Increased O-GlcNAcylation promotes osteoclast differentiation during the early stages, whereas its downregulation is required for osteoclast maturation. At the molecular level, O-GlcNAcylation affects several pathways including oxidative phosphorylation and cell-cell fusion. TNFα fosters the dynamic regulation of O-GlcNAcylation to promote osteoclastogenesis in inflammatory arthritis. Targeted pharmaceutical or genetic inhibition of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) arrests osteoclast differentiation during early stages of differentiation and during later maturation, respectively, and ameliorates bone loss in experimental arthritis. Knockdown of NUP153, an O-GlcNAcylation target, has similar effects as OGT inhibition and inhibits osteoclastogenesis. These findings highlight an important role of O-GlcNAcylation in osteoclastogenesis and may offer the potential to therapeutically interfere with pathologic bone resorption.
  • Article
    Open Access
    The metabolic profile of reconstituting T-cells, NK-cells, and monocytes following autologous stem cell transplantation and its impact on outcome
    (Springer Nature, 2023-07-03) Richter, Silja; Böttcher, Martin; Völkl, Simon; Mackensen, Andreas; Ullrich, Evelyn; Jacobs, Benedikt; Mougiakakos, Dimitrios
    Previous studies indicated a role of the reconstituting immune system for disease outcome upon high-dose chemotherapy (HDCT) and autologous stem cell transplantation (auto-SCT) in multiple myeloma (MM) and lymphoma patients. Since immune cell metabolism and function are closely interconnected, we used flow-cytometry techniques to analyze key components and functions of the metabolic machinery in reconstituting immune cells upon HDCT/auto-SCT. We observed increased proliferative activity and an upregulation of the glycolytic and fatty acid oxidation (FAO) machinery in immune cells during engraftment. Metabolic activation was more pronounced in T-cells of advanced differentiation stages, in CD56bright NK-cells, and CD14++CD16+ intermediate monocytes. Next, we investigated a potential correlation between the immune cells’ metabolic profile and early progression or relapse in lymphoma patients within the first twelve months following auto-SCT. Here, persistently increased metabolic parameters correlated with a rather poor disease course. Taken together, reconstituting immune cells display an upregulated bioenergetic machinery following auto-SCT. Interestingly, a persistently enhanced metabolic immune cell phenotype correlated with reduced PFS. However, it remains to be elucidated, if the clinical data can be confirmed within a larger set of patients and if residual malignant cells not detected by conventional means possibly caused the metabolic activation.
  • Article
    Open Access
    Specific features of ex-obese patients significantly influence the functional cell properties of adipose-derived stromal cells
    (Wiley, 2023-07-03) Schmitz, Deborah; Robering, Jan W.; Weisbach, Volker; Arkudas, Andreas; Ludolph, Ingo; Horch, Raymund E.; Boos, Anja M.; Kengelbach-Weigand, Annika
    Adipose-derived stromal cells (ADSC) are increasingly used in clinical applications due to their regenerative capabilities. However, ADSC therapies show variable results. This study analysed the effects of specific factors of ex-obese patients on ADSC functions. ADSC were harvested from abdominal tissues (N = 20) after massive weight loss. Patients were grouped according to age, sex, current and maximum body mass index (BMI), BMI difference, weight loss method, smoking and infection at the surgical site. ADSC surface markers, viability, migration, transmigration, sprouting, differentiation potential, cytokine secretion, telomere length and mtDNA copy number were analysed. All ADSC expressed CD73, CD90, CD105, while functional properties differed significantly among patients. A high BMI difference due to massive weight loss was negatively correlated with ADSC proliferation, migration and transmigration, while age, sex or weight loss method had a smaller effect. ADSC from female and younger donors and individuals after weight loss by increase of exercise and diet change had a higher activity. Telomere length, mtDNA copy number, differentiation potential and the secretome did not correlate with patient factors or cell function. Therefore, we suggest that factors such as age, sex, increase of exercise and especially weight loss should be considered for patient selection and planning of regenerative therapies.