TY - JOUR A1 - Reschke, Moritz A1 - Salvador, Ellaine A1 - Schlegel, Nicolas A1 - Burek, Malgorzata A1 - Karnati, Srikanth A1 - Wunder, Christian A1 - Förster, Carola Y. T1 - Isosteviol sodium (STVNA) reduces pro-inflammatory cytokine IL-6 and GM-CSF in an in vitro murine stroke model of the blood–brain barrier (BBB) JF - Pharmaceutics N2 - Early treatment with glucocorticoids could help reduce both cytotoxic and vasogenic edema, leading to improved clinical outcome after stroke. In our previous study, isosteviol sodium (STVNA) demonstrated neuroprotective effects in an in vitro stroke model, which utilizes oxygen-glucose deprivation (OGD). Herein, we tested the hypothesis that STVNA can activate glucocorticoid receptor (GR) transcriptional activity in brain microvascular endothelial cells (BMECs) as previously published for T cells. STVNA exhibited no effects on transcriptional activation of the glucocorticoid receptor, contrary to previous reports in Jurkat cells. However, similar to dexamethasone, STVNA inhibited inflammatory marker IL-6 as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. Based on these results, STVNA proves to be beneficial as a possible prevention and treatment modality for brain ischemia-reperfusion injury-induced blood–brain barrier (BBB) dysfunction. KW - IL-6 KW - ischemia KW - isosteviol sodium (STVNA) KW - dexamethasone KW - glucocorticoid receptor KW - cerebEND Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286275 SN - 1999-4923 VL - 14 IS - 9 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Nagai, Michiaki A1 - Ergün, Süleyman A1 - Braunger, Barbara M. A1 - Förster, Carola Y. T1 - The protective effects of neurotrophins and microRNA in diabetic retinopathy, nephropathy and heart failure via regulating endothelial function JF - Biomolecules N2 - Diabetes mellitus is a common disease affecting more than 537 million adults worldwide. The microvascular complications that occur during the course of the disease are widespread and affect a variety of organ systems in the body. Diabetic retinopathy is one of the most common long-term complications, which include, amongst others, endothelial dysfunction, and thus, alterations in the blood-retinal barrier (BRB). This particularly restrictive physiological barrier is important for maintaining the neuroretina as a privileged site in the body by controlling the inflow and outflow of fluid, nutrients, metabolic end products, ions, and proteins. In addition, people with diabetic retinopathy (DR) have been shown to be at increased risk for systemic vascular complications, including subclinical and clinical stroke, coronary heart disease, heart failure, and nephropathy. DR is, therefore, considered an independent predictor of heart failure. In the present review, the effects of diabetes on the retina, heart, and kidneys are described. In addition, a putative common microRNA signature in diabetic retinopathy, nephropathy, and heart failure is discussed, which may be used in the future as a biomarker to better monitor disease progression. Finally, the use of miRNA, targeted neurotrophin delivery, and nanoparticles as novel therapeutic strategies is highlighted. KW - diabetic retinopathy KW - diabetes mellitus KW - microvascular complications KW - diabetic nephropathy KW - heart failure KW - microRNA KW - neurotrophins Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285966 SN - 2218-273X VL - 12 IS - 8 ER - TY - JOUR A1 - Ergün, Süleyman A1 - Wörsdörfer, Philipp T1 - Organoids, assembloids and embryoids: New avenues for developmental biology, disease modeling, drug testing and toxicity assessment without animal experimentation JF - Organoids N2 - No abstract available KW - developmental biology KW - organoids Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284101 SN - 2674-1172 VL - 1 IS - 1 SP - 37 EP - 40 ER - TY - JOUR A1 - Schmidt, Sven A1 - Alt, Yvonne A1 - Deoghare, Nikita A1 - Krüger, Sarah A1 - Kern, Anna A1 - Rockel, Anna Frederike A1 - Wagner, Nicole A1 - Ergün, Süleyman A1 - Wörsdörfer, Philipp T1 - A blood vessel organoid model recapitulating aspects of vasculogenesis, angiogenesis and vessel wall maturation JF - Organoids N2 - Blood vessel organoids are an important in vitro model to understand the underlying mechanisms of human blood vessel development and for toxicity testing or high throughput drug screening. Here we present a novel, cost-effective, and easy to manufacture vascular organoid model. To engineer the organoids, a defined number of human induced pluripotent stem cells are seeded in non-adhesive agarose coated wells of a 96-well plate and directed towards a lateral plate mesoderm fate by activation of Wnt and BMP4 signaling. We observe the formation of a circular layer of angioblasts around days 5–6. Induced by VEGF application, CD31\(^+\) vascular endothelial cells appear within this vasculogenic zone at approximately day 7 of organoid culture. These cells arrange to form a primitive vascular plexus from which angiogenic sprouting is observed after 10 days of culture. The differentiation outcome is highly reproducible, and the size of organoids is scalable depending on the number of starting cells. We observe that the initial vascular ring forms at the interface between two cell populations. The inner cellular compartment can be distinguished from the outer by the expression of GATA6, a marker of lateral plate mesoderm. Finally, 14-days-old organoids were transplanted on the chorioallantois membrane of chicken embryos resulting in a functional connection of the human vascular network to the chicken circulation. Perfusion of the vessels leads to vessel wall maturation and remodeling as indicated by the formation of a continuous layer of smooth muscle actin expressing cells enwrapping the endothelium. In summary, our organoid model recapitulates human vasculogenesis, angiogenesis as well as vessel wall maturation and therefore represents