Differential regulation of TGF-β-induced, ALK-5-mediated VEGF release by SMAD2/3 versus SMAD1/5/8 signaling in glioblastoma

Background The transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF) pathways have a major role in the pathogenesis of glioblastoma, notably immunosuppression, migration, and angiogenesis, but their interactions have remained poorly understood. Methods We characterized TGF-β pathway activity in 9 long-term glioma cell lines (LTCs) and 4 glioma-initiating cell lines (GICs) in relation to constitutive and exogenous TGF-β-induced VEGF release. Results were validated using The Cancer Genome Atlas transcriptomics data. Results Glioma cells exhibit heterogeneous patterns of constitutive TGF-β pathway activation reflected by phosphorylation not only of SMAD2 and SMAD3 but also of SMAD1/5/8. Constitutive TGF-β pathway activity depends on the type I TGF-β receptor, ALK-5, and accounts for up to 69% of constitutive VEGF release, which is positively regulated by SMAD2/3 and negatively regulated by SMAD1/5/8 signaling in a cell line-specific manner. Exogenous TGF-β induces VEGF release in most cell lines in a SMAD- and ALK-5-dependent manner. There is no correlation between the fold induction of VEGF secretion induced by TGF-β compared with hypoxia. The role of SMAD5 signaling is highly context and cell-line dependent with a VEGF inhibitory effect at low TGF-β and pSMAD2 levels and a stimulatory effect when TGF-β is abundant. Conclusions TGF-β regulates VEGF release by glioma cells in an ALK-5-dependent manner involving SMAD2, SMAD3, and SMAD1/5/8 signaling. This crosstalk between the TGF-β and VEGF pathways may open up new avenues of biomarker-driven exploratory clinical trials focusing on the microenvironment in glioblastom

Cue restructuring in English u-fronting: The role of phonetics and phonology in feature-learning

Back tense /u/ is fronting in English in the Northeast US, which results in cue restructuring for the high front lax, back tense contrast (/u--I/). They are no longer distinguished by F2, but the F1 distinction between them is enhanced. In this paper I investigate whether this cue restructuring applies to the phonologically minimally different mid pair /o-E/. I present results from a perception experiment testing to what extent speakers use F1, F2, F3 and duration cues to distinguish between /u--I/ and /o--E/, respectively. Results show that while speakers use the new cues that are available for the /u-I/ contrast, this cue is not useful for the /o-E/, even though these sounds also differ in F1. F3 and duration are not used for either pair. This indicates that cue restructuring stemming from u-fronting does not happen on a featural level, therefore the experiment does not find evidence for a [+/-back] feature. By for a feature in a phonetically natural but phonologically inactive set, this work also contributes to research on mental representations

Kompetensöverföring : Hur arbetar arbetsgivare med kompetensöverföring för att säkra kompetenser vid personalomsättning?

Syftet med studien är att undersöka hur industriföretag inom Kronobergs län arbetar med kompetensöverföring för att säkra kompetensen när medarbetare slutar sin anställning. Det vill säga hur företagen arbetar förebyggande med kompetensöverföring av både den praktiska och tysta kunskapen. Studien baseras på kvalitativa intervjuer. I uppsatsen diskuteras också studiens resultat i förhållande till tidigare forskning och litteratur. Tydliga faktorer som påverkat utfallet av kompetensöverföring kan vara olika beroende på hur företagen jobbar när det gäller överföring av tyst kunskap, mentorskap, motivation och dokumentation. Studien visar att kompetensöverföring är en ständigt pågående process där mänskliga interaktioner, organisatoriskt lärande och kompetensbehov står i fokus för att säkra kompetensen i företaget. Att överföra den tysta kunskapen kan ske både i formella och informella former via bredvidgång med ett bra mentorskap och social interaktion. Det finns utmaningar i arbetet med kompetensöverföring som företagen är medvetna om och företagen arbetar med att undanröja de hinder som finns. 

