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- ItemInfluence of Autapses on Synchronization in Neural Networks With Chemical Synapses(Lausanne : Frontiers Media, 2020) Protachevicz, Paulo R.; Iarosz, Kelly C.; Caldas, Iberê L.; Antonopoulos, Chris G.; Batista, Antonio M.; Kurths, JürgenA great deal of research has been devoted on the investigation of neural dynamics in various network topologies. However, only a few studies have focused on the influence of autapses, synapses from a neuron onto itself via closed loops, on neural synchronization. Here, we build a random network with adaptive exponential integrate-and-fire neurons coupled with chemical synapses, equipped with autapses, to study the effect of the latter on synchronous behavior. We consider time delay in the conductance of the pre-synaptic neuron for excitatory and inhibitory connections. Interestingly, in neural networks consisting of both excitatory and inhibitory neurons, we uncover that synchronous behavior depends on their synapse type. Our results provide evidence on the synchronous and desynchronous activities that emerge in random neural networks with chemical, inhibitory and excitatory synapses where neurons are equipped with autapses. © Copyright © 2020 Protachevicz, Iarosz, Caldas, Antonopoulos, Batista and Kurths.
- ItemInfluence of Delayed Conductance on Neuronal Synchronization(Lausanne : Frontiers Media, 2020) Protachevicz, Paulo R.; Borges, Fernando S.; Iarosz, Kelly C.; Baptista, Murilo S.; Lameu, Ewandson L.; Hansen, Matheus; Caldas, Iberê L.; Szezech Jr., José D.; Batista, Antonio M.; Kurths, JürgenIn the brain, the excitation-inhibition balance prevents abnormal synchronous behavior. However, known synaptic conductance intensity can be insufficient to account for the undesired synchronization. Due to this fact, we consider time delay in excitatory and inhibitory conductances and study its effect on the neuronal synchronization. In this work, we build a neuronal network composed of adaptive integrate-and-fire neurons coupled by means of delayed conductances. We observe that the time delay in the excitatory and inhibitory conductivities can alter both the state of the collective behavior (synchronous or desynchronous) and its type (spike or burst). For the weak coupling regime, we find that synchronization appears associated with neurons behaving with extremes highest and lowest mean firing frequency, in contrast to when desynchronization is present when neurons do not exhibit extreme values for the firing frequency. Synchronization can also be characterized by neurons presenting either the highest or the lowest levels in the mean synaptic current. For the strong coupling, synchronous burst activities can occur for delays in the inhibitory conductivity. For approximately equal-length delays in the excitatory and inhibitory conductances, desynchronous spikes activities are identified for both weak and strong coupling regimes. Therefore, our results show that not only the conductance intensity, but also short delays in the inhibitory conductance are relevant to avoid abnormal neuronal synchronization. © Copyright © 2020 Protachevicz, Borges, Iarosz, Baptista, Lameu, Hansen, Caldas, Szezech, Batista and Kurths.
- ItemInstantaneous Cardiac Baroreflex Sensitivity: xBRS Method Quantifies Heart Rate Blood Pressure Variability Ratio at Rest and During Slow Breathing(Lausanne : Frontiers Media, 2020) Wessel, Niels; Gapelyuk, Andrej; Weiß, Jonas; Kraemer, Jan F.; Schmidt, Martin; Berg, Karsten; Malberg, Hagen; Stepan, Holger; Kurths, JürgenSpontaneous baroreflex sensitivity (BRS) is a widely used tool for the quantification of the cardiovascular regulation. Numerous groups use the xBRS method, which calculates the cross-correlation between the systolic beat-to-beat blood pressure and the R-R interval (resampled at 1 Hz) in a 10 s sliding window, with 0–5 s delays for the interval. The delay with the highest correlation is selected and, if significant, the quotient of the standard deviations of the R-R intervals and the systolic blood pressures is recorded as the corresponding xBRS value. In this paper we test the hypothesis that the xBRS method quantifies the causal interactions of spontaneous BRS from non-invasive measurements at rest. We use the term spontaneous BRS in the sense of the sensitivity curve is calculated from non-interventional, i.e., spontaneous, baroreceptor activity. This study includes retrospective analysis of 1828 measurements containing ECG as well as continues blood pressure under resting conditions. Our results show a high correlation between the heart rate – systolic blood pressure variability (HRV/BPV) quotient and the xBRS (r = 0.94, p < 0.001). For a deeper understanding we conducted two surrogate analyses by substituting the systolic blood pressure by its reversed time series. These showed that the xBRS method was not able to quantify causal relationships between the two signals. It was not possible to distinguish between random and baroreflex controlled sequences. It appears xBRS rather determines the HRV/BPV quotient. We conclude that the xBRS method has a potentially large bias in characterizing the capacity of the arterial baroreflex under resting conditions. During slow breathing, estimates for xBRS are significantly increased, which clearly shows that measurements at rest only involve limited baroreflex activity, but does neither challenge, nor show the full range of the arterial baroreflex regulatory capacity. We show that xBRS is exclusively dominated by the heart rate to systolic blood pressure ratio (r = 0.965, p < 0.001). Further investigations should focus on additional autonomous testing procedures such as slow breathing or orthostatic testing to provide a basis for a non-invasive evaluation of baroreflex sensitivity. © Copyright © 2020 Wessel, Gapelyuk, Weiß, Schmidt, Kraemer, Berg, Malberg, Stepan and Kurths.