an easy and cost-effective tool to study all steps of blood vessel development and maturation directly in the human setting without animal experimentation. KW - organoid KW - blood vessel KW - vasculogenesis KW - angiogenesis KW - induced pluripotent stem cells Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284043 SN - 2674-1172 VL - 1 IS - 1 SP - 41 EP - 53 ER - TY - JOUR A1 - Gergs, Ulrich A1 - Jahn, Tina A1 - Schulz, Nico A1 - Großmann, Claudia A1 - Rueckschloss, Uwe A1 - Demus, Uta A1 - Buchwalow, Igor B. A1 - Neumann, Joachim T1 - Protein phosphatase 2A improves cardiac functional response to ischemia and sepsis JF - International Journal of Molecular Sciences N2 - Reversible protein phosphorylation is a posttranslational modification of regulatory proteins involved in cardiac signaling pathways. Here, we focus on the role of protein phosphatase 2A (PP2A) for cardiac gene expression and stress response using a transgenic mouse model with cardiac myocyte-specific overexpression of the catalytic subunit of PP2A (PP2A-TG). Gene and protein expression were assessed under basal conditions by gene chip analysis and Western blotting. Some cardiac genes related to the cell metabolism and to protein phosphorylation such as kinases and phosphatases were altered in PP2A-TG compared to wild type mice (WT). As cardiac stressors, a lipopolysaccharide (LPS)-induced sepsis in vivo and a global cardiac ischemia in vitro (stop-flow isolated perfused heart model) were examined. Whereas the basal cardiac function was reduced in PP2A-TG as studied by echocardiography or as studied in the isolated work-performing heart, the acute LPS- or ischemia-induced cardiac dysfunction deteriorated less in PP2A-TG compared to WT. From the data, we conclude that increased PP2A activity may influence the acute stress tolerance of cardiac myocytes. KW - protein phosphorylation KW - PP2A KW - transgenic mice KW - heart KW - LPS KW - sepsis KW - ischemia Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284035 SN - 1422-0067 VL - 23 IS - 9 ER - TY - THES A1 - Höhn, Marie T1 - Veränderung der Tumorimmunumgebung muriner Mamma-Karzinome durch Inhibierung der Kollagensynthese T1 - Alteration of the tumor immune environment in murine mamma carcinomas by inhibition of collagen synthesis N2 - Das Mamma-Karzinom gehört zu den sogenannten desmoplastischen Tumorarten. Hierbei handelt es sich um Tumoren mit erhöhter Ansammlung von Bindegewebszellen und einer Akkumulation von Extrazellulärer Matrix (EZM). Diese verdichtete EZM wirkt sowohl auf mechanischer als auch auf Signalweg-vermittelter Ebene als eine Barriere, welche die therapeutische Wirksamkeit erheblich vermindert. Einer der Hauptbestandteile der EZM ist Kollagen. Durch Anwendung von Präparaten, welche die Kollagensynthese und -reifung inhibieren, kann die rigide Struktur aufgelockert werden. Daraus ergibt sich eine verbesserte Versorgung mit Nährstoffen und eine verbesserte Infiltrationsmöglichkeit für Immunzellen. Dies ist für die Effizienz der Immuntherapie, welche sich in den letzten Jahren als vielversprechende Alternative zu den Grundsäulen der Krebstherapie entwickelt hat, unabdinglich. In der vorliegenden Arbeit wurden murine Mamma-Karzinome der 4T1-Linie nach Behandlung mit EZM-destabilisierenden Kollageninhibitoren auf ihre Immunumgebung hin untersucht. Verwendet wurden drei Wirkstoffe, welche an unterschiedlichen Punkten in die Kollagensynthese und -reifung eingreifen: βAPN als LOX(L)-Inhibitor, 1,4-DPCA als P4HA-Inhibitor und Minoxidil als LH-Inhibitor. Die Behandlung führte zu einem deutlichen Anstieg aller untersuchten Immunzellen und deutet somit auf eine verbesserte Infiltrationsmöglichkeit hin. Zudem wurde die Expression maligner Signalwege, wie die der Angiogenese, Hypoxie, Metastasierungsneigung, Invasivität und Immunsuppression, verringert und tumorsuppressive Immunantworten verstärkt. Die Kollageninhibition hatte zusätzlich ein verringertes Tumorwachstum und eine Reduktion der Blutgefäßdichte zufolge. Als Fazit gilt es festzuhalten, dass die Verwendung von Kollageninhibitoren in der Immuntherapie eine vielversprechende Option zur Verbesserung der Effizienz dieser Therapeutika darstellt. Diese Erkenntnis gilt es im Rahmen künftiger wissenschaftlicher Untersuchungen weiterzuentwickeln. N2 - The mamma carcinoma is a desmoplastic tumor which shows an accumulation of fibrotic tissue and of extracellular matrix (ECM). This highly dense ECM acts as a physical and signaling-mediated barrier reducing the efficacy of various therapeutic approaches. One of the main components of the ECM is collagen. The rigid structure can be loosened by drugs which inhibit collagen synthesis and maturation. This potentially leads to improved infiltration with nutrients and a better access for immune cells. These are absolutely necessary for the effectiveness of the immune therapy that has been established as a promising alternative approach in the last years in addition to the classical cancer therapy options. In this dissertation murine mamma carcinomas of the 4T1-tumor cell line were treated with collagen inhibitors, with the aim to destabilize the rigid ECM and analyze following changes of the immune environment. The drugs, that were used, inhibit at different stages collagen synthesis and maturation: βAPN as a LOX(L)-inhibitor, 1,4-DPCA as a P4HA-inhibitor and Minoxidil as a LH-inhibitor. The treatment led to an accumulation of different kinds of immune cells which shows the improved infiltration. Furthermore, malignant pathways concerning angiogenesis, hypoxia, invasiveness, metastasis, and immunosuppression are reduced. Tumor suppressive immune responses are enhanced. Moreover, we could ascertain a reduced tumor growth and microvessel density after treatment. All in all, the tumors show, because of the changed quantity and constellation of immune cells, a stronger immune stimulating function. This embodies the promising