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Schiffmann, Susanne ; Gunne, Sandra ; Bende, Marina ; Ulshöfer, Thomas ; Steinhilber, Dieter ; Sethmann, Annette ; Parnham, Michael J.
Background: Sodium bituminosulfonate is derived from naturally occurring sulphur-rich oil shale and is used for the treatment of the inflammatory skin disease rosacea. Major molecular players in the development of rosacea include the release of enzymes that process antimicrobial peptides which, together with reactive oxygen species (ROS) and vascular endothelial growth factor (VEGF), promote pro-inflammatory processes and angiogenesis. The aim of this study was to address the molecular mechanism(s) underlying the therapeutic benefit of the formulation sodium bituminosulfonate dry substance (SBDS), which is indicated for the treatment of skin inflammation, including rosacea.
Methods: We investigated whether SBDS regulates the expression of cytokines, the release of the antimicrobial peptide LL-37, calcium mobilization, proteases (matrix metalloproteinase, elastase, kallikrein (KLK)5), VEGF or ROS in primary human neutrophils. In addition, activity assays with 5-lipoxygenase (5-LO) and recombinant human MMP9 and KLK5 were performed.
Results: We observed that SBDS reduces the release of the antimicrobial peptide LL-37, calcium, elastase, ROS and VEGF from neutrophils. Moreover, KLK5, the enzyme that converts cathelicidin to LL-37, and 5-LO that produces leukotriene (LT)A4, the precursor of LTB4, were both inhibited by SBDS with an IC50 of 7.6 μg/mL and 33 μg/mL, respectively.
Conclusion: Since LTB4 induces LL-37 which, in turn, promotes increased intracellular calcium levels and thereby, ROS/VEGF/elastase release, SBDS possibly regulates the LTB4/LL-37/calcium – ROS/VEGF/elastase axis by inhibiting 5-LO and KLK5. Additional direct effects on other pro-inflammatory pathways such as ROS generation cannot be ruled out. In summary, SBDS reduces the generation of inflammatory mediators from human neutrophils possibly accounting for its anti-inflammatory effects in rosacea.
Effects of foam rolling duration on tissue stiffness and perfusion: a randomized cross-over trial
(2021)
Despite its beneficial effects on flexibility and muscle soreness, there is still conflicting evidence regarding dose-response relationships and underlying mechanisms of foam rolling (FR). This study aimed to investigate the impact of different FR protocols on tissue perfusion and tissue stiffness. In a randomized crossover trial, two FR protocols (2x1 min, 2x3 min) were applied to the right anterior thigh of twenty healthy volunteers (11 females, 25 ± 4 years). Tissue perfusion (near infrared spectroscopy, NIRS) and stiffness (Tensiomyography, TMG and Myotonometry, MMT) were assessed before and after FR application. Variance analyses revealed a significant interaction of FR duration and tissue perfusion (F[1,19] = 7.098, p = 0.015). Local blood flow increased significantly from pre to post test (F[1,19] = 7.589, p = 0.013), being higher (Δ +9.7%) in the long-FR condition than in the short-FR condition (Δ +2.8%). Tissue stiffness (MMT) showed significant main effects for time (F[1,19] = 12.074, p = 0.003) and condition (F[1,19] = 7.165, p = 0.015) with decreases after short-FR (Δ -1.6%) and long-FR condition (Δ -1.9%). However, there was no time*dose-interaction (F[1,19] = 0.018, p = 0.895). No differences were found for TMG (p > 0.05). FR-induced changes failed to exceed the minimal detectable change threshold (MDC). Our data suggest that increased blood flow and altered tissue stiffness may mediate the effects of FR although statistical MDC thresholds were not achieved. Longer FR durations seem to be more beneficial for perfusion which is of interest for exercise professionals designing warm-up and cool-down regimes. Further research is needed to understand probable effects on parasympathetic outcomes representing systemic physiological responses to locally applied FR stimulations.
Ernsting, Jan ; Holstein, Vincent Leonard ; Winter, Nils Ralf ; Sarink, Kelvin ; Leenings, Ramona ; Gruber, Marius ; Repple, Jonathan ; Risse, Benjamin ; Dannlowski, Udo ; Hahn, Tim
Graph data is an omnipresent way to represent information in machine learning. Especially, in neuroscience research, data from Diffusion-Tensor Imaging (DTI) and functional Magnetic Resonance Imaging (fMRI) is commonly represented as graphs. Exploiting the graph structure of these modalities using graph-specific machine learning applications is currently hampered by the lack of easy-to-use software. PHOTONAI Graph aims to close the gap between domain experts of machine learning, graph experts and neuroscientists. Leveraging the rapid machine learning model development features of the Python machine learning API PHOTONAI, PHOTONAI Graph enables the design, optimization, and evaluation of reliable graph machine learning models for practitioners. As such, it provides easy access to custom graph machine learning pipelines including, hyperparameter optimization and algorithm evaluation ensuring reproducibility and valid performance estimates. Integrating established algorithms such as graph neural networks, graph embeddings and graph kernels, it allows researchers without significant coding experience to build and optimize complex graph machine learning models within a few lines of code. We showcase the versatility of this toolbox by building pipelines for both resting–state fMRI and DTI data in the hope that it will increase the adoption of graph-specific machine learning algorithms in neuroscience research.
