RepoMed (Medizinische Hochschule Hannover)
Not a member yet
3024 research outputs found
Sort by
Kritische Rolle des Glukokortikoidrezeptors in Makrophagen für die Heilung und das Remodeling nach Myokardinfarkt
Get PDFDie Operationsgenauigkeit von roboterassistierter Reposition von Femurschaftfrakturen im Vergleich der Eingabemethodik
Get PDFA Single Amino Acid Residue Regulates PTEN-Binding and Stability of the Spinal Muscular Atrophy Protein SMN.
Get PDFSpinal Muscular Atrophy (SMA) is a neuromuscular disease caused by decreased levels of the survival of motoneuron (SMN) protein. Post-translational mechanisms for regulation of its stability are still elusive. Thus, we aimed to identify regulatory phosphorylation sites that modulate function and stability. Our results show that SMN residues S290 and S292 are phosphorylated, of which SMN pS290 has a detrimental effect on protein stability and nuclear localization. Furthermore, we propose that phosphatase and tensin homolog (PTEN), a novel phosphatase for SMN, counteracts this effect. In light of recent advancements in SMA therapies, a significant need for additional approaches has become apparent. Our study demonstrates S290 as a novel molecular target site to increase the stability of SMN. Characterization of relevant kinases and phosphatases provides not only a new understanding of SMN function, but also constitutes a novel strategy for combinatorial therapeutic approaches to increase the level of SMN in SMA
Die pro-regenerative Rolle der langen nicht-kodierenden RNA H19 im ischämischen akuten Nierenversagen als Teil eines embryonalen Genprogramms
Get PDFModeling Human Cytomegalovirus in Humanized Mice for Vaccine Testing.
Get PDFHuman cytomegalovirus (HCMV or HHV-5) is a globally spread pathogen with strictly human tropism that establishes a lifelong persistence. After primary infection, high levels of long-term T and B cell responses are elicited, but the virus is not cleared. HCMV persists mainly in hematopoietic reservoirs, whereby occasional viral reactivation and spread are well controlled in immunocompetent hosts. However, when the immune system cannot control viral infections or reactivations, such as with newborns, patients with immune deficiencies, or immune-compromised patients after transplantations, the lytic outbursts can be severely debilitating or lethal. The development of vaccines for immunization of immune-compromised hosts has been challenging. Several vaccine candidates did not reach the potency expected in clinical trials and were not approved. Before anti-HCMV vaccines can be tested pre-clinically in immune-compromised hosts, reliable in vivo models recapitulating HCMV infection might accelerate their clinical translation. Therefore, immune-deficient mouse strains implanted with human cells and tissues and developing a human immune system (HIS) are being explored to test anti-HCMV vaccines. HIS-mice resemble immune-compromised hosts as they are equipped with antiviral human T and B cells, but the immune reactivity is overall low. Several groups have independently shown that HCMV infections and reactivations can be mirrored in HIS mice. However, these models and the analyses employed varied widely. The path forward is to improve human immune reconstitution and standardize the analyses of adaptive responses so that HIS models can be forthrightly used for testing novel generations of anti-HCMV vaccines in the preclinical pipeline
The Three-Dimensional Ultrastructure of the Human Alveolar Epithelium Revealed by Focused Ion Beam Electron Microscopy.
Get PDFThin type 1 alveolar epithelial (AE1) and surfactant producing type 2 alveolar epithelial (AE2) cells line the alveoli in the lung and are essential for normal lung function. Function is intimately interrelated to structure, so that detailed knowledge of the epithelial ultrastructure can significantly enhance our understanding of its function. The basolateral surface of the cells or the epithelial contact sites are of special interest, because they play an important role in intercellular communication or stabilizing the epithelium. The latter is in particular important for the lung with its variable volume. The aim of the present study was to investigate the three-dimensional (3D) ultrastructure of the human alveolar epithelium focusing on contact sites and the basolateral cell membrane of AE2 cells using focused ion beam electron microscopy and subsequent 3D reconstructions. The study provides detailed surface reconstructions of two AE1 cell domains and two AE2 cells, showing AE1/AE1, AE1/AE2 and AE2/AE2 contact sites, basolateral microvilli pits at AE2 cells and small AE1 processes beneath AE2 cells. Furthermore, we show reconstructions of a surfactant secretion pore, enlargements of the apical AE1 cell surface and long folds bordering grooves on the basal AE1 cell surface. The functional implications of our findings are discussed. These findings may lay the structural basis for further molecular investigations
Mechanism of Action of Ketogenic Diet Treatment: Impact of Decanoic Acid and Beta-Hydroxybutyrate on Sirtuins and Energy Metabolism in Hippocampal Murine Neurons.
