Developmental and tissue-specific expression of the Q5k gene

Expression of the Q5k gene was examined by northern blot analysis and polymerase chain reaction (PCR) in the AKR mouse and various cell lines, each of the H-2k haplotype. Our results show that Q5k mRNA is present during the whole postimplantational development of the AKR embryo/fetus (gestation day 6 to 15). In the juvenile mouse (week 2 to 4) transcription of the Q5k gene persisted in all organs examined. In contrast, in the adult animal expression of the Q5k gene was limited to the thymus and uterus of the pregnant mouse. Upon malignant transformation, the amount of Q5k-specific mRNA increased dramatically in thymus and could also be observed in the spleen of thymoma bearing animals. Expression of the Q5k gene was also detectable in several transformed mouse cell lines. Mitogen stimulation or treatment with cytokines induced Q5k expression in primary spleen cell cultures. A possible explanation for the tissue-restricted expression in the adult AKR mouse is discussed

Warum Lehrer/in werden? Idealismus, Sicherheit oder «da wusste ich nichts Besseres»? Ein Vergleich von Berufswahlmotiven zwischen deutschen und schweizerischen Lehramtsstudierenden und die Bedeutung von länderspezifischen Bedingungen

Die vorliegende Studie hat zum Ziel, Lehramtsstudierende zweier Länder (Deutschland, Bayern und der Schweiz, Kanton Zürich) sowie zweier Schulstufen (Primar- und Sekundarstufe I) auf ihre Berufswahlmotive hin zu vergleichen. Mit Hilfe von Faktorenanalysen wurde eine Faktorenstruktur entwickelt, die für varianz-analytische Vergleiche zwischen den untersuchten Gruppen sowie zwischen den clusteranalytisch gebildeten Typen genutzt wird. Intrinsische Motive, insbesondere die Arbeit mit Kindern und Jugendlichen, werden von den Lehramtsstudierenden als wichtiger angesehen als extrinsische Motive. In den Ausprägungen zeigen sich jedoch Unterschiede zwischen den untersuchten Gruppen. In den über die Berufswahlmotive clusteranalytisch identifizierten Typen schlagen sich länder- und schulstufenspezifische Faktoren nieder. Insbesondere in den extrinsischen und fehlenden Motiven zeigen sich Ländereffekte. Die Ergebnisse der Studie verweisen auf die Wichtigkeit, Erkenntnisse bezüglich der Motive von Lehramtsstudierenden nicht nur auf der individuellen Ebene, sondern auch in Hinblick auf spezifische Kontextbedingungen zu interpretieren.+repphzhbib201

Magnetically responsive tropoelastin hydrogel as a platform for soft tissue regeneration applications

Publicado em "European Cells and Materials. ISSN 1473-2262. Vol. 33, Suppl. 2, 2017 (0006)"The natural polymer tropoelastin is a structural protein of ECM of tissues requiring elasticity as part of their function, including ligaments and tendons. Tropoelastin has an innate capacity of self-assembly into high-order structures, and together with elastic resilience, structural stability and bioactivity bring forth pleasant singularities in adopting it as a building block to fabricate hydrogels. Moreover, easy tailoring of properties can be attained via incorporation of specific components into the polymeric network, including magnetic nanoparticles (MNPs), which are beneficial for on-demand therapies. Thus, the main goal of this work consisted in developing a magnetically responsive tropoelastin (MagTro) hydrogel as a platform to study the response of tendon cells to a mechanical stimulus induced by application of an external magnetic field (EMF). For this purpose, to first produce hydrogels, a solution of recombinant human tropoelastin was first freeze-dried overnight inside a mould and then chemically cross-linked inside an open desiccator via vapour glutaraldehyde. Thereafter, MagTro hydrogels were obtained through in situ precipitation of MNPs by immersing tropoelastin hydrogels in FeCl2 and FeCl3 solution overnight and secondly by soaking them in NaOH. Hydrogels were then analysed morphologically by Scanning Electron Microscopy (SEM and Cryo-SEM). Enzyme-triggered degradation was studied after 72h at 37oC in a human neutrophil elastase solution. Hydrogels exhibited a quick magnetic responsiveness to an EMF (Fig.1). Interestingly, MagTro hydrogels exhibited smaller pores as observed by Cryo-SEM. This feature can be tuned according to different soft tissue requirements by controlling different parameters of the fabrication process. Additionally, the release of tropoelastin into solution decreased, which suggests the formation of a surface coating of MNPs on tropoelastin network, protecting the hydrogel from a faster degradation. Preliminary results also indicate that cultured cells are viable and spread at the surface of the hydrogel. The application of an EMF to cell-laden MagTro hydrogels will be further investigated. Overall, the streamlined fabrication of MagTro hydrogels was successfully attained and the hydrogel formulation represents a promising potential platform for soft tissue regeneration.The authors acknowledge to BEAM-Master Joint Mobility Project an EU Australian cooperation in Biomedical Engineering Grant Agreement, 2014-1843/001 001-CPT EU-ICI-ECP and to FCT–Fundação para a Ciência e a Tecnologia in the framework of FCT-POPH-FSE, RC-A PhD grant SFRH/BD/96593/2013 and MEG grant IF/00685/2012.info:eu-repo/semantics/publishedVersio