potential of the usage of collagen inhibitors as an additional treatment to immune therapy to facilitate its efficacy, which has to be examined by further studies. KW - Brustkrebs KW - Kollagen KW - Immunsystem KW - Inhibition KW - Tumor KW - Tumorimmunumgebung KW - Kollageninhibition Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284929 ER - TY - JOUR A1 - Schlecht, Anja A1 - Wolf, Julian A1 - Boneva, Stefaniya A1 - Prinz, Gabriele A1 - Braunger, Barbara M. A1 - Wieghofer, Peter A1 - Agostini, Hansjürgen A1 - Schlunck, Günther A1 - Lange, Clemens T1 - Transcriptional and distributional profiling of microglia in retinal angiomatous proliferation JF - International Journal of Molecular Sciences N2 - Macular neovascularization type 3, formerly known as retinal angiomatous proliferation (RAP), is a hallmark of age-related macular degeneration and is associated with an accumulation of myeloid cells, such as microglia (MG) and infiltrating blood-derived macrophages (MAC). However, the contribution of MG and MAC to the myeloid cell pool at RAP sites and their exact functions remain unknown. In this study, we combined a microglia-specific reporter mouse line with a mouse model for RAP to identify the contribution of MG and MAC to myeloid cell accumulation at RAP and determined the transcriptional profile of MG using RNA sequencing. We found that MG are the most abundant myeloid cell population around RAP, whereas MAC are rarely, if ever, associated with late stages of RAP. RNA sequencing of RAP-associated MG showed that differentially expressed genes mainly contribute to immune-associated processes, including chemotaxis and migration in early RAP and proliferative capacity in late RAP, which was confirmed by immunohistochemistry. Interestingly, MG upregulated only a few angiomodulatory factors, suggesting a rather low angiogenic potential. In summary, we showed that MG are the dominant myeloid cell population at RAP sites. Moreover, MG significantly altered their transcriptional profile during RAP formation, activating immune-associated processes and exhibiting enhanced proliferation, however, without showing substantial upregulation of angiomodulatory factors. KW - AMD KW - Mactel 2 KW - macular neovascularization KW - MNV type 3 KW - retinal angiomatous proliferation KW - RAP KW - microglia KW - RNA sequencing KW - Cx3cr1 KW - CreERT2 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284072 SN - 1422-0067 VL - 23 IS - 7 ER - TY - JOUR A1 - Schlecht, Anja A1 - Thien, Adrian A1 - Wolf, Julian A1 - Prinz, Gabriele A1 - Agostini, Hansjürgen A1 - Schlunck, Günther A1 - Wieghofer, Peter A1 - Boneva, Stefaniya A1 - Lange, Clemens T1 - Immunosenescence in choroidal neovascularization (CNV) — Transcriptional profiling of naïve and CNV-associated retinal myeloid cells during aging JF - International Journal of Molecular Sciences N2 - Immunosenescence is considered a possible factor in the development of age-related macular degeneration and choroidal neovascularization (CNV). However, age-related changes of myeloid cells (MCs), such as microglia and macrophages, in the healthy retina or during CNV formation are ill-defined. In this study, Cx3cr1-positive MCs were isolated by fluorescence-activated cell sorting from six-week (young) and two-year-old (old) Cx3cr1\(^{GFP/+}\) mice, both during physiological aging and laser-induced CNV development. High-throughput RNA-sequencing was performed to define the age-dependent transcriptional differences in MCs during physiological aging and CNV development, complemented by immunohistochemical characterization and the quantification of MCs, as well as CNV size measurements. These analyses revealed that myeloid cells change their transcriptional profile during both aging and CNV development. In the steady state, senescent MCs demonstrated an upregulation of factors contributing to cell proliferation and chemotaxis, such as Cxcl13 and Cxcl14, as well as the downregulation of microglial signature genes. During CNV formation, aged myeloid cells revealed a significant upregulation of angiogenic factors such as Arg1 and Lrg1 concomitant with significantly enlarged CNV and an increased accumulation of MCs in aged mice in comparison to young mice. Future studies need to clarify whether this observation is an epiphenomenon or a causal relationship to determine the role of immunosenescence in CNV formation. KW - age-related macular degeneration (AMD) KW - choroidal neovascularization (CNV) KW - aging KW - immunosenescence KW - microglia KW - myeloid cells KW - RNA-sequencing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284342 SN - 1422-0067 VL - 22 IS - 24 ER - TY - THES A1 - Ruf, Theresa T1 - Immunhistologische Analyse der Effekte einer Kombinationstherapie im Brustkrebsmodell: Inhibition der Kollagensynthese durch PLOD-2-Blockade und Inhibierung des PD-1/PD-L1 Checkpoints T1 - Immunohistochemical analysis of the effects of combination therapy in the breast cancer model: Inhibition of Collagen Synthesis by PLOD-2 blockade and inhibition of the PD-1/PD-L1 checkpoint N2 - In dieser Arbeit wurden die histologischen und immunhistologischen Auswirkungen der Kombination aus Inhibition des PD-1/PD-1L-Checkpoints und PLOD-2-Blockade untersucht. Es konnte festgestellt werden, dass die Immuntherapie anschlägt und dabei als Monotherapie die stärksten Tumornekrosen induzierte. Das Ansprechen auf die Immuntherapie mit BMS-1166 war jedoch sehr unterschiedlich. In der Kombination mit dem PLOD-2-Inhibitor Minoxidil wurden hingegen einheitlichere, aber auch geringere Nekroseanteile festgestellt. Dabei muss jedoch beachtet werden, dass die Kombinationsbehandlung die stärkste Auswirkung auf das Tumorwachstum hatte. So waren diese Tumore die kleinsten und leichtesten, was in Zusammenhang mit dem ausgeprägten kollagenen Netzwerk dieser Gruppe stehen könnte. Die Kombination zeigte keine Auswirkung auf die Tumorvaskularisierung und die