Preparation of highly dispersible and tumor-accumulative, iron oxide nanoparticles Multi-point anchoring of PEG-b-poly(4-vinylbenzylphosphonate) improves performance significantly

This paper describes the preparation of iron oxide nanoparticles, surface of which was coated with extremely high immobilization stability and relatively higher density of poly(ethylene glycol) (PEG), which are referred to as PEG protected iron oxide nanoparticles (PEG-PIONs). The PEG-PIONs were obtained through alkali coprecipitation of iron salts in the presence of the PEG-poly(4-vinylbenzylphosphonate) block copolymer (PEG-b-PVBP). In this system, PEG-b-PVBP served as a surface coating that was bound to the iron oxide surface via multipoint anchoring of the phosphonate groups in the PVBP segment of PEG-b-PVBP. The binding of PEG-b-PVBP onto the iron oxide nanoparticle surface and the subsequent formation of a PEG brush layer were proved by FT-IR, zeta potential, and thermogravimetric measurements. The surface PEG-chain density of the PEG-PIONs varied depending on the [PEG-b-PVBP]/[iron salts] feed-weight ratio in the coprecipitation reaction. PEG-PIONs prepared at an optimal feed-weight ratio in this study showed a high surface PEG-chain surface density (≈0.8 chainsnm(-2)) and small hydrodynamic diameter (<50 nm). Furthermore, these PEG-PIONs could be dispersed in phosphate-buffered saline (PBS) that contains 10% serum without any change in their hydrodynamic diameters over a period of one week, indicating that PEG-PIONs would provide high dispersion stability under in vivo physiological conditions as well as excellent anti-biofouling properties. In fact we have confirmed the prolong blood circulation time and facilitate tumor accumulation (more than 15% IDg(-1) tumor) of PEG-PIONs without the aid of any target ligand in mouse tumor models. The majority of the PEG-PIONs accumulated in the tumor by 96 h after administration, whereas those in normal tissues were smoothly eliminated by 96 h, proving the enhancement of tumor selectivity in the PEG-PION localization. The results obtained here strongly suggest that originally synthesized PEG-b-PVBP, having multipoint anchoring character by the phosphonate groups, is rational design for improvement in nanoparticle as in vivo application. Two major points, viz., extremely stable anchoring character and dense PEG chains tethered on the nanoparticle surface, worked simultaneously to become PEG-PIONs as an ideal biomedical devices intact for prolonged periods in harsh biological environments.     

A re-investigation of the crystal structure and luminescence of BaCa2MgSi2O8:Eu

Barium calcium magnesium silicate (BaCa₂MgSi₂O₈), a compound whose space group was obtained via X-ray diffraction data, was re-investigated using neutron diffraction techniques. A combined powder X-ray and neutron Rietveld method revealed that BaCa₂MgSi₂O₈ crystallizes in the trigonal space group P3? (Z=1, a=5.42708(5) Å, c=6.79455(7) Å, V=173.310(4) Å³; R_p/R_wp=5.52%/7.63%), instead of the previously believed space group P3?m1. The difference in the two structures arises from the displacement of the O2 atom. Blue emission from Ba_0.98Eu_0.02Ca₂MgSi₂O₈ under 325-nm excitation is ascribed to the 4f⁶5d¹→4f⁷ transitions of Eu²⁺ ions at Ba sites and Ca sites. Site assignment of Eu²⁺ ions in the titled compound was performed by analysis of emission spectra at temperatures in the range of 4.2-300 K.     

A photocleavable rapamycin conjugate for spatiotemporal control of small GTPase activity

We developed a novel method to spatiotemporally control the activity of signaling molecules. A newly synthesized photocaged rapamycin derivative induced rapid dimerization of FKBP (FK-506 binding protein) and FRB (FKBP-rapamycin binding protein) upon UV irradiation. With this system and the spatially confined UV irradiation, we achieved subcellularly localized activation of Rac, a member of small GTPases. Our technique offers a powerful approach to studies of dynamic intracellular signaling events.     

Synthesis and structural revision of phomopsin B, a novel polyketide carrying a 10-membered cyclic-ether ring

Total synthesis of the proposed structure 2 for phomopsin B was achieved by using an intramolecular olefin metathesis as a key step. The spectral data, however, did not match with those of the natural product reported. Re-examination of the reported NMR data led to the structural revision of phomopsin B to known dothiorelone A 18. The R configuration of dothiorelone A was determined by total synthesis through a cross-metathesis with a chiral olefin 19.     

Distribution of phospholipid molecular species in autogenous access grafts for hemodialysis analyzed using imaging mass spectrometry

Arteriovenous fistulae (AVF) using vein grafts are frequently used for vascular access in hemodialysis. When superficial veins are used as autogenous access grafts for hemodialysis, atherosclerotic-like tissue degeneration often causes stenosis and obstruction. Although the differences between the pathology of degeneration in AVF and atherosclerosis (i.e., peripheral artery occlusive disease (PAD)) are known, their underlying molecular mechanisms are not. We determined the characteristic abnormal lipid metabolism of AVF. Oil red O staining clearly showed the accumulation of lipid molecules in AVF and PAD tissues. We found that the staining pattern was different between AVF and PAD tissues. The media and adventitia of AVF and the intima and media of PAD were intensely stained. Quantitative lipid analysis revealed that the amount of PL was significantly increased in AVF and PAD. Next, we performed matrix-assisted laser desorption/ionization imaging mass spectroscopy and determined the characteristic distribution of lysophosphatidylcholine (LPC) and phosphatidylcholine (PC) in AVF. The distribution patterns of LPC (1-acyl 16:0) and PC (diacyl 16:0/20:4) were consistent with the Oil red O staining images, suggesting that metabolisms related to LPC (1-acyl 16:0) and PC (diacyl 16:0/20:4) are altered in AVF.     

