In vivo assessment of the permeability of the blood--brain barrier and blood-retinal barrier to fluorescent indoline derivatives in zebrafish

ABSTRACT: BACKGROUND: Successful delivery of compounds to the brain and retina is a challenge in the development of therapeutic drugs and imaging agents. This challenge arises because internalization of compounds into the brain and retina is restricted by the blood--brain barrier (BBB) and blood-retinal barrier (BRB), respectively. Simple and reliable in vivo assays are necessary to identify compounds that can easily cross the BBB and BRB. METHODS: We developed six fluorescent indoline derivatives (IDs) and examined their ability to cross the BBB and BRB in zebrafish by in vivo fluorescence imaging. These fluorescent IDs were administered to live zebrafish by immersing the zebrafish larvae at 7--8 days post fertilization in medium containing the ID, or by intracardiac injection. We also examined the effect of multidrug resistance proteins (MRPs) on the permeability of the BBB and BRB to the ID using MK571, a selective inhibitor of MRPs. RESULTS: The permeability of these barriers to fluorescent IDs administered by simple immersion was comparable to when administered by intracardiac injection. Thus, this finding supports the validity of drug administration by simple immersion for the assessment of BBB and BRB permeability to fluorescent IDs. Using this zebrafish model, we demonstrated that the length of the methylene chain in these fluorescent IDs significantly affected their ability to cross the BBB and BRB via MRPs. CONCLUSIONS: We demonstrated that in vivo assessment of the permeability of the BBB and BRB to fluorescent IDs could be simply and reliably performed using zebrafish. The structure of fluorescent IDs can be flexibly modified and, thus, the permeability of the BBB and BRB to a large number of IDs can be assessed using this zebrafish-based assay. The large amount of data acquired might be useful for in silico analysis to elucidate the precise mechanisms underlying the interactions between chemical structure and the efflux transporters at the BBB and BRB. In turn, understanding these mechanisms may lead to the efficient design of compounds targeting the brain and retina.     

Precise measurement of positronium hyperfine splitting using the Zeeman effect

Positronium is an ideal system for the research of the quantum electrodynamics (QED) in bound state. The hyperfine splitting (HFS) of positronium, Δ_HFS, gives a good test of the bound state calculations and probes new physics beyond the Standard Model. A new method of QED calculations has revealed the discrepancy by 15 ppm (3.9σ) of Δ_HFS between the QED prediction and the experimental average. There would be possibility of new physics or common systematic uncertainties in the previous all experiments. We describe a new experiment to reduce possible systematic uncertainties and will provide an independent check of the discrepancy. We are now taking data and the current result of Δ_HFS?=?203.395 1 ±0.002 4 (stat., 12 ppm) ±0.001 9 (sys., 9.5 ppm) GHz has been obtained so far. A measurement with a precision of O(ppm) is expected within a year.     

Power extraction using flow-induced vibration of a circular cylinder placed near another fixed cylinder

We conducted an experiment in a towing tank to investigate the performance of an energy extraction system using the flow-induced vibration of a circular cylinder. This experiment tested three different cases involving the following arrangements of cylinder(s) of identical diameter: the upstream fixed–downstream movable arrangement (case F); the upstream movable–downstream fixed arrangement (case R); and a movable isolated cylinder (case I). In cases F and R, the separation distance (ratio of the distance between the centers of the two cylinders to their diameters) is fixed at 1.30. Measurement results show that while cases F and I generate vortex-induced vibration (VIV) resonance responses, case R yields wake-induced vibration (WIV) at reduced velocity over 9.0, which is significantly larger than that of the VIV response, leading to the induction of higher electronic power in a generator. Accordingly, primary energy conversion efficiency is higher in the case involving WIV.     

Formation mechanism of element distribution in glass under femtosecond laser irradiation

We report on the formation mechanism of element distribution in glass under high-repetition-rate femtosecond laser irradiation. We simultaneously focused two beams of femtosecond laser pulses inside a glass and confirmed the formation of characteristically shaped element distributions. The results of the numerical simulation in which we considered concentration- and temperature-gradient-driven diffusions were in excellent qualitative agreement with the experimental results, indicating that the main driving force is the sharp temperature gradient. Since the composition of a glass affects its refractive index, absorption, and luminescence property, the results in this study provide a framework to fabricate a functional optical device such as optical circuits with a high-repetition-rate femtosecond laser.     

Structural phase transitions at clean and metal-covered Si(111) surfaces investigated by RHEED spot analysis

Structural phase transitions between various kinds of superlattice structures formed on a Si(111) surface have been investigated by spot analysis of reflection high-energy electron diffraction (RHEED). Reversible transitions induced by temperature changes and irreversible ones induced by metal depositions were observed. Detailed discussions on the dynamics of the phase transitions are made by quantitative analyses of integrated spot intensity and profile. For a phase transition of 7′7  1′1 structures on a clean Si(111) surface, a hysteresis with temperature difference of 5°C. between in heating and cooling processes was found in the spot intensity change, indicating a first-order transition. Hysteresis was hardly recognized, on the other hand, for transitions of Au-induced superstructures (5×2-Au or ×-Au)  1×1-Au. The spot profiles were found to be broadened during the transition of Si(111)-×-Au  1×1-Au, which was a signature of a continuous transition, while the profiles remained unchanged during the transitions of the 7×7  1×1 and 5×2-Au  1×1-Au phases. Structural conversions induced by In adsorption on the Si(111) surface kept at constant temperatures were also analyzed. The conversions at room temperature were totally dependent on the initial substrate surface structures; the 7×7 surface did not show any structural conversion with In adsorption, while the ×-In surface successively converted to a 2×2 and a × phase with coverage increase. The structural transitions at elevated temperatures were sensitively dependent on the temperatures. Sequences of transitions among the 7×7, 4×1, ×, 1×, and ×4 were quantitatively revealed as changes in RHEED spot intensity.     

Refractive index behavior of SiO2-P2O5 glass in optical fiber application

The refractive index of SiO₂-P₂O₅ glass prepared by a modified chemical vapor deposition method is measured using an interference microscope. It is found that the refractive index in bulk form increases linearly at 9.5×10^-4 (mol.%)^-1 as the P₂O₅ concentration increases. It is also found that quenching at extremely high speed reduces the refractive index over 2 mol.% P₂O₅. The wavelength dispersion of the refractive index dn/dλ is constant up to 5 mol.% P₂O₅ producing a refractive index difference of 5×10^-3 compared with fused silica. Consequently, this glass materials is thought to be suitable for wide band-width optical fiber applications.     

Digital image analysis of polymer blends morphology

Application of digital image analysis (DIA) to polymer blends morphology is discussed with examples. Various operations in DIA including two-dimensional Fourier transformation (2DFT), intensity distribution, recursive region extraction, etc. are applied to morphology of polymer blends due to spinodal decomposition (SD), nucleation 6 growth (NG), and eutectic solidification (ES). Merits and drawbacks of DIA to study polymer blends morphology are discussed and the possibility of future development is presented.