Neural stem cells and strategies for the regeneration of the central nervous system

The adult mammalian central nervous system (CNS), especially that of adult humans, is a representative example of organs that do not regenerate. However, increasing interest has focused on the development of innovative therapeutic methods that aim to regenerate damaged CNS tissue by taking advantage of recent advances in stem cell and neuroscience research. In fact, the recapitulation of normal neural development has become a vital strategy for CNS regeneration. Normal CNS development is initiated by the induction of stem cells in the CNS, i.e., neural stem cells (NSCs). Thus, the introduction or mobilization of NSCs could be expected to lead to CNS regeneration by recapitulating normal CNS development, in terms of the activation of the endogenous regenerative capacity and cell transplantation therapy. Here, the recent progress in basic stem cell biology, including the author’s own studies, on the prospective identification of NSCs, the elucidation of the mechanisms of ontogenic changes in the differentiation potential of NSCs, the induction of neural fate and NSCs from pluripotent stem cells, and their therapeutic applications are summarized. These lines of research will, hopefully, contribute to a basic understanding of the nature of NSCs, which should in turn lead to feasible strategies for the development of ideal “stem cell therapies” for the treatment of damaged brain and spinal cord tissue.     

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.     

Electroluminescence properties of In-doped Zn2SiO4 thin films prepared by sol–gel process

The effect of In doping on the electroluminescence (EL) properties of Zn₂SiO₄:In thin films was investigated. In-doped Zn₂SiO₄ thin films were deposited on BaTiO₃ substrates and their EL properties were characterized in this study. X-ray powder diffraction patterns of In-doped Zn₂SiO₄ powders revealed a single phase of Zn₂SiO₄ for In concentrations up to approximately 1.5 mol%, whereas a secondary phase of In₂O₃ was observed for In concentrations in the range of 2–10 mol%. The maximum luminance of thin film electroluminescent (TFEL) devices varied significantly with the amount of In doping. The highest luminance with blue emission was obtained when 2 mol% In was doped. The blue emission of In-doped Zn₂SiO₄ thin film may be related to the In substitution for Zn. The 2 mol% In-doped Zn₂SiO₄ thin film exhibited blue emission with CIE color coordinates of x=0.208 and y=0.086.     

Detection of high-energy gamma rays from winter thunderclouds

A report is made on a comprehensive observation of a burstlike gamma-ray emission from thunderclouds on the Sea of Japan, during strong thunderstorms on 6 January 2007. The detected emission, lasting for approximately 40 sec, preceded cloud-to-ground lightning discharges. The burst spectrum, extending to 10 MeV, can be interpreted as consisting of bremsstrahlung photons originating from relativistic electrons. This ground-based observation provides the first clear evidence that strong electric fields in thunderclouds can continuously accelerate electrons beyond 10 MeV prior to lightning discharges.     

Total synthesis of PDE-I and -II by copper-mediated double aryl amination

A concise total synthesis of PDE-I and -II featuring copper-mediated double aryl amination with the combination of CuI, CsOAc, and Cs₂CO₃ is described. The highly substituted pyrroloindole skeleton was constructed by a one-pot five-step sequence including double aryl amination, β-elimination, deprotection of a Cbz group, and unexpected formation of an indole via removal of an Ns group followed by rearomatization. The undesired elimination of the protecting group (Ns group) was hampered by using the Boc group as a protecting group in the second-generation synthesis, which excluded the reduction of the indole required in the first-generation synthesis.     

Interplay between structure and magnetism in Mo12S9I9 nanowires

We investigate the equilibrium geometry and electronic structure of Mo12S9I9 nanowires using ab initio density functional calculations. The skeleton of these unusually stable nanowires consists of rigid, functionalized Mo octahedra, connected by flexible, bistable sulfur bridges. This structural flexibility translates into a capability to stretch up to approximately 20% at almost no energy cost. The nanowires change from conductors to narrow-gap magnetic semiconductors in one of their structural isomers.     

Predicting experimental yields as an index to rank synthesis routes II: application to the Curtius rearrangement

Synthesis yields of organic reactions are one of the most important factors in ranking synthesis routes created by synthesis route design systems such as Transform‐Oriented Synthesis Planning and Knowledge base‐Oriented Synthesis Planning. If it is possible to predict the yields of synthesis reactions before starting experiments, one can easily determine an order of synthesis routes for experimental works. In the present study, the reaction profiles of the Curtius rearrangement with different substituents were calculated to generate an equation predicting experimental yields of this reaction. Reactions followed by the formation of isocyanates were also analyzed to consider the relationship between reaction times and experimental yields. A partial least squares (PLS) regression was used to correlate the experimental yields with the calculated activation energies, E_a(calc), together with experimental conditions such as dielectric constants of solvents, reaction times, and reaction temperatures as explanatory variables. Although the PLS regression using all the data gave very poor results, we succeeded in making a model equation with R² = 0.887 using a modified data set. However, there is a conflict between the predictability and the interpretability on the reaction time. This discrepancy mainly comes from unnecessarily long reaction times in the experiments for azides with calculated E_a values of less than 33 kcal mol^–1. To construct a good model equation for the experimental yields of the Curtius reaction, we have to use data sets obtained from within 90 min of the reaction for the PLS regression. Copyright © 2011 John Wiley & Sons, Ltd.     

A novel synthesis of half-protected 1,3-dicarbonyl compounds

It has been found that the reaction of enol silyl ethers with 2-ethoxy-1,3-dithiolane proceeds smoothly in the presence of zinc chloride catalyst to afford half-protected 1,3-dicarbony1 compounds in moderately good yields.