Authenticity assessment of beef origin by principal component analysis of matrix-assisted laser desorption/ionization mass spectrometric data

It has become necessary to assess the authenticity of beef origin because of concerns regarding human health hazards. In this study, we used a metabolomic approach involving matrix-assisted laser desorption/ionization imaging mass spectrometry to assess the authenticity of beef origin. Highly accurate data were obtained for samples of extracted lipids from beef of different origin; the samples were grouped according to their origin. The analysis of extracted lipids in this study ended within 10 min, suggesting this approach can be used as a simple authenticity assessment before a definitive identification by isotope analysis.     

Visualization of phosphatidylcholine,lysophosphatidylcholine and sphingomyelin in mouse tongue body by matrix-assisted laser desorption/ionization imaging mass spectrometry

The mammalian tongue is one of the most important organs during food uptake because it is helpful for mastication and swallowing. In addition, taste receptors are present on the surface of the tongue. Lipids are the second most abundant biomolecules after water in the tongue. Lipids such as phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and sphingomyelin (SM) are considered to play fundamental roles in the mediation of cell signaling. Imaging mass spectrometry (IMS) is powerful tool for determining and visualizing the distribution of lipids across sections of dissected tissue. In this study, we identified and visualized the PC, LPC, and SM species in a mouse tongue body section with matrix-assisted laser desorption/ionization (MALDI)-IMS. The ion image constructed from the peaks revealed that docosahexaenoic acid (DHA)-containing PC, LPC, linoleic acid-containing PC and SM (d18:1/16:0), and oleic acid-containing PC were mainly distributed in muscle, connective tissue, stratified epithelium, and the peripheral nerve, respectively. Furthermore, the distribution of SM (d18:1/16:0) corresponded to the distribution of nerve tissue relating to taste in the stratified epithelium. This study represents the first visualization of PC, LPC and SM localization in the mouse tongue body.     

Abnormal phospholipids distribution in the prefrontal cortex from a patient with schizophrenia revealed by matrix-assisted laser desorption/ionization imaging mass spectrometry

Schizophrenia is one of the major psychiatric disorders, and lipids have focused on the important roles in this disorder. In fact, lipids related to various functions in the brain. Previous studies have indicated that phospholipids, particularly ones containing polyunsaturated fatty acyl residues, are deficient in postmortem brains from patients with schizophrenia. However, due to the difficulties in handling human postmortem brains, particularly the large size and complex structures of the human brain, there is little agreement regarding the qualitative and quantitative abnormalities of phospholipids in brains from patients with schizophrenia, particularly if corresponding brain regions are not used. In this study, to overcome these problems, we employed matrix-assisted laser desorption/ionization imaging mass spectrometry (IMS), enabling direct microregion analysis of phospholipids in the postmortem brain of a patient with schizophrenia via brain sections prepared on glass slides. With integration of traditional histochemical examination, we could analyze regions of interest in the brain at the micrometric level. We found abnormal phospholipid distributions within internal brain structures, namely, the frontal cortex and occipital cortex. IMS revealed abnormal distributions of phosphatidylcholine molecular species particularly in the cortical layer of frontal cortex region. In addition, the combined use of liquid chromatography/electrospray ionization tandem mass spectrometry strengthened the capability for identification of numerous lipid molecular species. Our results are expected to further elucidate various metabolic processes in the neural system.     

Minitwistor spaces,Severi varieties,and Einstein–Weyl structure

In this article, we show that the space of nodal rational curves, which is so called a Severi variety (of rational curves), on any non-singular projective surface is always equipped with a natural Einstein–Weyl structure, if the space is 3-dimensional. This is a generalization of the Einstein–Weyl structure on the space of smooth rational curves on a complex surface, given by Hitchin. As geometric objects naturally associated to Einstein–Weyl structure, we investigate null surfaces and geodesics on the Severi varieties. Also, we see that if the projective surface has an appropriate real structure, then the real locus of the Severi variety becomes a positive definite Einstein–Weyl manifold. Moreover, we construct various explicit examples of rational surfaces having 3-dimensional Severi varieties of rational curves.     

Ellagic Acid Suppresses ApoB Secretion and Enhances ApoA-1 Secretion from Human Hepatoma Cells,HepG2

The effect of ellagic acid (EA), a naturally occurring polyphenolic compound, on the secretion of apolipoproteins from human hepatocytes, HepG2, was investigated. The levels of apoB and apoA-1 secreted in the cell culture medium were determined by sandwich ELISA. EA did not affect cell viability at the tested concentrations (up to 50 µM). EA suppressed the secretion of apoB and enhanced that of apoA-1 from HepG2 cells. However, cellular apoB levels were increased, suggesting that EA inhibited the trafficking of apoB during the process of secretion. In contrast, the increase in the cellular levels of apoA-1 was consistent with its secreted levels. These results indicate that EA inhibits the secretion of apoB from hepatocytes and increases the secretion of apoA-1. Both of these effects are beneficial for lipoprotein metabolism in the prevention of lifestyle-related diseases. The detailed mechanism underlying these effects of EA on lipoprotein metabolism should be elucidated in the future, but this naturally occurring polyphenolic compound might be antihyperlipidemic. Based on these results, EA is suggested as a candidate food-derived compound for the prevention of hyperlipidemia.