Zellteilungsaktivität, sowie auch keine Auffälligkeiten bezüglich der Infiltration mit Immunzellen. Lungenmetastasen kamen in allen Behandlungsgruppen vor. Bei der Kombinationsbehandlung waren jedoch die durchschnittlich größten Lungenmetastasen festzustellen. In dieser Arbeit konnte keine klare signifikante Verbesserung der Brustkrebstherapie durch die Kombination von Inhibition der Kollagensynthese durch PLOD-2-Blockade und Inhibierung des PD-1/PD-1L-Checkpoints aufgezeigt werden. Das kollagene Netzwerk war auffällig und sollte genauer untersucht werden. Es lohnt sich weiter an Kombinationen aus Immuntherapeutikum und EZM-Destabilisierung zu arbeiten. Die TME muss dabei weiterhin Ansatzpunkt der Forschung bleiben, um eine erleichterte Penetration der Medikamente in den Tumor zu erzielen. Hier ist der Austausch des Medikaments zur EZM-Destabilisierung empfehlenswert. Die LOX-Inhibierung hat sich bereits in Kombination mit Chemotherapie als vorteilhaft erwiesen (Rossow et al., 2018) und sollte nachfolgend in einem ähnlichen Versuchsaufbau mit dem Immuntherapeutikum BMS-1166 ausprobiert werden. N2 - In this thesis, the histological and immunohistological effects of the combination of PD-1/PD-1L checkpoint inhibition and PLOD-2 blockade were investigated. It was found, that the immunotherapy was effective and induced the strongest tumor necrosis as monotherapy. The response to immunotherapy with BMS-1166 was highly variable. In combination with the PLOD-2 inhibitor minoxidil, more uniform but also lower levels of necrosis proportions were observed. It must be noted, that the combination treatment had the strongest effect on tumor growth. Thus tumors were the smallest and lightest, which may be related to the pronounced collagenous network of this group. The combination showed no effect on tumor vascularization and cell division activity, as well as no abnormalities regarding infiltration with immune cells. Lung metastases occurred in all treatment groups. However, in the combination treatment group were observed the largest lung metastases. In this thesis, no clear significant improvement of breast cancer therapy could be shown with the combination of inhibition of collagen synthesis by PLOD-2 blockade and inhibition of the PD-1/PD-1L checkpoint. The collagen network was conspicuous and should be investigated further. It is worthwhile to further investigate combinations of immunotherapeutic agents and ECM destabilization. The TME must remain the starting point of research to facilitate drug penetration into the tumor. Here, the replacement of the Drug for ECM destabilization is recommended. LOX inhibition has already been shown to be beneficial in combination with chemotherapy (Rossow et al., 2018) and should be subsequently tested in a similar experimental setting with the immunotherapeutic BMS-1166. KW - Immunhistochemie KW - Kombinationstherapie KW - Minoxidil KW - PD-1/PD-L1 KW - Immuncytochemie KW - Immun-Checkpoint Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320380 ER - TY - JOUR A1 - Rajendran, Ranjithkumar A1 - Rajendran, Vinothkumar A1 - Giraldo-Velasquez, Mario A1 - Megalofonou, Fevronia-Foivi A1 - Gurski, Fynn A1 - Stadelmann, Christine A1 - Karnati, Srikanth A1 - Berghoff, Martin T1 - Oligodendrocyte-specific deletion of FGFR1 reduces cerebellar inflammation and neurodegeneration in MOG\(_{35-55}\)-induced EAE JF - International Journal of Molecular Sciences N2 - Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1\(^{ind−/−}\) was achieved by tamoxifen application, EAE was induced using the MOG\(_{35-55}\) peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1\(^{ind−/−}\) mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1\(^{ind−/−}\)mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1\(^{ind−/−}\) mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1\(^{ind−/−}\) mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS. KW - FGFR1 KW - oligodendrocytes KW - demyelination KW - inflammation KW - cerebellum KW - EAE KW - MS Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284296 SN - 1422-0067 VL - 22 IS - 17 ER - TY - JOUR A1 - Koeniger, Tobias A1 - Kuerten, Stefanie T1 - Splitting the "unsplittable": Dissecting resident and infiltrating macrophages in experimental autoimmune encephalomyelitis JF - International Journal of Molecular Sciences N2 - Macrophages predominate the inflammatory landscape within multiple sclerosis (MS) lesions, not only regarding cellularity but also with respect to the diverse functions this cell fraction provides during disease progression and remission. Researchers have been well aware of the fact that the macrophage pool during central nervous system (CNS) autoimmunity consists of a mixture of myeloid cells. Yet, separating these populations to define their unique contribution to disease pathology has long been challenging due to their similar marker expression. Sophisticated lineage tracing approaches as well as comprehensive transcriptome analysis have elevated our insight into macrophage biology to a new level enabling scientists to dissect the roles of resident (microglia and non-parenchymal macrophages) and infiltrating macrophages with unprecedented precision. To do so in an accurate way, researchers have to know their toolbox, which has been filled with diverse, discriminating approaches from decades of studying neuroinflammation in animal models. Every method has its own strengths and weaknesses, which will be addressed in this review. The focus will be on tools to manipulate and/or identify different macrophage subgroups within the injured murine CNS. KW - CNS KW - distinction KW - experimental autoimmune encephalomyelitis KW - inflammation KW - macrophages KW - markers KW - microglia KW - monocytes Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285067 SN - 1422-0067 VL - 18 IS - 10 ER - TY - JOUR A1 - Wang, Hongjie A1 - Karnati, Srikanth A1 - Madhusudhan, Thati T1 - Regulation of the homeostatic unfolded protein response in diabetic nephropathy JF - Pharmaceuticals N2 - A growing body of scientific evidence indicates that protein homeostasis, also designated as proteostasis, is causatively linked to chronic diabetic nephropathy (DN). Experimental studies have demonstrated that the insulin signaling in podocytes maintain the homeostatic unfolded protein response (UPR). Insulin signaling via the insulin receptor non-canonically activates the spliced X-box binding protein-1 (sXBP1), a highly conserved endoplasmic reticulum (ER) transcription factor, which regulates the expression of genes that control proteostasis. Defective insulin signaling in mouse models of diabetes or the genetic disruption of the insulin signaling pathway in podocytes propagates hyperglycemia induced maladaptive UPR and DN. Insulin resistance in podocytes specifically promotes activating transcription factor 6 (ATF6) dependent pathogenic UPR. Akin to insulin, recent studies have identified that the cytoprotective effect of anticoagulant serine protease-activated protein C (aPC) in DN is mediated by sXBP1. In mouse models of DN, treatment with chemical chaperones that improve protein folding provides an additional benefit on top of currently used ACE inhibitors. Understanding the molecular mechanisms that transmute renal cell specific adaptive responses and that deteriorate renal function in diabetes will enable researchers to develop new therapeutic regimens for DN. Within this review, we focus on the current understanding of homeostatic mechanisms by which UPR is regulated in DN. KW - unfolded protein response KW - ER stress KW - diabetic nephropathy KW - insulin signaling KW - aPC KW - podocytes KW - XBP1 KW - ATF6 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267143 SN - 1424-8247 VL - 15 IS - 4 ER - TY - JOUR A1 - Feldheim, Jonas A1 - Wend, David A1 - Lauer, Mara J. A1 - Monoranu, Camelia M. A1 - Glas, Martin A1 - Kleinschnitz, Christoph A1 - Ernestus, Ralf-Ingo A1 - Braunger, Barbara M. A1 - Meybohm, Patrick A1 - Hagemann, Carsten A1 - Burek, Malgorzata T1 - Protocadherin Gamma C3 (PCDHGC3) is strongly expressed in glioblastoma and its high expression is associated with longer progression-free survival of patients JF - International Journal of Molecular Sciences N2 - Protocadherins (PCDHs) belong to the cadherin superfamily and represent the largest subgroup of calcium-dependent adhesion molecules. In the genome, most PCDHs are arranged in three clusters, α, β, and γ on chromosome 5q31. PCDHs are highly expressed in the central nervous system (CNS). Several PCDHs have tumor suppressor functions, but their individual role in primary brain tumors has not yet been elucidated. Here, we examined the mRNA expression of PCDHGC3, a member of the PCDHγ cluster, in non-cancerous brain tissue and in gliomas of different World Health Organization (WHO) grades and correlated it with the clinical data of the patients. We generated a PCDHGC3 knockout U343 cell line and examined its growth rate and migration in a wound healing assay. We showed that PCDHGC3 mRNA and protein were significantly overexpressed in glioma tissue compared to a non-cancerous brain specimen. This could be confirmed in glioma cell lines. High PCDHGC3 mRNA expression correlated with longer progression-free survival (PFS) in glioma patients. PCDHGC3 knockout in U343 resulted in a slower growth rate but a significantly faster migration rate in the wound healing assay and decreased the expression of several genes involved in WNT signaling. PCDHGC3 expression should therefore be further investigated as a PFS-marker in gliomas. However, more studies are needed to elucidate the molecular mechanisms underlying the PCDHGC3 effects. KW - glioblastoma multiforme KW - glioma KW - astrocytoma KW - recurrence KW - relapse KW - mRNA KW - protein KW - brain KW - expression KW - PCDHGC3 KW - WNT signaling Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284433 SN - 1422-0067 VL - 23 IS - 15 ER - TY - JOUR A1 - Behera, Ananyaashree A1 - Jain, Preeti A1 - Ganguli, Geetanjali A1 - Biswas, Mainak A1 - Padhi, Avinash A1 - Pattanaik, Kali Prasad A1 - Nayak, Barsa A1 - Ergün, Süleyman A1 - Hagens, Kristine A1 - Redinger, Natalja A1 - Saqib, Mohd A1 - Mishra, Bibhuti B. A1 - Schaible, Ulrich E. A1 - Karnati, Srikanth A1 - Sonawane, Avinash T1 - Mycobacterium tuberculosis acetyltransferase suppresses oxidative stress by inducing peroxisome formation in macrophages JF - International Journal of Molecular Sciences N2 - Mycobacterium tuberculosis (Mtb) inhibits host oxidative stress responses facilitating its survival in macrophages; however, the underlying molecular mechanisms are poorly understood. Here, we identified a Mtb acetyltransferase (Rv3034c) as a novel counter actor of macrophage oxidative stress responses by inducing peroxisome formation. An inducible Rv3034c deletion mutant of Mtb failed to induce peroxisome biogenesis, expression of the peroxisomal β-oxidation pathway intermediates (ACOX1, ACAA1, MFP2) in macrophages, resulting in reduced intracellular survival compared to the parental strain. This reduced virulence phenotype was rescued by repletion of Rv3034c. Peroxisome induction depended on the interaction between Rv3034c and the macrophage mannose receptor (MR). Interaction between Rv3034c and MR induced expression of the peroxisomal biogenesis proteins PEX5p, PEX13p, PEX14p, PEX11β, PEX19p, the peroxisomal membrane lipid transporter ABCD3, and catalase. Expression of PEX14p and ABCD3 was also enhanced in lungs from Mtb aerosol-infected mice. This is the first report that peroxisome-mediated control of ROS balance is essential for innate immune responses to Mtb but can be counteracted by the mycobacterial acetyltransferase Rv3034c. Thus, peroxisomes represent interesting targets for host-directed therapeutics to tuberculosis. KW - peroxisome KW - Rv3034c KW - acetyltransferase