Towards understanding the mechanism of action of the multidrug resistance-linked half-ABC transporter ABCG2: a molecular modeling study

The ATP-binding cassette protein ABCG2 is a member of a broad family of ABC transporters with potential clinical importance as a mediator of multidrug resistance. We carried out a homology and knowledge-based, and mutationally improved molecular modeling study to establish a much needed structural framework for the protein, which could serve as guidance for further genetic, biochemical, and structural analyses. Based on homology with known structures of both full-length and nucleotide-binding domains (NBD) of ABC transporters and structural knowledge of integral membrane proteins, an initial model of ABCG2 was established. Subsequent refinement to conform to the lipophilic index distributions in the transmembrane domain (TMD) and to the results of site-directed mutagenesis experiments led to an improved model. The complete ABCG2 model consists of two identical subunits facing each other in a closed conformation. The dimeric interface in the nucleotide-binding domain (NBD) involves a characteristic nucleotide sandwich and the interface in the TMD consists of the TM helices 1–3 of one subunit and the helices 5 and 6 of the other. The interface between the NBD and the TMD is bridged by the conserved structural motif between TM2 and TM3, the intracellular domain 1 (ICD1), and the terminal β-strand (S6) of the central β-sheet in the NBD. The apparent flexibility of the ICD1 may play a role in transmitting conformational changes from the NBD to the TMD or from the TMD to the NBD.     

Switching in polystyrene and polymethyl methacrylate thin films: effect of preparation conditions of the polymers

Switching without any break in the electrodes was observed in polystyrene and polymethyl methacrylate films by controlling the current using a high resistance connected in series with the sample. The effect of the method of polymerization on the switching characteristics were studies for both polymers. Polymers were prepared by -ray irradiation or by catalytic or noncatalytic thermal polymerization. The switching characteristics gave poor reproducibility for the catalytically polymerized polystyrene, but no difference was observed for the three types of polymethyl methacrylate from different origins. In the case of polystyrene, the lower the molecule weight, the higher was the threshold voltage. With polymethyl methacrylate such a dependence was not observed. In both polymers the on-state is relatively stable. When the samples in the on-state were heated above 100° C, they were converted to the offstate. No dots or breaks on the sample were detected by scanning electron microscopy (SEM) after switching has occurred.     

Polyphenols and fatty acids responsible for anti-cyanobacterial allelopathic effects of submerged macrophyte Myriophyllum spicatum

Myriophyllum spicatum is known to inhibit the growth of cyanobacteria such as Microcystis aeruginosa by releasing anti-cyanobacterial allelochemicals. The allelochemicals possibly responsible for the inhibition include five polyphenols and three fatty acids, but the extent to which these are indeed responsible for the anti-cyanobacterial effects is unclear. The goal of this research was to determine the contribution of these compounds to the allelopathic effect of M. spicatum on M. aeruginosa. We first collected information on the release rates of these compounds and then added the compounds to a cyanobacterial medium on the basis of their release rates so as to simulate their excretion by M. spicatum. Addition of the polyphenols and fatty acids inhibited the growth of M. aeruginosa, and the interaction of the polyphenols and fatty acids was additive. The EC50 of a polyphenol and fatty acid mixture was compared with that of M. spicatum itself as previously determined in a mixed culture system in which M. spicatum and M. aeruginosa were incubated. The former was about 1.9 times higher than that of the latter, the implication being that the inhibitory effect of the polyphenols and fatty acids contributed about 53% of the allelopathic effect of M. spicatum. This paper is the first to describe allelochemicals that account for a half of the anti-cyanobacterial allelopathic effect of a macrophyte.     

Study on high performance ice slurry formed by cooling emulsion in ice storage (discussion on adaptability of emulsion to thermal storage material)

This study focuses on an emulsion as a new thermal storage material for ice storage. Two types of emulsions were formed using an oil–water mixture with a small amount of additive. A silicone, light and lump oils were used. The water contents of the emulsions were 70, 80 and 90%. The additive was an amino group modified silicone oil. No depression of freezing point was observed for the emulsions because of their hydrophobic properties. In order to determine the structure of the emulsions, their electrical resistances were measured. Moreover, components of the liquids separating from the emulsions were analyzed. The results indicated that one emulsion was a W/O type emulsion, while the other was an O/W type. Finally, adaptability of the two emulsions to ice storage was discussed, it was concluded that a high performance ice slurry could be formed by the W/O type emulsion.     

Three dimensional virtual crack closure-integral method (VCCM) with skewed and non-symmetric mesh arrangement at the crack front

In this paper, an extension of virtual crack closure-integral method (VCCM) for three dimensional linear fracture mechanics analysis using hexahedron finite elements is presented. In conventional three dimensional VCCM, there are some inherent requirements on the finite element model. They are (i) the faces of finite elements across the crack front have the same areas and (ii) they must be arranged symmetrically across the crack front. In present study, we developed a three dimensional VCCM without such requirements by considering work required to open one element face area whose shape is arbitrary. Though we assume the use of an ordinary 20 node serendipity element, present approach can be applied to other types of hexahedron elements.     