- ItemToll-Like Receptor 2 Release by Macrophages: An Anti-inflammatory Program Induced by Glucocorticoids and Lipopolysaccharide(Lausanne : Frontiers Media, 2019) Hoppstädter, Jessica; Dembek, Anna; Linnenberger, Rebecca; Dahlem, Charlotte; Barghash, Ahmad; Fecher-Trost, Claudia; Fuhrmann, Gregor; Koch, Marcus; Kraegeloh, Annette; Huwer, Hanno; Kiemer, Alexandra K.Glucocorticoids (GCs) are widely prescribed therapeutics for the treatment of inflammatory diseases, and endogenous GCs play a key role in immune regulation. Toll-like receptors (TLRs) enable innate immune cells, such as macrophages, to recognize a wide variety of microbial ligands, thereby promoting inflammation. The interaction of GCs with macrophages in the immunosuppressive resolution phase upon prolonged TLR activation is widely unknown. Treatment of human alveolar macrophages (AMs) with the synthetic GC dexamethasone (Dex) did not alter the expression of TLRs -1, -4, and -6. In contrast, TLR2 was upregulated in a GC receptor-dependent manner, as shown by Western blot and qPCR. Furthermore, long-term lipopolysaccharide (LPS) exposure mimicking immunosuppression in the resolution phase of inflammation synergistically increased Dex-mediated TLR2 upregulation. Analyses of publicly available datasets suggested that TLR2 is induced during the resolution phase of inflammatory diseases, i.e., under conditions associated with high endogenous GC production. TLR2 induction did not enhance TLR2 signaling, as indicated by reduced cytokine production after treatment with TLR2 ligands in Dex- and/or LPS-primed AMs. Thus, we hypothesized that the upregulated membrane-bound TLR2 might serve as a precursor for soluble TLR2 (sTLR2), known to antagonize TLR2-dependent cell actions. Supernatants of LPS/Dex-primed macrophages contained sTLR2, as demonstrated by Western blot analysis. Activation of metalloproteinases resulted in enhanced sTLR2 shedding. Additionally, we detected full-length TLR2 and assumed that this might be due to the production of TLR2-containing extracellular vesicles (EVs). EVs from macrophage supernatants were isolated by sequential centrifugation. Both untreated and LPS/Dex-treated cells produced vesicles of various sizes and shapes, as shown by cryo-transmission electron microscopy. These vesicles were identified as the source of full-length TLR2 in macrophage supernatants by Western blot and mass spectrometry. Flow cytometric analysis indicated that TLR2-containing EVs were able to bind the TLR2 ligand Pam3CSK4. In addition, the presence of EVs reduced inflammatory responses in Pam3CSK4-treated endothelial cells and HEK Dual reporter cells, demonstrating that TLR2-EVs can act as decoy receptors. In summary, our data show that sTLR2 and full-length TLR2 are released by macrophages under anti-inflammatory conditions, which may contribute to GC-induced immunosuppression.
