TY - JOUR A1 - Ohlebusch, Barbara A1 - Borst, Angela A1 - Frankenbach, Tina A1 - Klopocki, Eva A1 - Jakob, Franz A1 - Liedtke, Daniel A1 - Graser, Stephanie T1 - Investigation of alpl expression and Tnap-activity in zebrafish implies conserved functions during skeletal and neuronal development JF - Scientific Reports N2 - Hypophosphatasia (HPP) is a rare genetic disease with diverse symptoms and a heterogeneous severity of onset with underlying mutations in the ALPL gene encoding the ectoenzyme Tissue-nonspecific alkaline phosphatase (TNAP). Considering the establishment of zebrafish (Danio rerio) as a new model organism for HPP, the aim of the study was the spatial and temporal analysis of alpl expression in embryos and adult brains. Additionally, we determined functional consequences of Tnap inhibition on neural and skeletal development in zebrafish. We show that expression of alpl is present during embryonic stages and in adult neuronal tissues. Analyses of enzyme function reveal zones of pronounced Tnap-activity within the telencephalon and the mesencephalon. Treatment of zebrafish embryos with chemical Tnap inhibitors followed by axonal and cartilage/mineralized tissue staining imply functional consequences of Tnap deficiency on neuronal and skeletal development. Based on the results from neuronal and skeletal tissue analyses, which demonstrate an evolutionary conserved role of this enzyme, we consider zebrafish as a promising species for modeling HPP in order to discover new potential therapy strategies in the long-term. KW - nonspecific alkaline-phosphae KW - in situ hybridization KW - hypophosphatasia KW - promotes KW - model KW - neurotransmission KW - differentiation KW - mineraliztion KW - metabolism KW - vertebrate Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230024 VL - 10 ER - TY - JOUR A1 - Petritsch, Bernhard A1 - Pannbecker, Pauline A1 - Weng, Andreas M. A1 - Grunz, Jan-Peter A1 - Veldhoen, Simon A1 - Bley, Thorsten A. A1 - Kosmala, Aleksander T1 - Split-filter dual-energy CT pulmonary angiography for the diagnosis of acute pulmonary embolism: a study on image quality and radiation dose JF - Quantitative Imaging in Medicine and Surgery N2 - Background: Computed tomography (CT) pulmonary angiography is the diagnostic reference standard in suspected pulmonary embolism (PE). Favorable results for dual-energy CT (DECT) images have been reported for this condition. Nowadays, dual-energy data acquisition is feasible with different technical options, including a single-source split-filter approach. Therefore, the aim of this retrospective study was to investigate image quality and radiation dose of thoracic split-filter DECT in comparison to conventional single-energy CT in patients with suspected PE. Methods: A total of 110 CT pulmonary angiographies were accomplished either as standard single-energy CT with automatic tube voltage selection (ATVS) (n=58), or as split-filter DECT (n=52). Objective [pulmonary artery CT attenuation, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR)] and subjective image quality [four-point Likert scale; three readers (R)] were compared among the two study groups. Size-specific dose estimates (SSDE), dose-length-product (DLP) and volume CT dose index (CTDIvol) were assessed for radiation dose analysis. Results: Split-filter DECT images yielded 67.7% higher SNR (27.0 vs. 16.1; P<0.001) and 61.9% higher CNR (22.5 vs. 13.9; P<0.001) over conventional single-energy images, whereas CT attenuation was significantly lower (344.5 vs. 428.2 HU; P=0.013). Subjective image quality was rated good or excellent in 93.0%/98.3%/77.6% (R1/R2/R3) of the single-energy CT scans, and 84.6%/82.7%/80.8% (R1/R2/R3) of the split-filter DECT scans. SSDE, DLP and CTDIvol were significantly lower for conventional single-energy CT compared to split-filter DECT (all P<0.05), which was associated with 26.7% higher SSDE. Conclusions: In the diagnostic workup of acute PE, the split-filter allows for dual-energy data acquisition from single-source single-layer CT scanners. The existing opportunity to assess pulmonary “perfusion” based on analysis of iodine distribution maps is associated with higher radiation dose in terms of increased SSDE