KW - macrophages KW - oxidative stress KW - Mycobacterium tuberculosis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284080 SN - 1422-0067 VL - 23 IS - 5 ER - TY - JOUR A1 - Kleefeldt, Florian A1 - Upcin, Berin A1 - Bömmel, Heike A1 - Schulz, Christian A1 - Eckner, Georg A1 - Allmanritter, Jan A1 - Bauer, Jochen A1 - Braunger, Barbara A1 - Rueckschloss, Uwe A1 - Ergün, Süleyman T1 - Bone marrow-independent adventitial macrophage progenitor cells contribute to angiogenesis JF - Cell Death & Disease N2 - Pathological angiogenesis promotes tumor growth, metastasis, and atherosclerotic plaque rupture. Macrophages are key players in these processes. However, whether these macrophages differentiate from bone marrow-derived monocytes or from local vascular wall-resident stem and progenitor cells (VW-SCs) is an unresolved issue of angiogenesis. To answer this question, we analyzed vascular sprouting and alterations in aortic cell populations in mouse aortic ring assays (ARA). ARA culture leads to the generation of large numbers of macrophages, especially within the aortic adventitia. Using immunohistochemical fate-mapping and genetic in vivo-labeling approaches we show that 60% of these macrophages differentiate from bone marrow-independent Ly6c\(^{+}\)/Sca-1\(^{+}\) adventitial progenitor cells. Analysis of the NCX\(^{−/-}\) mouse model that genetically lacks embryonic circulation and yolk sac perfusion indicates that at least some of those progenitor cells arise yolk sac-independent. Macrophages represent the main source of VEGF in ARA that vice versa promotes the generation of additional macrophages thereby creating a pro-angiogenetic feedforward loop. Additionally, macrophage-derived VEGF activates CD34\(^{+}\) progenitor cells within the adventitial vasculogenic zone to differentiate into CD31\(^{+}\) endothelial cells. Consequently, depletion of macrophages and VEGFR2 antagonism drastically reduce vascular sprouting activity in ARA. In summary, we show that angiogenic activation induces differentiation of macrophages from bone marrow-derived as well as from bone marrow-independent VW-SCs. The latter ones are at least partially yolk sac-independent, too. Those VW-SC-derived macrophages critically contribute to angiogenesis, making them an attractive target to interfere with pathological angiogenesis in cancer and atherosclerosis as well as with regenerative angiogenesis in ischemic cardiovascular disorders. KW - macrophages KW - angiogenesis KW - bone marrow-derived monocytes Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299724 VL - 13 IS - 3 ER - TY - JOUR A1 - Jordan, Martin C. A1 - Bröer, David A1 - Fischer, Christian A1 - Heilig, Philipp A1 - Gilbert, Fabian A1 - Hölscher-Doht, Stefanie A1 - Kalogirou, Charis A1 - Popp, Kevin A1 - Grunz, Jan-Peter A1 - Huflage, Henner A1 - Jakubietz, Rafael G. A1 - Ergün, Süleyman A1 - Meffert, Rainer H. T1 - Development and preclinical evaluation of a cable-clamp fixation device for a disrupted pubic symphysis JF - Communications Medicine N2 - Background Traumatic separation of the pubic symphysis can destabilize the pelvis and require surgical fixation to reduce symphyseal gapping. The traditional approach involves open reduction and the implantation of a steel symphyseal plate (SP) on the pubic bone to hold the reposition. Despite its widespread use, SP-fixation is often associated with implant failure caused by screw loosening or breakage. Methods To address the need for a more reliable surgical intervention, we developed and tested two titanium cable-clamp implants. The cable served as tensioning device while the clamp secured the cable to the bone. The first implant design included a steel cable anterior to the pubic symphysis to simplify its placement outside the pelvis, and the second design included a cable encircling the pubic symphysis to stabilize the anterior pelvic ring. Using highly reproducible synthetic bone models and a limited number of cadaver specimens, we performed a comprehensive biomechanical study of implant stability and evaluated surgical feasibility. Results We were able to demonstrate that the cable-clamp implants provide stability equivalent to that of a traditional SP-fixation but without the same risks of implant failure. We also provide detailed ex vivo evaluations of the safety and feasibility of a trans-obturator surgical approach required for those kind of fixation. Conclusion We propose that the developed cable-clamp fixation devices may be of clinical value in treating pubic symphysis separation. KW - pubic symphysis KW - cable-clamp implants KW - SP-fixation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299800 VL - 2 IS - 1 ER - TY - THES A1 - Müller, Jonathan T1 - Charakterisierung von CEACAM1 in der Retina und Choroidea am Mausmodell T1 - Characterization of CEACAM1 in retina and choroid in mouse model N2 - Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) ist ein multifunktionales Zell-Zell Adhäsionsprotein, das in eine Vielzahl an zellulären Prozessen involviert ist, wie zum Beispiel der Differenzierung von Geweben, der Tumorsuppression, Metastasierung, Angiogenese und Apoptose. Außerdem hat es modulierende Eigenschaften auf die angeborene und erworbene Immunantwort. In der vorliegenden Arbeit charakterisierte ich initial die Lokalisation und die CEACAM1-exprimierenden Zelltypen im Auge und bestimmte quantitativ die Expression von Ceacam1 in der Retina und Choroidea zu unterschiedlichen Zeitpunkten. Es zeigte sich hierbei, dass Ceacam1 zu allen untersuchten Zeitpunkten, sowohl während der Entwicklung als auch im adulten retinalen und choroidalen Gewebe nachweisbar war. Mittels Immunhistochemie konnte die Expression von CEACAM1 im Corneaepithel, den Gefäßen der Iris und des Ziliarkörpers, im nicht-pigmentierten Epithel des Ziliarkörpers, sowie in den retinalen und choroidalen Gefäßen nachgewiesen werden. Durch Doppelfärbung mit Kollagen IV