Context information supports serial dependence of multiple visual objects across memory episodes
(2019)
Fischer, Cora ; Czoschke, Stefan ; Peters, Benjamin ; Rahm, Benjamin ; Kaiser, Jochen ; Bledowski, Christoph
Visual perception operates in an object-based manner, by integrating associated features via attention. Working memory allows a flexible access to a limited number of currently relevant objects, even when they are occluded or physically no longer present. Recently, it has been shown that we compensate for small changes of an object’s feature over memory episodes, which can support its perceptual stability. This phenomenon was termed ‘serial dependence’ and has mostly been studied in situations that comprised only a single relevant object. However, since we are typically confronted with situations where several objects have to be perceived and held in working memory, the central question of how we selectively create temporal stability of several objects has remained unsolved. As different objects can be distinguished by their accompanying context features, like their color or temporal position, we tested whether serial dependence is supported by the congruence of context features across memory episodes. Specifically, we asked participants to remember the motion directions of two sequentially presented colored dot fields per trial. At the end of a trial one motion direction was cued for continuous report either by its color (Experiment 1) or serial position (Experiment 2). We observed serial dependence, i.e., an attractive bias of currently toward previously memorized objects, between current and past motion directions that was clearly enhanced when items had the same color or serial position across trials. This bias was particularly pronounced for the context feature that was used for cueing and for the target of the previous trial. Together, these findings demonstrate that coding of current object representations depends on previous representations, especially when they share similar content and context features. Apparently the binding of content and context features is not completely erased after a memory episode, but it is carried over to subsequent episodes. As this reflects temporal dependencies in natural settings, the present findings reveal a mechanism that integrates corresponding bundles of content and context features to support stable representations of individualized objects over time.
As the current SARS-CoV-2 pandemic continues, serological assays are urgently needed for rapid diagnosis, contact tracing and for epidemiological studies. So far, there is little data on how commercially available tests perform with real patient samples and if detected IgG antibodies provide protective immunity. Focusing on IgG antibodies, we demonstrate the performance of two ELISA assays (Euroimmun SARS-CoV-2 IgG & Vircell COVID-19 ELISA IgG) in comparison to one lateral flow assay ((LFA) FaStep COVID-19 IgG/IgM Rapid Test Device) and two in-house developed assays (immunofluorescence assay (IFA) and plaque reduction neutralization test (PRNT)). We tested follow up serum/plasma samples of individuals PCR-diagnosed with COVID-19. Most of the SARS-CoV-2 samples were from individuals with moderate to severe clinical course, who required an in-patient hospital stay.
For all examined assays, the sensitivity ranged from 58.8 to 76.5% for the early phase of infection (days 5-9) and from 93.8 to 100% for the later period (days 10-18) after PCR-diagnosed with COVID-19. With exception of one sample, all positive tested samples in the analysed cohort, using the commercially available assays examined (including the in-house developed IFA), demonstrated neutralizing (protective) properties in the PRNT, indicating a potential protective immunity to SARS-CoV-2. Regarding specificity, there was evidence that samples of endemic coronavirus (HCoV-OC43, HCoV-229E) and Epstein Barr virus (EBV) infected individuals cross-reacted in the ELISA assays and IFA, in one case generating a false positive result (may giving a false sense of security). This need to be further investigated.
Endothelial tip cells are essential for VEGF-induced angiogenesis, but underlying mechanisms are elusive. Endothelial-specific deletion of EVL, a member of the mammalian Ena/VASP protein family, reduced the expression of the tip cell marker protein endothelial cell specific molecule-1 (Esm1) and compromised the radial sprouting of the vascular plexus in the postnatal mouse retina. The latter effects could at least partly be attributed to reduced VEGF receptor 2 (VEGFR2) internalization and signaling but the underlying mechanisms(s) are not fully understood. In the present study, we revealed that the expression of the long non-coding RNA H19 was significantly reduced in endothelial cells from postnatal EVL-/- mice and in siRNA-transfected human endothelial cells under hypoxic conditions. H19 was recently shown to promote VEGF expression and bioavailability via Esm1 and hypoxia inducible factor 1α (HIF-1α). Similar to EVL-/- mice, the radial outgrowth of the vascular plexus was significantly delayed in the postnatal retina of H19-/- mice. In summary, our data suggests that loss of EVL not only impairs VEGFR2 internalition and downstream signaling, but also impairs VEGF expression and bioavailability in the hypoxic retina via downregulation of lncRNA H19.
