A magnesium (Mg) solid solution with a long periodic hexagonal structure was found in a Mg 97 Zn 1 Y 2 (at.%) alloy in a bulk form prepared by warm extrusion of atomized powders at 573 K. The novel structure has an ABACAB-type six layered packing with lattice parameters of a ס 0.322 nm and c ס 3 × 0.521 nm. The Mg solid solution has fine grain sizes of 100 to 150 nm and contains 0.78 at.% Zn and 1.82 at.% Y. In addition, cubic Mg 24 Y 5 particles with a size of about 7 nm are dispersed at small volume fractions of less than 10% in the Mg matrix. The specific density () of the extruded bulk Mg-Zn-Y alloy was 1.84 Mg/m 3 . The tensile yield strength ( y ) and elongation (␦) are 610 MPa and 5%, respectively, at room temperature, and the specific yield strength defined by the ratio of y to is as high as 3.3 × 10 5 Nm/kg. High y values exceeding 400 MPa are also maintained at temperatures up to 473 K. It is noticed that the y levels are 2.5 to 5 times higher than those for conventional high-strength type Mg-based alloys. The Mg-based alloy also exhibits a high-strain-rate superplasticity with large ␦ of 700 to 800% at high strain rates of 0.1 to 0.2 s −1 and 623 K. The excellent mechanical properties are due to the combination of the fine grain size, new long periodic hexagonal solid solution containing Y and Zn, and dispersion of fine Mg 24 Y 5 particles. The new Mg-based alloy is expected to be used in many fields.
Running title: miRNAs and temozolomide resistance in glioblastoma Key words: glioblastoma, resistance, microRNA,, miR-10a*, temozolomide. ABSTRACTTo identify microRNAs (miRNAs) specifically involved in the acquisition of temozolomide (TMZ) resistance in glioblastoma multiforme (GBM), we first established a resistant variant, U251R cells from TMZ-sensitive GBM cell line, U251MG. We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a* were the three most up-regulated miRNAs in the resistant cells. To investigate the functional role of these miRNAs in TMZ resistance, U251R cells were transfected with miRNA inhibitors consisting of DNA/LNA hybrid oligonucleotides. Suppression of miR-455-3p or miR-10a* had no effect on cell growth, but showed modest cell killing effect in the presence of TMZ. On the other hand, knockdown of miR-195 alone displayed moderate cell killing effect, and combination with TMZ strongly enhanced the effect. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs. In conclusion, our findings suggest that those miRNAs may play a role in acquired TMZ resistance and could be a novel target for recurrent GBM treatment.
The objective of this study is to improve the viability and osteogenic differentiation of cultured rat bone marrow-derived mesenchymal stem cells (MSC) by the use of gelatin hydrogel microspheres. Gelatin was dehydrothermally crosslinked at 140° C for 48 h in a water in oil emulsion state. When cultured with the gelatin hydrogel microspheres in round, U-bottomed wells of 96-well plates coated with poly(vinyl alcohol) MSC formed aggregates homogeneously incorporating the microspheres. The viability of the cell aggregates was significantly higher compared with that of aggregates formed without microspheres. MSC proliferation in the aggregates depended on the number and diameter of the incorporated microspheres. Higher MSC proliferation was observed for aggregates incorporating a greater number of larger gelatin microspheres. When evaluated as a measure of aerobic glycolysis the ratio of l-lactic acid production/glucose consumption in MSC was significantly lower for MSC cultured with gelatin microspheres than those without microspheres. MSC production of alkaline phosphatase (ALP) and sulfated glycosaminaglycan (sGAG) was examined to evaluate their potential osteogenic and chondrogenic differentiation. The amount of ALP produced was significantly higher for MSC aggregates cultured with gelatin microspheres than that of MSC cultured without microspheres. On the other hand, the amount of sGAG produced was significantly lower for MSC aggregates containing microspheres. It is concluded that the incorporation of gelatin hydrogel microspheres prevents the aggregated MSC suffering from a lack of oxygen, resulting in enhanced MSC aggregation and cell proliferation and osteogenic differentiation.
We investigate unfolding/folding force kinetics in DNA hairpins exhibiting two and three states with newly designed short dsDNA handles (29 bp) using optical tweezers. We show how the higher stiffness of the molecular setup moderately enhances the signal/noise ratio (SNR) in hopping experiments as compared to conventional long-handled constructs (≅700 bp). The shorter construct results in a signal of higher SNR and slower folding/unfolding kinetics, thereby facilitating the detection of otherwise fast structural transitions. A novel analysis, as far as we are aware, of the elastic properties of the molecular setup, based on high-bandwidth measurements of force fluctuations along the folded branch, reveals that the highest SNR that can be achieved with short handles is potentially limited by the marked reduction of the effective persistence length and stretch modulus of the short linker complex.
Rap proteins regulate the activity of response regulators including Spo0F, DegU and ComA. We found that overexpression of either RapG or RapH severely downregulated the expression of srfA, which belongs to the ComA regulon. Disruption of those genes, however, showed small effects on srfA expression. These observations suggested that Bacillus subtilis cells possess a repressor for rapG and rapH. To identify candidate repressors we developed a novel transcription factor array (TF array) assay, in which disruptions of 287 genes encoding regulatory proteins were independently transformed into a strain carrying rapH-lacZ and the resultant transformants were grown on agar plates containing Xgal to detect beta-galactosidase activity. We identified a yvaN disruptant which showed a rapH-overproducing phenotype. DNA microarray analysis of the yvaN mutant suggested that both rapG and rapH were overproduced, leading to inhibition of srfA expression. In a gel retardation assay, purified His-tagged YvaN specifically bound to promoter sequences of rapG and rapH. Further footprint and gel retardation analyses using various deleted probes uncovered critical sequences for YvaN binding. In addition, a lacZ fusion analysis confirmed the significance of YvaN binding for transcription regulation of rapG and rapH. Thus, YvaN was renamed RghR (rapG and rapH repressor). As the rapH gene is activated by ComK and RapH inhibits comK indirectly, this constitutes an autoregulatory loop modulated by RghR.
Aminoglycosides, cisplatin, and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used pharmacological agents. There is a possibility, however, that the use of these agents may induce transient or permanent hearing loss and tinnitus as side effects. Recent animal studies have clarified mechanisms leading to the ototoxicity induced by these agents, at least in part. The permanent hearing loss caused by aminoglycosides and cisplatin is suggested to be predominantly associated with the apoptotic death of outer hair cells. Both drugs generate reactive oxygen species (ROS) in the inner ear. ROS can activate cell-death pathways such as the c-Jun Nterminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways, which in turn, induce hair cell apoptosis. On the other hand, the abuse of NSAIDs may transiently cause tinnitus and mild to moderate hearing loss. NSAIDs impair the active process of the outer hair cells and affect peripheral and central auditory neurons. Conversely, recent reports clarified that NSAIDs are potential therapeutic agents against cochlear injuries. In this review, recent findings from animal studies regarding the ototoxicity induced by aminoglycosides, cisplatin, and NSAIDs are summarized. Their ototoxic mechanisms are focused on.
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