konnte die endotheliale Expression von CEACAM1 in den Endothelzellen der Gefäße bestätigt werden. Im zweiten Teil meiner Arbeit untersuchte ich die Funktion von CEACAM1 im Auge und verglich dazu wildtypische Retinae mit Cc1-/--Retinae. Es zeigten sich keine offensichtlichen morphologischen Veränderungen der retinalen Schichten und die anschließend durchgeführten morphometrischen Analysen der Schichtdicken der retinalen Neurone zeigte keine Anzeichen einer Neurodegeneration. Allerdings waren in Cc1-/--Retinae kleine Zysten und IBA1 positive, phagozytisch aktive Zellen im subneuroretinalen Raum, also dem Bereich zwischen RPE und den Außensegmenten der Photorezeptoren zu erkennen. Die anschließend durchgeführten Expressionsanalysen immunmodulierender Faktoren und von Mitgliedern des TGF-β-Signalwegs in retinalen und choroidealen Proben wildtypischer und Cc1-/--Mäusen zeigten keine veränderte Expression für Iba1, Ccl2 sowie Tnf-α. Jedoch konnten signifikant erhöhte Werte für TGF-β1 in der Gruppe der 2-4 als auch der Gruppe der 9 Monate alten Cc1-/--Retinae im Vergleich zu wildtypischen Retinae nachgewiesen werden. Basierend auf den Daten der vorliegenden Arbeit kann geschlussfolgert werden, dass die Deletion von CEACAM1 unter physiologischen Bedingungen die Struktur der Retina und Choroidea nicht offensichtlich beeinflusst. Allerdings führt die Deletion zu erhöhten Tgfβ1 Spiegeln in der Retina und zur Aktivierung und Akkumulation von IBA1 positiven Zellen im subneuroretinalen Raum. N2 - Carcinoembryonic antigen-related cell adhesion molecule 1 (Ceacam1, Cc1) is a multi-functional cell– cell adhesion protein, involved in the differentiation and arrangement of tissue three-dimensional structure, tumor suppression, metastasis, angiogenesis and apoptosis. Moreover, it has been shown to modulate innate and adaptive immune responses. Amongst others, it is expressed in vascular endothelial cells during vascular development and in adult blood vessels that are activated by angiogenic processes. In this study, we aimed to learn about the function of Ceacam1 in the eye. We therefore characterized the cell type specific expression of Ceacam1 in the ocular tissues, analyzed its retinal and choroidal expression at different developmental time points and studied the ocular morphology of Ceacam1- knockout (Cc1-/-) mice. Finally, we analyzed the molecular expression levels of immune modulating factors and members of the TGF-β signaling family in retinal and choroidal tissues of Cc1-/- mice. Our data show that Ceacam1 is expressed in developing and mature retinal and choroidal endothelial cells. Furthermore, its deletion promotes the accumulation of phagocytic active and Iba1-positive cells in the subretinal space and significant upregulated TGF-β1 expression levels in the retina. KW - Angiogenese KW - Vaskularisation KW - Netzhaut KW - Aderhaut KW - CEACAM1 KW - Retina KW - Choroidea Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305546 ER - TY - JOUR A1 - Bielmeier, Christina B. A1 - Schmitt, Sabrina I. A1 - Kleefeldt, Nikolai A1 - Boneva, Stefaniya K. A1 - Schlecht, Anja A1 - Vallon, Mario A1 - Tamm, Ernst R. A1 - Hillenkamp, Jost A1 - Ergün, Süleyman A1 - Neueder, Andreas A1 - Braunger, Barbara M. T1 - Deficiency in retinal TGFβ signaling aggravates neurodegeneration by modulating pro-apoptotic and MAP kinase pathways JF - International Journal of Molecular Sciences N2 - Transforming growth factor β (TGFβ) signaling has manifold functions such as regulation of cell growth, differentiation, migration, and apoptosis. Moreover, there is increasing evidence that it also acts in a neuroprotective manner. We recently showed that TGFβ receptor type 2 (Tgfbr2) is upregulated in retinal neurons and Müller cells during retinal degeneration. In this study we investigated if this upregulation of TGFβ signaling would have functional consequences in protecting retinal neurons. To this end, we analyzed the impact of TGFβ signaling on photoreceptor viability using mice with cell type-specific deletion of Tgfbr2 in retinal neurons and Müller cells (Tgfbr2\(_{ΔOC}\)) in combination with a genetic model of photoreceptor degeneration (VPP). We examined retinal morphology and the degree of photoreceptor degeneration, as well as alterations of the retinal transcriptome. In summary, retinal morphology was not altered due to TGFβ signaling deficiency. In contrast, VPP-induced photoreceptor degeneration was drastically exacerbated in double mutant mice (Tgfbr2\(_{ΔOC}\); VPP) by induction of pro-apoptotic genes and dysregulation of the MAP kinase pathway. Therefore, TGFβ signaling in retinal neurons and Müller cells exhibits a neuroprotective effect and might pose promising therapeutic options to attenuate photoreceptor degeneration in humans. KW - TGFβ signaling KW - retina KW - retinitis pigmentosa KW - neuro-/photoreceptor degeneration KW - MAP kinase pathway KW - ferroptosis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-283971 SN - 1422-0067 VL - 23 IS - 5 ER - TY - JOUR A1 - Karnati, Srikanth A1 - Guntas, Gulcan A1 - Rajendran, Ranjithkumar A1 - Shityakov, Sergey A1 - Höring, Marcus A1 - Liebisch, Gerhard A1 - Kosanovic, Djuro A1 - Ergün, Süleyman A1 - Nagai, Michiaki A1 - Förster, Carola Y. T1 - Quantitative lipidomic analysis of Takotsubo syndrome patients' serum JF - Frontiers in Cardiovascular Medicine N2 - Takotsubo syndrome (TTS), also known as the transient left ventricular apical ballooning syndrome, is in contemporary times known as novel acute cardiac syndrome. It is characterized by transient left ventricular apical akinesis and hyperkinesis of the basal left ventricular portions. Although the precise etiology of TTS is unknown, events like the sudden release of stress hormones, such as the catecholamines and the increased inflammatory status might be plausible causes leading to the cardiovascular pathologies. Recent studies have highlighted that an imbalance