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.     

Magnetic dipole moment of the doubly-closed-shell plus one proton nucleus ^{49}sc

The nucleus ^{49}Sc, having a single f_{7/2} proton outside doubly magic ^{48}Ca (Z=20, N=28), is one of the very few isotopes which makes possible testing of the fundamental theory of nuclear magnetism. The magnetic moment has been measured by online β NMR of nuclei oriented at milli-Kelvin temperatures to be (+)5.616(25) μ_{N}. The result is discussed in terms of a detailed theory of the structure of the magnetic moment operator, showing excellent agreement with calculated departure from the f_{7/2} Schmidt limit extreme single-particle value. The measurement completes the sequence of moments of Sc isotopes with even numbers of f_{7/2} neutrons: the first such isotopic chain between two major shells for which a full set of moment measurements exists. The result further completes the isotonic sequence of ground-state moments of nuclei with an odd number of f_{7/2} protons coupled to a closed subshell of f_{7/2} neutrons. Comparison with a recent shell-model calculation of the latter sequence is made.     

Tumescenamide C,an antimicrobial cyclic lipodepsipeptide from Streptomyces sp.

Tumescenamide C, a new cyclic lipodepsipeptide, was isolated from a culture broth of an actinomycete Streptomyces sp. KUSC_F05. Tumescenamide C was a congener of tumescenamides A and B, representing a sixteen-membered ring system, consisting of two proteinogenic and three non-proteinogenic amino acids, to which a methyl-branched fatty acid was attached. The planar structure was determined by spectroscopic analysis, while its absolute stereochemistry was determined by chemical degradation and asymmetric synthesis. Tumescenamide C exhibited antimicrobial activity with high selectivity against Streptomyces species.     

Studies on the mechanism for stereoisomerization of 1-zirconacyclopent-3-yne compounds

The stereoisomerization of 2,5-disubstituted 1-zirconacyclopent-3-yne compounds, stable five-membered cycloalkynes, has been studied with regard to the mechanism. The bimetallic complex of 1,4-bis(trimethylsilyl)butatriene was synthesized and structurally characterized, although it seems unimportant for the stereoisomerization reactions. The isomerization of trans-1,1-bis(η⁵-cyclopentadienyl)-2,5-bis(trimethylsilyl)-1-zirconacyclopent-3-yne 2a into the cis-form in benzene-d₆ solution were observed using ¹H NMR spectroscopy at 50 °C in various concentrations. The reaction was first order with respect to trans-2a. This ruled out the possibility that a bimetallic complex was responsible for the isomerization. A kinetic isotope effect was observed (k_H/k_D = 1.8), suggesting that C–H activation is involved in the rate-determining step. A mechanism via hydrogen elimination from the complex of η⁴-π,π-coordination mode is proposed.     

Total Synthesis of Hydroxy-α- and Hydroxy-β-sanshool Using Suzuki-Miyaura Coupling

Here, we describe the first total synthesis of hydroxyl-α- and hydroxyl-β-sanshool, which involves Suzuki-Miyaura coupling (SMC). Hydroxy-α-sanshool (1) was synthesized by SMC of bromoalkyne 4 with boronate 3 followed by (Z)-selective reduction of the triple bond in the coupling product. Hydroxy-β-sanshool (2) was synthesized by regio- and (E)-selective conversion of 4 to iodoalkene 11 followed by SMC with 3.     

The intercalation of N,N,N',N'-tetramethyl-ethane-1,2-diamine (tmeda) into C6Li and C12Li

Liquid N,N,N',N'-tetramethyl-ethane-1,2-diamine (tmeda) was intercalated into preprepared C(6)Li or C(12)Li. X-ray diffraction from the ternary compound indicates an identity period of 11.5 ?. The (13)C NMR line shifts show that tmeda molecules form a screen between the graphene planes and the lithium ions. Small-angle X-ray scattering showed that no higher structural ordering was present but revealed a progressive roughening of the surfaces with successive intercalation of lithium and amine into the graphite galleries.     

Core temperature and density profile measurements in inertial confinement fusion implosions

We have measured time-integrated and time-gated electron temperature (T_e) and density (N_e) spatial profiles from indirect-drive implosions. In our experiments, we used a multiple-pinhole two-dimensional imaging spectrometer to obtain multispectral X-ray images of the imploded core. Quantitative comparisons between quasi-monochromatic images in different energy bands allowed T_e and N_e spatial profiles to be determined using two independent and validated techniques: a multi-objective search and reconstruction analysis, and an analytical analysis. We then compared the results to a simple one-dimensional (1D) mix-free hydrodynamics simulation in order to evaluate the ability of such a model to predict our experiments. Our data show spatial T_e profiles that are qualitatively consistent with the predictions of our 1D simulations, but we observe central cores that are 10–25% cooler and emit X-rays as late as 200 ps after peak compression. We infer time-gated spatial N_e profiles that are consistent with our 1D simulations near the times of peak compression, but we find significant disagreement between time-integrated data and 1D simulation predictions at large radii. Careful analysis of the time-gated and time-integrated T_e and N_e spatial profiles, together with streaked X-ray emission spectra from core and shell dopants, suggests mixing of shell material into the core is an important process that our 1D hydrodynamics simulations fail to capture, and comparison between image data and a simple analytical model suggests that 2–5 μm of the initial inner shell thickness mixes into the core during the time period of significant X-ray emission. This mix width is consistent with the predictions of a growth-factor analysis that treats instability growth seeded by capsule surface roughness, and points to the need to consider time-dependent mixing effects when interpreting T_e and N_e spatial profiles derived from multispectral X-ray image data, particularly at large radii where mixing effects will be most significant.     

Brute-force NMR-ON on 90NbCu, 101mRhCu and110mAgAg

Brute-force nuclear magnetic resonance on oriented nuclei (BF-NMRON) experiments have been performed for ⁹⁰NbCu, ^101m RhCu and ^110m AgAg at about 10mK. Narrow resonance spectra were detected. Using the known values of the g-factors, the Knight shift has been deduced: K(⁹⁰NbCu) = 0.62(24) %, K(^101m RhCu) = 0.87(27)%. The effective spin–lattice relaxation times were also measured.     

Multiresolution Approach to Image Reconstruction with Phase-Diversity Technique

A multiresolution analysis is adopted to improve an image reconstruction with a phase-diversity technique. The phase distribution at low resolution is first estimated and then is used as an initial estimate for phase reconstruction at a higher resolution level. Computer simulations are conducted to confirm the proposed method. The method is applied for image reconstruction of solar granulation.     

Experimental and theoretical study of recovery mechanism of impurity effect by the addition of EDTA

The impurity effect by trivalent metal ion such as Al³⁺, Fe³⁺ and Cr³⁺ during crystal growth of KDP is reasonably well documented. If a metal ion is adsorbed onto the crystal surface, it prevents the step propagation relevant to the crystal growth rate. However, this impurity adsorption mechanism is still not well understood. Recently, in our work on the addition of chelate agents, a recovery effect of the metal ion adsorption was discovered. However, its recovery mechanism is not clearly understood both theoretically and phenomenally. In this research, ethylene‐diamine‐tetra‐acetic acid, EDTA, which is the most common chelate agent, was used as a recovery agent. The recovery mechanism was considered from the correlation of experimental data and the interfacial distribution model that we proposed in our former study. Furthermore, quantum calculation of EDTA metal complex can explain the relaxation of impurity adsorption by the addition of EDTA. (© 2007 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)