Immunological and tumor-intrinsic mechanisms mediate the synergistic growth suppression of experimental glioblastoma by radiotherapy and MET inhibition

The hepatocyte growth factor (HGF)/MET signaling pathway has been proposed to be involved in the resistance to radiotherapy of glioblastoma via proinvasive and DNA damage response pathways.Here we assessed the role of the MET pathway in the response to radiotherapy in vitro and in vivo in syngeneic mouse glioma models. We find that the murine glioma cell lines GL-261, SMA-497, SMA-540 and SMA-560 express HGF and its receptor MET and respond to exogenous HGF with MET phosphorylation. Glioma cell viability or proliferation are unaffected by genetic or pharmacological MET inhibition using tepotinib or CRISPR/Cas9-engineered Met gene knockout and MET inhibition fails to sensitize glioma cells to irradiation in vitro. In contrast, the combination of tepotinib with radiotherapy prolongs survival of orthotopic SMA-560 or GL-261 glioma-bearing mice compared with radiotherapy or tepotinib treatment alone. Synergy is lost when such experiments are conducted in immunodeficient Rag1$^{-/-}$ mice, and, importantly, also when Met gene expression is disrupted in the tumor cells. Combination therapy suppresses a set of pro-inflammatory mediators including matrix metalloproteases that are upregulated by radiotherapy alone and that have been linked to poor outcome in glioblastoma. Several of these mediators are positively regulated by transforming growth factor (TGF)-β, and pSMAD2 levels as a surrogate marker of TGF-β pathway activity are suppressed by combination treatment. We conclude that synergistic suppression of experimental syngeneic glioma growth by irradiation and MET inhibition requires MET expression in the tumor as well as an intact immune system. Clinical evaluation of this combined strategy in newly diagnosed glioblastoma is warranted

Comparing the Toxicological Responses of Pulmonary Air–Liquid Interface Models upon Exposure to Differentially Treated Carbon Fibers

In recent years, the use of carbon fibers (CFs) in various sectors of industry has been increasing. Despite the similarity of CF degradation products to other toxicologically relevant materials such as asbestos fibers and carbon nanotubes, a detailed toxicological evaluation of this class of material has yet to be performed. In this work, we exposed advanced air–liquid interface cell culture models of the human lung to CF. To simulate different stresses applied to CF throughout their life cycle, they were either mechanically (mCF) or thermo-mechanically pre-treated (tmCF). Different aspects of inhalation toxicity as well as their possible time-dependency were monitored. mCFs were found to induce a moderate inflammatory response, whereas tmCF elicited stronger inflammatory as well as apoptotic effects. Furthermore, thermal treatment changed the surface properties of the CF resulting in a presumed adhesion of the cells to the fiber fragments and subsequent cell loss. Triple-cultures encompassing epithelial, macrophage, and fibroblast cells stood out with an exceptionally high inflammatory response. Only a weak genotoxic effect was detected in the form of DNA strand breaks in mono- and co-cultures, with triple-cultures presenting a possible secondary genotoxicity. This work establishes CF fragments as a potentially harmful material and emphasizes the necessity of further toxicological assessment of existing and upcoming advanced CF-containing materials