in lipid accumulation might promote a deviant immune response as observed in TTS. However, there is no information on comprehensive profiling of serum lipids of TTS patients. Therefore, we investigated a detailed quantitative lipid analysis of TTS patients using ES-MSI. Our results showed significant differences in the majority of lipid species composition in the TTS patients compared to the control group. Furthermore, the computational analyses presented was able to link the altered lipids to the pro-inflammatory cytokines and disseminate possible mechanistic pathways involving TNFα and IL-6. Taken together, our study provides an extensive quantitative lipidome of TTS patients, which may provide a valuable Pre-diagnostic tool. This would facilitate the elucidation of the underlying mechanisms of the disease and to prevent the development of TTS in the future. KW - TTS KW - inflammation KW - lipids KW - TNF-α KW - IL6 KW - PIK3R1 KW - NF-kappa-B KW - phosphatidylinositol Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270832 SN - 2297-055X VL - 9 IS - 797154 ER - TY - JOUR A1 - Dunkel, Franz G. A1 - Drenckhahn, Detlev A1 - Zonneveld, Ben ED - Meierott, Lenz ED - Drenckhahn, Detlev ED - Dunkel, Franz G. ED - Ewald, Jörg ED - Fleischmann, Andreas T1 - Forum Geobotanicum 10 (2021/2022) N2 - Forum Geobotanicum is an electronic journal devoted to disseminate information concerning geographical distribution, ecology, morphology, taxonomy and conservation of vascular plants in the European Union with a main focus on middle Europe. It covers from molecular biology to environmental aspects. The focus is to publish original papers, reviews and announcements for the educated generalist as well as the specialist in this broad field. Forum Geobotanicum does not aim to supplant existing paper journals, but will be much more flexible in format, publication time and world-wide distribution than paper journals. Many important studies are being currently published in local journals and booklets and some of them are published privately. Hence, these studies will become aware to only a limited readership. Forum Geobotanicum will encourage authors of such papers to submit them as special issues of the journal. Moreover, the journal is planning to build up an E-mail-address section to support communication between geobotanists in Europe. The editors are optimistic that this electronic journal will develop to a widely used communication forum that will help to stimulate activities in the entire field of geobotany in middle Europe. To overcome problems of long term archivation and effective taxonomic publication of articles published electronically in Forum Geobotanicum, print versions of each volume of the journal and appropriate digital storage devices will be delivered freely to selected university libraries and state libraries in middle Europe. N2 - Forum Geobotanicum ist eine elektronische Plattform, deren Zielsetzung darin besteht, neue Erkenntnisse der geobotanischen Forschung in der Europäischen Union mit Schwerpunkt Mitteleuropa umfassend zu verbreiten. Das Journal befasst sich mit allen Fragen von Verbreitung, Ökologie, Morphologie und Taxonomie von Gefäßpflanzen und soll das gesamte Spektrum der Geobotanik von molekularbiologischen Aspekten bis zu Umwelt- und Naturschutzfragen abdecken. Der Hauptfokus liegt auf der Publikation von Originaluntersuchungen und Übersichtsartikeln sowie Behandlung aktueller Fragen des Naturschutzes. Die Zielgruppen sind Personen mit Allgemeinkenntnissen in der Botanik und Floristik sowie Spezialisten auf den Gebieten der Geobotanik und Pflanzensystematik. Das Journal soll keine Zeitschrift in Druckform ersetzen, sondern eine Ergänzung zu den traditionellen Publikationsorganen bilden. Der Vorteil der Zeitschrift liegt in ihrer Flexibilität und raschen Publikationszeit nach Begutachtung der eingereichten Manuskripte und den Möglichkeiten, in größerem Umfang Fotografien und andere Abbildungen zu veröffentlichen. Der Vorteil einer elektronischen Zeitschrift besteht weiterhin darin, dass die Veröffentlichungen weltweit jedermann sofort zugänglich sind. Viele durchaus wichtige Untersuchungen aus dem Bereich der Geobotanik erscheinen in lokalen Publikationsorganen, wie Jahrbüchern und Heimatkalendern, oder auch im Eigenverlag. Da solche Veröffentlichungen bibliographisch kaum erfasst werden, können sie auch nicht in adäquater Weise wahrgenommen werden. Forum Geobotanicum soll ermöglichen, dass auch solche Publikationen in einer Literaturrubrik bekannt gemacht werden und ggf. nach Klärung von Copyright-Fragen als Supplemente der Zeitschrift ins Netz gestellt werden. Forum Geobotanicum nutzt die Vorteile des Internets, indem es abrufbare Hilfen, wie ein Verzeichnis von Adressen, Pflanzenlisten etc. zur Verfügung stellt. Insgesamt soll die Kommunikation zwischen Geobotanikern in Mitteleuropa erleichtert und eine Kommunikationsplattform etabliert werden, die die Aktivitäten auf dem gesamten Wissenschaftsgebiet stimuliert. Das Journal ist uneigennützig und für Autoren und Benutzer kostenfrei. Für die Kostendeckung sind Sponsoren erwünscht, denen eine begrenzte Möglichkeit zur Darstellung eingeräumt werden kann. In der Anfangsphase wird das Journal von einem kleinen Herausgebergremiumbetrieben. Sollte sich Forum Geobotanicum erfolgreich weiter entwickeln, ist an eine Erweiterung des Herausgebergremiums auf Experten aus allen Nationen des mitteleuropäischen Raums gedacht. Um eine langfristige Verfügbarkeit der Publikationen zu gewährleisten, wird jeder Jahrgang von Forum Geobotanicum ausgedruckt, gebunden und mit digitalem Datenträger versehen an ausgewählte Universitätsbibliotheken, Landes- und Staatsbibliotheken Deutschlands und wichtiger Städte Mitteleuropas zur Archivierung und Ausleihe versandt. KW - Geobotanik KW - Pflanzengeographie Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-298926 SN - 1867-9315 VL - 10(2021/2022) ER -