Cinétique et photochimie atmosphériques des composés organiques volatils oxygénés

Les composés organiques volatils oxygénés (COVOs) sont des espèces chimiques importantes de l atmosphère. Ils incluent, par exemple, les alcools aliphatiques, les aldéhydes, les cétones et les acides organiques. Dans la troposphère libre, l abondance des COVOs est plus importante que celle des hydrocarbures non méthaniques et leur réactivité globale avec OH est comparable avec celle du méthane. En revanche le méthane est présent à une concentration plus élevée. La dégradation des COVOs dans l atmosphère s effectue soit par la réaction avec le radical OH, soit par photolyse. La dégradation des COVOs produit des radicaux libres qui vont influencer la capacité oxydante de l atmosphère, les concentrations en oxydes d azotes, en radical OH et en ozone troposphérique. L ozone est le troisième plus important gaz à effet de serre dans l atmosphère et est l un des composants toxiques principaux des pollutions urbaines et intervient donc dans des problèmes environnementaux graves comme le réchauffement climatique et la dégradation de la qualité de l air. L objectif de ce travail est de contribuer à la compréhension du comportement atmosphérique de quelques COVOs en mesurant leurs paramètres cinétiques et photochimiques apportant des donnés afin de permettre la réalisation de modélisations informatiques et l amélioration de la connaissance des mécanismes chimiques ayant lieu dans l atmosphère.Oxygenated volatile organic compounds (OVOCs) are important constituents of the atmosphere. They include, e.g., aliphatic alcohols, aldehydes, ketones, and organic acids. In the free troposphere, the abundance of OVOCs is higher than that of the non-methane hydrocarbons and their overall reactivity with OH is comparable with that of methane, in contrast that methane is present in much higher concentration. Degradation of OVOCs in the atmosphere takes place via the reaction with OH radicals and, in the case of photochemically active molecules, via photolysis. Free radicals are formed in the photooxidative degradations of the oxygen containing organics which basically determine the oxidative capacity of the atmosphere, the transformation of nitrogen oxides and the concentration of OH radicals and tropospheric ozone. Ozone is the third most important greenhouse gas in the atmosphere, it is one of the toxic components of urban smog and so it is related to such grave environmental problems as global warming and the quality of air. The aim of this work is to contribute to the understanding of the atmospheric behaviour of a few OVOCs by measuring their kinetic and photochemical parameters. One of the major goals of a laboratory basic research in atmospheric chemistry is to provide kinetic and photochemical data for computer modelling and to deduce atmospheric transformation mechanisms in the case of some important chemicals.LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF

Epidermal growth factor receptor and ligand family expression and activity in glioblastoma

Epidermal growth factor family of receptor tyrosine kinases (ERBB) family cell surface receptors, including epidermal growth factor receptor (EGFR/ERBB1), are phosphorylated upon binding by various EGF family ligands and signal via multiple kinase pathways. EGFR signaling is enhanced because of mutational activation of EGFR in almost half of glioblastomas, the most common malignant primary brain tumor. Therapeutic targeting of EGFR in glioblastoma has remained largely unsuccessful. Here, we profiled nine long-term (LTC) and five glioma-initiating (GIC) cell lines for expression and activation of ERBB family receptors and expression of their ligands. Receptors and ligands were abundantly expressed, with patterns overall similar to glioblastoma expression profiles in vivo as deposited in The Cancer Genome Atlas database. No differences between LTC and GIC emerged. Irrespective of ligand or receptor expression, neither an EGFR antibody, erbitux, nor an EGFR tyrosine kinase inhibitor, gefitinib, were particularly active against LTC or GIC at clinically relevant concentrations. Self-renewal capacity of GIC was severely compromised by epidermal growth factor (EGF) withdrawal, but rescued by transforming growth factor alpha (TGF-α), although not by neuregulin-1 (NRG-1). Subcellular fractionation indicated high levels of nuclear phosphorylated EGFR in all LTC and GIC. In LN-229 cells, pERBB2 and pERBB3 were also detected in the nucleus. Nuclear pERBB2 was less sensitive, whereas pERBB3 was induced, in response to gefitinib. This study provides an extensive characterization of human glioma cell models, including stem-like models, with regard to ERBB receptor/ligand expression and signaling. Redundant signaling involving multiple ERBB family ligands and receptors may contribute to the challenges of developing more effective EGFR-targeted therapies for glioblastoma