- ItemHigh Glucose Enhances Cytotoxic T Lymphocyte-Mediated Cytotoxicity(Lausanne : Frontiers Media, 2021) Zhu, Jie; Yang, Wenjuan; Zhou, Xiangda; Zöphel, Dorina; Soriano-Baguet, Leticia; Dolgener, Denise; Carlein, Christopher; Hof, Chantal; Zhao, Renping; Ye, Shandong; Schwarz, Eva C.; Brenner, Dirk; Prates Roma, Leticia; Qu, BinCytotoxic T lymphocytes (CTLs) are key players to eliminate tumorigenic or pathogen-infected cells using lytic granules (LG) and Fas ligand (FasL) pathways. Depletion of glucose leads to severely impaired cytotoxic function of CTLs. However, the impact of excessive glucose on CTL functions still remains largely unknown. Here we used primary human CD8+ T cells, which were stimulated by CD3/CD28 beads and cultured in medium either containing high glucose (HG, 25 mM) or normal glucose (NG, 5.6 mM). We found that in HG-CTLs, glucose uptake and glycolysis were enhanced, whereas proliferation remained unaltered. Furthermore, CTLs cultured in HG exhibited an enhanced CTL killing efficiency compared to their counterparts in NG. Unexpectedly, expression of cytotoxic proteins (perforin, granzyme A, granzyme B and FasL), LG release, cytokine/cytotoxic protein release and CTL migration remained unchanged in HG-cultured CTLs. Interestingly, additional extracellular Ca2+ diminished HG-enhanced CTL killing function. Our findings suggest that in an environment with excessive glucose, CTLs could eliminate target cells more efficiently, at least for a certain period of time, in a Ca2+-dependent manner.
- ItemIschemic stroke and concomitant gastrointestinal complications- a fatal combination for patient recovery(Lausanne : Frontiers Media, 2022) Tuz, Ali A.; Hasenberg, Anja; Hermann, Dirk M.; Gunzer, Matthias; Singh, VikramjeetStroke is primarily a neurodegenerative disease but can also severely impact the functions of other vital organs and deteriorate disease outcomes. A malfunction of the gastrointestinal tract (GIT), commonly observed in stroke patients, is often characterized by severe bowel obstruction, intestinal microbiota changes and inflammation. Over-activated immune cells after stroke are the major contributors to endorse intestinal inflammation and may induce damage to single-layer epithelial cell barriers. The post-stroke leakage of intestinal barriers may allow the translocation and dissemination of resident microflora to systemic organs and cause sepsis. This overshooting systemic immune reaction fuels ongoing inflammation in the degenerating brain and slows recovery. Currently, the therapeutic options to treat these GIT-associated anomalies are very limited and further research is required to develop novel treatments. In this mini-review, we first discuss the current knowledge from clinical studies and experimental stroke models that provide strong evidence of the existence of post-stroke GIT complications. Then, we review the literature regarding novel therapeutic approaches that might help to maintain GIT homeostasis and improve neurological outcomes in stroke patients.
- ItemCoupling between leg muscle activation and EEG during normal walking, intentional stops, and freezing of gait in Parkinson's disease(Lausanne : Frontiers Media, 2019) Günther, Moritz; Bartsch, Ronny P.; Miron-Shahar, Yael; Hassin-Baer, Sharon; Inzelberg, Rivka; Kurths, Jürgen; Plotnik, Meir; Kantelhardt, Jan W.In this paper, we apply novel techniques for characterizing leg muscle activation patterns via electromyograms (EMGs) and for relating them to changes in electroencephalogram (EEG) activity during gait experiments. Specifically, we investigate changes of leg-muscle EMG amplitudes and EMG frequencies during walking, intentional stops, and unintended freezing-of-gait (FOG) episodes. FOG is a frequent paroxysmal gait disturbance occurring in many patients suffering from Parkinson's disease (PD). We find that EMG amplitudes and frequencies do not change significantly during FOG episodes with respect to walking, while drastic changes occur during intentional stops. Phase synchronization between EMG signals is most pronounced during walking in controls and reduced in PD patients. By analyzing cross-correlations between changes in EMG patterns and brain-wave amplitudes (from EEGs), we find an increase in EEG-EMG coupling at the beginning of stop and FOG episodes. Our results may help to better understand the enigmatic pathophysiology of FOG, to differentiate between FOG events and other gait disturbances, and ultimately to improve diagnostic procedures for patients suffering from PD. Copyright © 2019 Günther, Bartsch, Miron-Shahar, Hassin-Baer, Inzelberg, Kurths, Plotnik and Kantelhardt.