Get PDFThe ketogenic diet (KD), a high-lipid and low-carbohydrate diet, has been used in the treatment of epilepsy, neurodegenerative disorders, inborn errors of metabolism and cancer; however, the exact mechanism/s of its therapeutic effect is not completely known. We hypothesized that sirtuins (SIRT)-a group of seven NAD-dependent enzymes and important regulators of energy metabolism may be altered under KD treatment. HT22 hippocampal murine neurons were incubated with two important KD metabolites-beta-hydroxybutyrate (BHB) (the predominant ketone body) and decanoic acid (C10), both accumulating under KD. Enzyme activity, protein, and gene expressions of SIRT 1-4, enzyme capacities of the mitochondrial respiratory chain complexes (MRC), citrate synthase (CS) and gene expression of monocarboxylate transporters were measured in control (untreated) and KD-treated cells. Incubation with both-BHB and C10 resulted in significant elevation of SIRT1 enzyme activity and an overall upregulation of the MRC. C10 incubation showed prominent increases in maximal activities of complexes I + III and complex IV of the MRC and ratios of their activities to that of CS, pointing towards a more efficient functioning of the mitochondria in C10-treated cells
Safety and feasibility of transjugular intrahepatic portosystemic shunt in elderly patients with liver cirrhosis and refractory ascites.
Get PDFBACKGROUND & AIMS:The management of patients with refractory ascites (RA) is challenging, particularly at higher age. Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment for RA, but safety data in elderly patients are rare. Our aim was to evaluate the safety and feasibility of TIPS in elderly patients with RA. METHODS:Overall, 160 consecutive cirrhotic patients receiving a TIPS for RA at Hannover Medical School between 2012 and 2018 were considered for this retrospective analysis. Periinterventional complications such as acute-on-chronic liver failure (ACLF) as well as survival were compared between patients <65 and ≥65 years. Propensity score matching was conducted to match elderly TIPS patients and patients treated with paracentesis. RESULTS:A number of 53 out of the 160 patients were ≥65 years (33%). Periinterventional course in those ≥65 years appeared to be slightly more complicated than in <65 years as reflected by a significantly longer hospital stay (p = 0.030) and more ACLF-episodes (21% vs. 9%; p = 0.044). 28-day mortality was similar between both groups (p = 0.350), whereas survival of the younger patients was significantly higher at 90 days (p = 0.029) and numerically higher at 1 year (p = 0.171). In the multivariate analysis age ≥65 years remained an independent predictor for 90-day mortality (HR: 2.58; p = 0.028), while it was not associated with 28-day and 1-year survival. Importantly, after matching for potential confounders 1-year survival was similar in elderly patients if treated with TIPS or paracentesis (p = 0.419). CONCLUSIONS:TIPS placement in elderly patients with RA appears to be slightly more complicated compared to younger individuals, but overall feasible and at least not inferior to paracentesis
Fibrocystin Is Essential to Cellular Control of Adhesion and Epithelial Morphogenesis.
Get PDFMutations of the Pkhd1 gene cause autosomal recessive polycystic kidney disease (ARPKD). Pkhd1 encodes fibrocystin/polyductin (FPC), a ciliary type I membrane protein of largely unknown function, suggested to affect adhesion signaling of cells. Contributions of epithelial cell adhesion and contractility to the disease process are elusive. Here, we link loss of FPC to defective epithelial morphogenesis in 3D cell culture and altered cell contact formation. We study Pkhd1-silenced Madin-Darby Canine Kidney II (MDCKII) cells using an epithelial morphogenesis assay based on micropatterned glass coverslips. The assay allows analysis of cell adhesion, polarity and lumen formation of epithelial spheroids. Pkhd1 silencing critically affects the initial phase of the morphogenesis assay, leading to a reduction of correctly polarized spheroids by two thirds. Defects are characterized by altered cell adhesion and centrosome positioning of FPC-deficient cells in their 1-/2-cell stages. When myosin II inhibitor is applied to reduce cellular tension during the critical early phase of the assay, Pkhd1 silencing no longer inhibits formation of correctly polarized epithelia. We propose that altered sensing and cell interaction of FPC-deficient epithelial cells promote progressive epithelial defects in ARPKD