than conventional single-energy CT with ATVS. Moreover, a proportion of up to 3.8% non-diagnostic examinations in the current reference standard test for PE is not negligible. KW - dual-energy KW - CT-angiography KW - vascular KW - pulmonary arteries KW - embolism/thrombosis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231456 VL - 11 IS - 5 ER - TY - JOUR A1 - Froehlich, Matthias A1 - Schwaneck, Eva C. A1 - Gernert, Michael A1 - Gadeholt, Ottar A1 - Strunz, Patrick-Pascal A1 - Morbach, Henner A1 - Tony, Hans-Peter A1 - Schmalzing, Marc T1 - Autologous Stem Cell Transplantation in Common Variable Immunodeficiency: A Case of Successful Treatment of Severe Refractory Autoimmune Encephalitis JF - Frontiers in Immunology N2 - Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. It is associated with hypogammaglobulinemia, recurring infections and autoimmune phenomena. Treatment includes immunoglobulin substitution and immunosuppressants. Autoimmune neurological manifestations of CVID are rare and occur predominantly as granulomatous disease. We report the case of a 35-year-old woman with CVID who developed autoimmune encephalitis as demonstrated by double cerebral biopsy. Infectious or malignant causes could be excluded. Despite intensive immunosuppressive therapy with common regimens no significant improvement could be achieved. Ultimately, an autologous hematopoietic stem cell transplantation (HSCT) was performed, resulting in lasting complete remission of the encephalitis. To our knowledge, this is the first report of refractory autoimmune phenomena in CVID treated by autologous HSCT. KW - common variable immunodeficiency KW - primary immunodeficiencies KW - autoimmunity KW - autologous stem cell transplantation KW - autoimmune encephalitis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206972 SN - 1664-3224 VL - 11 IS - 1317 ER - TY - JOUR A1 - Shukla, A. A1 - Mannheim, K. T1 - Gamma-ray flares from relativistic magnetic reconnection in the jet of the quasar 3C 279 JF - Nature Communications N2 - Spinning black holes in the centres of galaxies can release powerful magnetised jets. When the jets are observed at angles of less than a few degrees to the line-of-sight, they are called blazars, showing variable non-thermal emission across the electromagnetic spectrum from radio waves to gamma rays. It is commonly believed that shock waves are responsible for this dissipation of jet energy. Here we show that gamma-ray observations of the blazar 3C 279 with the space-borne telescope Fermi-LAT reveal a characteristic peak-in-peak variability pattern on time scales of minutes expected if the particle acceleration is instead due to relativistic magnetic reconnection. The absence of gamma-ray pair attenuation shows that particle acceleration takes place at a distance of ten thousand gravitational radii from the black hole where the fluid dynamical kink instability drives plasma turbulence. KW - kink instability KW - energy KW - radiation KW - blazars KW - variability KW - absorption KW - telescope KW - shocks Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231328 VL - 11 ER - TY - JOUR A1 - Cao, Liyu A1 - Chen, Xinyu A1 - Haendel, Barbara F. T1 - Overground Walking Decreases Alpha Activity and Entrains Eye Movements in Humans JF - Frontiers in Human Neuroscience N2 - Experiments in animal models have shown that running increases neuronal activity in early visual areas in light as well as in darkness. This suggests that visual processing is influenced by locomotion independent of visual input. Combining mobile electroencephalography, motion- and eye-tracking, we investigated the influence of overground free walking on cortical alpha activity (~10 Hz) and eye movements in healthy humans. Alpha activity has been considered a valuable marker of inhibition of sensory processing and shown to negatively correlate with neuronal firing rates. We found that walking led to a decrease in alpha activity over occipital cortex compared to standing. This decrease was present during walking in darkness as well as during light. Importantly, eye movements could not explain the change in alpha activity. Nevertheless, we found that walking and eye related movements were