Male, Christoph ; Andersson, Nadine G. ; Rafowicz, Anne ; Liesner, Ri ; Kurnik, Karin ; Fischer, Kathelijn ; Platokouki, Helen ; Santagostino, Elena ; Chambost, Hervé ; Nolan, Beatrice ; Königs, Christoph ; Kenet, Gili ; Ljung, Rolf ; Berg, Hendrika M. van den
The incidence of FIX inhibitors in severe hemophilia B (SHB) is not well defined. Frequencies of 3-5% have been reported but most studies to date were small, including patients with different severities, and without prospective follow-up for inhibitor incidence. Study objective was to investigate inhibitor incidence in patients with SHB followed up to 500 exposure days (ED), the frequency of allergic reactions, and the relationship with genotypes. Consecutive previously untreated patients (PUPs) with SHB enrolled into the PedNet cohort were included. Detailed data was collected for the first 50 ED, followed by annual collection of inhibitor status and allergic reactions. Presence of inhibitors was defined by at least two consecutive positive samples. Additionally, data on factor IX gene mutation was collected. 154 PUPs with SHB were included; 75% were followed until 75 ED, and 43% until 500 ED. Inhibitors developed in 14 patients (7 high-titre). Median number of ED at inhibitor manifestation was 11 (IQR 6.5-36.5). Cumulative inhibitor incidence was 9.3% (95%CI 4.4-14.1) at 75 ED, and 10.2% (5.1-15.3) at 500 ED. Allergic reactions occurred in 4 (28.6%) inhibitor patients. Missense mutations were most frequent (46.8%) overall but not associated with inhibitors. Nonsense mutations and deletions with large structural changes comprised all mutations among inhibitor patients and were associated with an inhibitor risk of 26.9% and 33.3%, respectively. In an unselected, well-defined cohort of PUPs with SHB, cumulative inhibitor incidence was 10.2% at 500 ED. Nonsense mutations and large deletions were strongly associated with the risk of inhibitor development. The PedNet Registry is registered at clinicaltrials.gov; identifier: NCT02979119
Nieraad, Hendrik ; Bruin, Natasja de ; Arne, Olga ; Hofmann, Martine C. J. ; Gurke, Robert ; Schmidt, Dominik ; Ritter, Marcel ; Parnham, Michael J. ; Geisslinger, Gerd
Hyperhomocysteinemia has been suggested potentially to contribute to a variety of pathologies, such as Alzheimer’s disease (AD). While the impact of hyperhomocysteinemia on AD has been investigated extensively, there are scarce data on the effect of AD on hyperhomocysteinemia. The aim of this in vivo study was to investigate the kinetics of homocysteine (HCys) and homocysteic acid (HCA) and effects of AD-like pathology on the endogenous levels. The mice received a B-vitamin deficient diet for eight weeks, followed by the return to a balanced control diet for another eight weeks. Serum, urine, and brain tissues of AppNL-G-F knock-in and C57BL/6J wild type mice were analyzed for HCys and HCA using LC-MS/MS methods. Hyperhomocysteinemic levels were found in wild type and knock-in mice due to the consumption of the deficient diet for eight weeks, followed by a rapid normalization of the levels after the return to control chow. Hyperhomocysteinemic AppNL-G-F mice had significantly higher HCys in all matrices, but not HCA, compared to wild type control. Higher serum concentrations were associated with elevated levels in both the brain and in urine. Our findings confirm a significant impact of AD-like pathology on hyperhomocysteinemia in the AppNL-G-F mouse model. The immediate normalization of HCys and HCA after the supply of B-vitamins strengthens the idea of a B-vitamin intervention as a potentially preventive treatment option for HCys-related disorders such as AD.
Neef, Vanessa ; Vo, Linda ; Herrmann, Eva ; Triphaus, Chris ; Judd, Leonie ; Winter, Andreas ; Zacharowski, Kai ; Choorapoikayil, Suma ; Meybohm, Patrick
Introduction: Cell salvage (CS) is an integral part of patient blood management (PBM) and aims to reduce allogeneic red blood cell (RBC) transfusion.
Material and methods: This observational study analysed patients scheduled for elective cardiac surgery requiring cardiopulmonary bypass (CPB) between November 2015 and October 2018. Patients were divided into a CS group (patients receiving CS) and a control group (no CS). Primary endpoints were the number of patients exposed to allogeneic RBC transfusions and the number of RBC units transfused per patient.
Results: A total of 704 patients undergoing cardiac surgery were analysed, of whom 338 underwent surgery with CS (CS group) and 366 were without CS (control group). Intraoperatively, 152 patients (45%) were exposed to allogeneic RBC transfusions in the CS group and 93 patients (25%) in the control group (P < 0.001). Considering the amount of intraoperative blood loss, regression analysis revealed a significant association between blood loss and increased use of RBC units in patients of the control compared to the CS group (1000 mL: 1.0 vs. 0.6 RBC units; 2000 mL: 2.2 vs. 1.1 RBC units; 3000 mL: 3.4 vs. 1.6 RBC units). Thus, CS was significantly associated with a reduced number of allogeneic RBCs by 40% for 1000 mL, 49% for 2000 mL, and 52% for 3000 mL of blood loss compared to patients without CS.
Conclusions: Cell salvage was significantly associated with a reduced number of allogeneic RBC transfusions. It supports the beneficial effect of CS in cardiac surgical patients as an individual measure in a comprehensive PBM program.