Thermomechanical fatigue behavior of the third-generation,single-crystal superalloy TMS-75: Deformation structure

The deformation structure after the out-of-phase thermomechanical fatigue (OP TMF) of the single-crystal (SC), Ni-based superalloy TMS-75 has been studied. Mechanical experiments were performed at temperatures between 400 °C and 900 °C under different total strain ranges with varying hold times in the compression stage. The lives of TMF for samples with hold times of 10 and 60 minutes dropped drastically by one order of magnitude as compared with those without it. Different structures developed during TMF were correlated to the difference in mechanical behavior for the two cases. The dislocations in the γ phase and the stacking faults (SFs) in the γ′ phase were quantitatively analyzed by transmission electron microscopy (TEM). This work verified that shearing of the γ′ precipitates occurred with a single-dislocation mechanism rather than a dislocation-reaction mechanism. The implications of this work on the design of superalloys are presented.     

Out‐of‐Plane Strain Induced in a Moiré Superstructure of Monolayer MoS2 and MoSe2 on Au(111)

Making contact of transition metal dichalcogenides (TMDCs) with a metal surface is essential for fabricating and designing electronic devices and catalytic systems. It also generates strain in the TMDCs that plays significant role in both electronic and phonon structures. Therefore, detailed understanding of mechanism of the strain generation is important to fully comprehend the modulation effect for the electronic and phonon properties. Here, MoS₂ and MoSe₂ monolayers are grown on Au surface by chemical vapor deposition and it is demonstrated that the contact with a crystalline Au(111) surface gives rise to only out‐of‐plane strain in both MoS₂ and MoSe₂ layers, whereas no strain generation is observed on polycrystalline Au or SiO₂/Si surfaces. Scanning tunneling microscopy analysis provides information regarding consequent specific adsorption sites between lower S (Se) atoms in the S? Mo? S (Se? Mo? Se) structure and Au atoms via unique moiré superstructure formation for MoS₂ and MoSe₂ layers on Au(111). This observation indicates that the specific adsorption sites give rise to out‐of‐plane strain in the TMDC layers. Furthermore, it also leads to effective modulation of the electronic structure of the MoS₂ or MoSe₂ layer.     

Dimethyl Fumarate Induces Apoptosis via Inhibition of NF-κB and Enhances the Effect of Paclitaxel and Adriamycin in Human TNBC Cells

Triple-negative breast cancer (TNBC) has the poorest prognosis of all breast cancer subtypes. Recently, the activation of NF-κB, which is involved in the growth and survival of malignant tumors, has been demonstrated in TNBC, suggesting that NF-κB may serve as a new therapeutic target. In the present study, we examined whether dimethyl fumarate (DMF), an NF-κB inhibitor, induces apoptosis in TNBC cells and enhances the apoptosis-inducing effect of paclitaxel and adriamycin. Cell survival was analyzed by the trypan blue assay and apoptosis assay. Protein detection was examined by immunoblotting. The activation of NF-κB p65 was correlated with poor prognosis in patients with TNBC. DMF induced apoptosis in MDA-MB-231 and BT-549 cells at concentrations that were non-cytotoxic to the normal mammary cell line MCF-10A. Furthermore, DMF inhibited NF-κB nuclear translocation and Survivin, XIAP, Bcl-xL, and Bcl-2 expression in MDA-MB-231 and BT-549 cells. Moreover, DMF enhanced the apoptosis-inducing effect of paclitaxel and adriamycin in MDA-MB-231 cells. These findings suggest that DMF may be an effective therapeutic agent for the treatment of TNBC, in which NF-κB is constitutively active. DMF may also be useful as an adjuvant therapy to conventional anticancer drugs.     

Hematopoietic–Mesenchymal Signals Regulate the Properties of Mesenchymal Stem Cells

It is well known that the properties of hematopoietic stem/progenitor cells (HSCs), such as their self-renewal ability and multipotency, are maintained through interactions with mesenchymal stem/stromal cells (MSCs). MSCs are rare cells that are present in the bone marrow and are useful for clinical applications due to their functional ability. To obtain the necessary number of cells, MSCs must be cultured to expand, but this causes a remarkable decrease in stem cell properties, such as multipotency and proliferation ability. In this study, we show that the c-Mpl signal, which is related to the maintenance of hematopoietic stem cells, has an important effect on the proliferation and differentiation ability of MSCs. Utilizing a co-culture system comprising MSCs and HSCs, it is suggested that signaling from hematopoietic cells to MSCs supports cell proliferation. Interestingly, the enhanced proliferation ability of the HSCs was decreased in c-Mpl knock-out HSCs (c-Mpl-KO). In addition, the MSCs co-cultured with c-Mpl-KO HSCs had reduced MSC marker expression (PDGFRa and Sca-1) compared to the MSCs co-cultured with c-Mpl-wild-type HSCs. These results suggest that a hematopoietic–mesenchymal signal exists, and that the state of the HSCs is important for the stability of MSC properties.