linked. While the blink rate increased with increasing walking speed independent of light or darkness, saccade rate was only significantly linked to walking speed in the light. Pupil size, on the other hand, was larger during darkness than during light, but only showed a modulation by walking in darkness. Analyzing the effect of walking with respect to the stride cycle, we further found that blinks and saccades preferentially occurred during the double support phase of walking. Alpha power, as shown previously, was lower during the swing phase than during the double support phase. We however could exclude the possibility that the alpha modulation was introduced by a walking movement induced change in electrode impedance. Overall, our work indicates that the human visual system is influenced by the current locomotion state of the body. This influence affects eye movement pattern as well as neuronal activity in sensory areas and might form part of an implicit strategy to optimally extract sensory information during locomotion. KW - mobile EEG KW - alpha oscillations KW - blinks KW - saccades KW - locomotion KW - pupil size KW - walking phase KW - motor entrainment Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219872 SN - 1662-5161 VL - 14 ER - TY - JOUR A1 - Vogel, Cassandra A1 - Chunga, Timothy L. A1 - Sun, Xiaoxuan A1 - Poveda, Katja A1 - Steffan-Dewenter, Ingolf T1 - Higher bee abundance, but not pest abundance, in landscapes with more agriculture on a late-flowering legume crop in tropical smallholder farms JF - PeerJ N2 - Background Landscape composition is known to affect both beneficial insect and pest communities on crop fields. Landscape composition therefore can impact ecosystem (dis)services provided by insects to crops. Though landscape effects on ecosystem service providers have been studied in large-scale agriculture in temperate regions, there is a lack of representation of tropical smallholder agriculture within this field of study, especially in sub-Sahara Africa. Legume crops can provide important food security and soil improvement benefits to vulnerable agriculturalists. However, legumes are dependent on pollinating insects, particularly bees (Hymenoptera: Apiformes) for production and are vulnerable to pests. We selected 10 pigeon pea (Fabaceae: Cajunus cajan (L.)) fields in Malawi with varying proportions of semi-natural habitat and agricultural area within a 1 km radius to study: (1) how the proportion of semi-natural habitat and agricultural area affects the abundance and richness of bees and abundance of florivorous blister beetles (Coleoptera: Melloidae), (2) if the proportion of flowers damaged and fruit set difference between open and bagged flowers are correlated with the proportion of semi-natural habitat or agricultural area and (3) if pigeon pea fruit set difference between open and bagged flowers in these landscapes was constrained by pest damage or improved by bee visitation. Methods We performed three, ten-minute, 15 m, transects per field to assess blister beetle abundance and bee abundance and richness. Bees were captured and identified to (morpho)species. We assessed the proportion of flowers damaged by beetles during the flowering period. We performed a pollinator and pest exclusion experiment on 15 plants per field to assess whether fruit set was pollinator limited or constrained by pests. Results In our study, bee abundance was higher in areas with proportionally more agricultural area surrounding the fields. This effect was mostly driven by an increase in honeybees. Bee richness and beetle abundances were not affected by landscape characteristics, nor was flower damage or fruit set difference between bagged and open flowers. We did not observe a positive effect of bee density or richness, nor a negative effect of florivory, on fruit set difference. Discussion In our study area, pigeon pea flowers relatively late—well into the dry season. This could explain why we observe higher densities of bees in areas dominated by agriculture rather than in areas with more semi-natural habitat where resources for bees during this time of the year are scarce. Therefore, late flowering legumes may be an important food resource for bees