Drag-Based CME Modeling With Heliospheric Images Incorporating Frontal Deformation : ELEvoHI 2.0

The evolution and propagation of coronal mass ejections (CMEs) in interplanetary space is still not well understood. As a consequence, accurate arrival time and arrival speed forecasts are an unsolved problem in space weather research. In this study, we present the ELlipse Evolution model based on HI observations (ELEvoHI) and introduce a deformable front to this model. ELEvoHI relies on heliospheric imagers (HI) observations to obtain the kinematics of a CME. With the newly developed deformable front, the model is able to react to the ambient solar wind conditions during the entire propagation and along the whole front of the CME. To get an estimate of the ambient solar wind conditions, we make use of three different models: Heliospheric Upwind eXtrapolation model (HUX), Heliospheric Upwind eXtrapolation with time dependence model (HUXt), and EUropean Heliospheric FORecasting Information Asset (EUHFORIA). We test the deformable front on a CME first observed in STEREO-A/HI on February 3, 2010 14:49 UT. For this case study, the deformable front provides better estimates of the arrival time and arrival speed than the original version of ELEvoHI using an elliptical front. The new implementation enables us to study the parameters influencing the propagation of the CME not only for the apex, but for the entire front. The evolution of the CME front, especially at the flanks, is highly dependent on the ambient solar wind model used. An additional advantage of the new implementation is given by the possibility to provide estimates of the CME mass.Peer reviewe

Chimeric antigen receptor T cell-based targeting of CD317 as a novel immunotherapeutic strategy against glioblastoma

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has proven to be successful against hematological malignancies. However, exploiting CAR T cells to treat solid tumors is more challenging for various reasons including the lack of suitable target antigens. Here, we identify the transmembrane protein CD317 as a novel target antigen for CAR T cell therapy against glioblastoma, one of the most aggressive solid tumors. METHODS: CD317-targeting CAR T cells were generated by lentivirally transducing human T cells from healthy donors. The anti-glioma activity of CD317-CAR T cells toward various glioma cells was assessed in vitro in cell lysis assays. Subsequently, we determined the efficacy of CD317-CAR T cells to control tumor growth in vivo in clinically relevant mouse glioma models. RESULTS: We generated CD317-specific CAR T cells and demonstrate strong anti-tumor activity against several glioma cell lines as well as primary patient-derived cells with varying CD317 expression levels in vitro. A CRISPR/Cas9-mediated knockout of CD317 protected glioma cells from CAR T cell lysis, demonstrating the target specificity of the approach. Silencing of CD317 expression in T cells by RNA interference reduced fratricide of engineered T cells and further improved their effector function. Using orthotopic glioma mouse models, we demonstrate the antigen-specific anti-tumor activity of CD317-CAR T cells, which resulted in prolonged survival and cure of a fraction of CAR T cell-treated animals. CONCLUSIONS: These data reveal a promising role of CD317-CAR T cell therapy against glioblastoma, which warrants further evaluation to translate this immunotherapeutic strategy into clinical neuro-oncology

Markers of Inflammation and Fibrosis in Alcoholic Hepatitis and Viral Hepatitis C

High levels of profibrinogenic cytokine transforming factor beta (TGF-β), metalloprotease (MMP2), and tissue inhibitor of matrix metalloprotease 1 (TIMP1) contribute to fibrogenesis in hepatitis C virus (HCV) infection and in alcohol-induced liver disease (ALD). The aim of our study was to correlate noninvasive serum markers in ALD and HCV patients with various degrees of inflammation and fibrosis in their biopsies. Methods. Serum cytokines levels in HCV-infected individuals in the presence or absence of ALD were measured. Student's-t-test with Bonferroni correction determined the significance between the groups. Results. Both tumor-necrosis-factor- (TNF)-α and TGF-β levels increased significantly with the severity of inflammation and fibrosis. TGF-β levels increased significantly in ALD patients versus the HCV patients. Proinflammatory cytokines' responses to viral and/or toxic injury differed with the severity of liver inflammation. A combination of these markers was useful in predicting and diagnosing the stages of inflammation and fibrosis in HCV and ALD. Conclusion. Therapeutic monitoring of TGF-β and metalloproteases provides important insights into fibrosis