- ItemIn ovo model in cancer research and tumor immunology(Lausanne : Frontiers Media, 2022) Miebach, Lea; Berner, Julia; Bekeschus, SanderConsidering cancer not only as malignant cells on their own but as a complex disease in which tumor cells interact and communicate with their microenvironment has motivated the establishment of clinically relevant 3D models in past years. Technological advances gave rise to novel bioengineered models, improved organoid systems, and microfabrication approaches, increasing scientific importance in preclinical research. Notwithstanding, mammalian in vivo models remain closest to mimic the patient’s situation but are limited by cost, time, and ethical constraints. Herein, the in ovo model bridges the gap as an advanced model for basic and translational cancer research without the need for ethical approval. With the avian embryo being a naturally immunodeficient host, tumor cells and primary tissues can be engrafted on the vascularized chorioallantoic membrane (CAM) with high efficiencies regardless of species-specific restrictions. The extraembryonic membranes are connected to the embryo through a continuous circulatory system, readily accessible for manipulation or longitudinal monitoring of tumor growth, metastasis, angiogenesis, and matrix remodeling. However, its applicability in immunoncological research is largely underexplored. Dual engrafting of malignant and immune cells could provide a platform to study tumor-immune cell interactions in a complex, heterogenic and dynamic microenvironment with high reproducibility. With some caveats to keep in mind, versatile methods for in and ex ovo monitoring of cellular and molecular dynamics already established in ovo are applicable alike. In this view, the present review aims to emphasize and discuss opportunities and limitations of the chicken embryo model for pre-clinical research in cancer and cancer immunology.
- ItemTargeting the Microtubule-Network Rescues CTL Killing Efficiency in Dense 3D Matrices(Lausanne : Frontiers Media, 2021) Zhao, Renping; Zhou, Xiangda; Khan, Essak S.; Alansary, Dalia; Friedmann, Kim S.; Yang, Wenjuan; Schwarz, Eva C.; Del Campo, Aránzazu; Hoth, Markus; Qu, BinEfficacy of cytotoxic T lymphocyte (CTL)-based immunotherapy is still unsatisfactory against solid tumors, which are frequently characterized by condensed extracellular matrix. Here, using a unique 3D killing assay, we identify that the killing efficiency of primary human CTLs is substantially impaired in dense collagen matrices. Although the expression of cytotoxic proteins in CTLs remained intact in dense collagen, CTL motility was largely compromised. Using light-sheet microscopy, we found that persistence and velocity of CTL migration was influenced by the stiffness and porosity of the 3D matrix. Notably, 3D CTL velocity was strongly correlated with their nuclear deformability, which was enhanced by disruption of the microtubule network especially in dense matrices. Concomitantly, CTL migration, search efficiency, and killing efficiency in dense collagen were significantly increased in microtubule-perturbed CTLs. In addition, the chemotherapeutically used microtubule inhibitor vinblastine drastically enhanced CTL killing efficiency in dense collagen. Together, our findings suggest targeting the microtubule network as a promising strategy to enhance efficacy of CTL-based immunotherapy against solid tumors, especially stiff solid tumors.
- ItemUnspecific CTL Killing Is Enhanced by High Glucose via TNF-Related Apoptosis-Inducing Ligand(Lausanne : Frontiers Media, 2022) Yang, Wenjuan; Denger, Andreas; Diener, Caroline; Küppers, Frederic; Soriano-Baguet, Leticia; Schäfer, Gertrud; Yanamandra, Archana K.; Zhao, Renping; Knörck, Arne; Schwarz, Eva C.; Hart, Martin; Lammert, Frank; Roma, Leticia Prates; Brenner, Dirk; Christidis, Grigorios; Helms, Volkhard; Meese, Eckart; Hoth, Markus; Qu, BinTNF-related apoptosis inducing ligand (TRAIL) is expressed on cytotoxic T lymphocytes (CTLs) and TRAIL is linked to progression of diabetes. However, the impact of high glucose on TRAIL expression and its related killing function in CTLs still remains largely elusive. Here, we report that TRAIL is substantially up-regulated in CTLs in environments with high glucose (HG) both in vitro and in vivo. Non-mitochondrial reactive oxygen species, NFκB and PI3K/Akt are essential in HG-induced TRAIL upregulation in CTLs. TRAILhigh CTLs induce apoptosis of pancreatic beta cell line 1.4E7. Treatment with metformin and vitamin D reduces HG-enhanced expression of TRAIL in CTLs and coherently protects 1.4E7 cells from TRAIL-mediated apoptosis. Our work suggests that HG-induced TRAILhigh CTLs might contribute to the destruction of pancreatic beta cells in a hyperglycemia condition.
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