during a period of scarcity in the seasonal tropics. The differences in patterns between our study and those conducted in temperate regions highlight the need for landscape-scale studies in areas outside the temperate region. KW - Pollination KW - Small-holder agriculture KW - Legume crops KW - Insect pests KW - Tropical agriculture KW - Landscape ecology KW - Plant-insect interactions KW - African agriculture KW - Ecosystem services KW - Agro-ecology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231491 VL - 9 ER - TY - JOUR A1 - Gabbert, Lydia A1 - Dilling, Christina A1 - Meybohm, Patrick A1 - Burek, Malgorzata T1 - Deletion of Protocadherin Gamma C3 Induces Phenotypic and Functional Changes in Brain Microvascular Endothelial Cells In Vitro JF - Frontiers in Pharmacology N2 - Inflammation of the central nervous system (CNS) is associated with diseases such as multiple sclerosis, stroke and neurodegenerative diseases. Compromised integrity of the blood-brain barrier (BBB) and increased migration of immune cells into the CNS are the main characteristics of brain inflammation. Clustered protocadherins (Pcdhs) belong to a large family of cadherin-related molecules. Pcdhs are highly expressed in the CNS in neurons, astrocytes, pericytes and epithelial cells of the choroid plexus and, as we have recently demonstrated, in brain microvascular endothelial cells (BMECs). Knockout of a member of the Pcdh subfamily, PcdhgC3, resulted in significant changes in the barrier integrity of BMECs. Here we characterized the endothelial PcdhgC3 knockout (KO) cells using paracellular permeability measurements, proliferation assay, wound healing assay, inhibition of signaling pathways, oxygen/glucose deprivation (OGD) and a pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) treatment. PcdhgC3 KO showed an increased paracellular permeability, a faster proliferation rate, an altered expression of efflux pumps, transporters, cellular receptors, signaling and inflammatory molecules. Serum starvation led to significantly higher phosphorylation of extracellular signal-regulated kinases (Erk) in KO cells, while no changes in phosphorylated Akt kinase levels were found. PcdhgC3 KO cells migrated faster in the wound healing assay and this migration was significantly inhibited by respective inhibitors of the MAPK-, β-catenin/Wnt-, mTOR- signaling pathways (SL327, XAV939, or Torin 2). PcdhgC3 KO cells responded stronger to OGD and TNFα by significantly higher induction of interleukin 6 mRNA than wild type cells. These results suggest that PcdhgC3 is involved in the regulation of major signaling pathways and the inflammatory response of BMECs. KW - blood-brain barrier KW - protocadherin gamma C3 KW - inflammation KW - oxygen/glucose deprivation KW - stroke KW - tumor necrosis factor-α KW - proliferation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219828 SN - 1663-9812 VL - 11 ER - TY - JOUR A1 - Lotz, Christopher A1 - Notz, Quirin A1 - Kranke, Peter A1 - Kredel, Markus A1 - Meybohm, Patrick T1 - Unconventional approaches to mechanical ventilation - step-by-step through the COVID-19 crisis JF - Critical Care N2 - No abstract available. KW - COVID 19 KW - mechanical ventilation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229868 VL - 24 ER - TY - JOUR A1 - Curtaz, Carolin J. A1 - Schmitt, Constanze A1 - Herbert, Saskia-Laureen A1 - Feldheim, Jonas A1 - Schlegel, Nicolas A1 - Gosselet, Fabien A1 - Hagemann, Carsten A1 - Roewer, Norbert A1 - Meybohm, Patrick A1 - Wöckel, Achim A1 - Burek, Malgorzata T1 - Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood-brain barrier model JF - Fluids and Barriers of the CNS N2 - Background The most threatening metastases in breast cancer are brain metastases, which correlate with a very poor overall survival, but also a limited quality of life. A key event for the metastatic progression of breast cancer into the brain is the migration of cancer cells across the blood-brain barrier (BBB). Methods We adapted and validated the CD34\(^+\) cells-derived human in vitro BBB model (brain-like endothelial cells, BLECs) to analyse the effects of patient serum on BBB properties. We collected serum samples from healthy donors, breast cancer