Developing older adults' learner autonomy through one-to-one counselling: Results of an exploratory investigation

Developing autonomous learning to maintain independent learning practice in an effective way is a crucial ability in adult education (Confessore & Park, 2004). Therefore, this study investigates the potential of one-to-one learning counselling to promote older learners' learner autonomy (aged 50 and older). Twenty-five older learners participated in the exploratory study. Reflective learning diaries and qualitatively oriented questionnaires were used as research tools to track participants' autonomous learning behaviour. We applied grounded theory and network analysis to see the complex interrelations of underlying constructs. Results show that comprehension and speaking development are significant incentives for older adults' language learning. Further, self-awareness in learning and metacognitive knowledge were identified as important constructs for self-study practice. Cognitive stimulation, sustained learner motivation and certain self-relating constructs continuously affected older adults' learning behaviour. Application of cognitive-and memory-enhancing learning strategies, as well as technology-supported learning materials, played an important role in independent learning practice. General perceived self-efficacy and self-management were areas developed beyond language learning

Controlled release oral delivery of apigenin containing pellets with antioxidant activity.

BACKGROUND: Drug delivery of phytochemicals has gained interest recently due to their remarkable health effects. Apigenin, a plant flavonoid, has antioxidant, anti-inflammatory and anticancer activities but its delivery is challenging. It could be absorbed through the whole intestine, however, it has poor bioavailability due to its low aqueous solubility. In Europe, the daily intake was estimated to be as low as 3+/-1 mg. Pellets offer several advantages such as improved bioavailability and various resultant drug release profiles can be obtained by simply mixing pellets with different coatings. OBJECTIVE: The objective of our study was to develop a carrier system containing 20 mg apigenin thus enhancing intake and to offer reduction of oxidative stress which can cause inflammation in the intestine. METHOD: The apigenin powder was dispersed in aqueous solution of binding material and layered onto the inert cores in a fluidized bed apparatus. The layered cores were further coated with enteric polymers and the process parameters were optimized. RESULTS: The prepared pellets met with the requirements and have good physical characteristic. 10 % (w/w) Eudragit(R) L was suitable for enteric coating with a complete release at pH 6.8 within 1 hour. 15% (w/w) Eudragit(R) FS coating ensured acid resistance ability and colonic delivery. The therapeutic efficiency was confirmed with antioxidant activity measurement by using DPPH* assay. CONCLUSION: Enteric coated spheres allow targeted delivery into the intestine and colon thus reaching the main absorption site. Pellets were proved to be an optimal delivery system for apigenin thus providing enhanced apigenin intake

MicroRNA-mediated down-regulation of NKG2D ligands contributes to glioma immune escape

Malignant gliomas are intrinsic brain tumors with a dismal prognosis. They are well-adapted to hypoxic conditions and poorly immunogenic. NKG2D is one of the major activating receptors of natural killer (NK) cells and binds to several ligands (NKG2DL). Here we evaluated the impact of miRNA on the expression of NKG2DL in glioma cells including stem-like glioma cells. Three of the candidate miRNA predicted to target NKG2DL were expressed in various glioma cell lines as well as in glioblastomas in vivo: miR-20a, miR-93 and miR-106b. LNA inhibitor-mediated miRNA silencing up-regulated cell surface NKG2DL expression, which translated into increased susceptibility to NK cell-mediated lysis. This effect was reversed by neutralizing NKG2D antibodies, confirming that enhanced lysis upon miRNA silencing was mediated through the NKG2D system. Hypoxia, a hallmark of glioblastomas in vivo, down-regulated the expression of NKG2DL on glioma cells, associated with reduced susceptibility to NK cell-mediated lysis. This process, however, was not mediated through any of the examined miRNA. Accordingly, both hypoxia and the expression of miRNA targeting NKG2DL may contribute to the immune evasion of glioma cells at the level of the NKG2D recognition pathway. Targeting miRNA may therefore represent a novel approach to increase the immunogenicity of glioblastoma