patients with primary cancer, and breast cancer patients with, bone, visceral or cerebral metastases. We analysed cytokine levels in these sera utilizing immunoassays and correlated them with clinical data. We used paracellular permeability measurements, immunofluorescence staining, Western blot and mRNA analysis to examine the effects of patient sera on the properties of BBB in vitro. Results The BLECs cultured together with brain pericytes in transwells developed a tight monolayer with a correct localization of claudin-5 at the tight junctions (TJ). Several BBB marker proteins such as the TJ proteins claudin-5 and occludin, the glucose transporter GLUT-1 or the efflux pumps PG-P and BCRP were upregulated in these cultures. This was accompanied by a reduced paracellular permeability for fluorescein (400 Da). We then used this model for the treatment with the patient sera. Only the sera of breast cancer patients with cerebral metastases had significantly increased levels of the cytokines fractalkine (CX3CL1) and BCA-1 (CXCL13). The increased levels of fractalkine were associated with the estrogen/progesterone receptor status of the tumour. The treatment of BLECs with these sera selectively increased the expression of CXCL13 and TJ protein occludin. In addition, the permeability of fluorescein was increased after serum treatment. Conclusion We demonstrate that the CD34\(^+\) cell-derived human in vitro BBB model can be used as a tool to study the molecular mechanisms underlying cerebrovascular pathologies. We showed that serum from patients with cerebral metastases may affect the integrity of the BBB in vitro, associated with elevated concentrations of specific cytokines such as CX3CL1 and CXCL13. KW - Metastatic breast cancer KW - Blood–brain barrier KW - In vitro models KW - CX3CL1 KW - CXCL13 Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229940 VL - 17 ER - TY - JOUR A1 - Schlesinger, Tobias A1 - Weißbrich, Benedikt A1 - Wedekink, Florian A1 - Notz, Quirin A1 - Herrmann, Johannes A1 - Krone, Manuel A1 - Sitter, Magdalena A1 - Schmid, Benedikt A1 - Kredel, Markus A1 - Stumpner, Jan A1 - Dölken, Lars A1 - Wischhusen, Jörg A1 - Kranke, Peter A1 - Meybohm, Patrick A1 - Lotz, Christpher T1 - Biodistribution and serologic response in SARS-CoV-2 induced ARDS: A cohort study JF - PLoS One N2 - Background The viral load and tissue distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain important questions. The current study investigated SARS-CoV-2 viral load, biodistribution and anti-SARS-CoV-2 antibody formation in patients suffering from severe corona virus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS). Methods This is a retrospective single-center study in 23 patients with COVID-19-induced ARDS. Data were collected within routine intensive care. SARS-CoV-2 viral load was assessed via reverse transcription quantitative polymerase chain reaction (RT-qPCR). Overall, 478 virology samples were taken. Anti-SARS-CoV-2-Spike-receptor binding domain (RBD) antibody detection of blood samples was performed with an enzyme-linked immunosorbent assay. Results Most patients (91%) suffered from severe ARDS during ICU treatment with a 30-day mortality of 30%. None of the patients received antiviral treatment. Tracheal aspirates tested positive for SARS-CoV-2 in 100% of the cases, oropharyngeal swabs only in 77%. Blood samples were positive in 26% of the patients. No difference of viral load was found in tracheal or blood samples with regard to 30-day survival or disease severity. SARS-CoV-2 was never found in dialysate. Serologic testing revealed significantly lower concentrations of SARS-CoV-2 neutralizing IgM and IgA antibodies in survivors compared to non-survivors (p = 0.009). Conclusions COVID-19 induced ARDS is accompanied by a high viral load of SARS-CoV-2 in tracheal aspirates, which remained detectable in the majority throughout intensive care treatment. Remarkably, SARS-CoV-2 RNA was never detected in dialysate even in patients with RNAemia. Viral load or the buildup of neutralizing antibodies was not associated with 30-day survival or disease severity. KW - viral load Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231348 VL - 15, 2020 IS - 11 ER -