Bulk Alignment of Chromonic Aggregates During Swelling of Hydrogels.

This study demonstrates that the bulk alignment of chromonic aggregates can be achieved during the swelling of hydrogels. Swelling of an ionic hydrogel immersed in an aqueous solution of disodium cromoglycate reorients the chromonic aggregates, and millimeter-thick optically anisotropic hydrogels are obtained. These anisotropic hydrogels contain the chromonic aggregates at a condensed concentration as high as in the columnar phase of a normal chromonic aqueous solution, although the X-ray diffraction results show much less stacking order and orientational order of the aggregates. Furthermore, anisotropic mechanical properties of the hydrogels are observed due to the anisotropic alignment of the chromonic aggregates.

Molecular Design for Preparation of Hexagonal-Ordered Porous Films Based on Side-Chain-Type Liquid-Crystalline Star Polymer.

Fabrication of regularly porous films by the breath-figure method has attracted much attention. The simple, low-cost technique uses the condensation of water droplets to produce these structures, but the phenomenon itself is complex, requiring control over many interacting parameters that change throughout the process. Developing a unified understanding for the molecular design of polymers to prepare ordered porous films is challenging, but required for further advancements. In this article, the effects of the chemical structure of polymers in the breath-figure technique were systematically explored using side-chain-type liquid-crystalline star polymers. The formation of porous films was affected by the structure of the polymers. Although the entire film surface of poly(11-[4-(4-cyanobiphenyl)oxy]undecyl methacrylate) (P11CB) had a hexagonal ordered porous structure over a certain Mn value, regularly arranged holes did not easily form in poly(methyl methacrylate) (PMMA), even though the main chain of PMMA is similar to that of P11CB. A comparison of P11CB and poly(11-[(1,1'-biphenyl)-4-yloxy]undecyl methacrylate) (P11B) (P11CB without cyano groups) showed that the local polar groups in hydrophobic polymers promoted the formation of ordered porous films. No holes were formed in poly(4-cyanobiphenyl methacrylate) (P0CB) (P11CB without alkyl spacers) films due to its hydrophilicity. The introduction of alkyl chains in P0CB allowed the preparation of honeycomb-structured films by increasing the internal tension. However, alkyl chains in the side chain alone did not result in a porous structure, as in the case of poly(undecyl methacrylate) (P11). Aromatic rings are also required to increase the Tg and improve film formability. In the present study, suitable molecular designs of polymers were found, specifically hydrophobic polymers with local polar groups, to form a regularly porous structure. Development of clear guidelines for the molecular design of polymers is the subject of our current research, which will enable the fabrication of porous films using various functional polymers.

Chiral lyotropic chromonic liquid crystals composed of disodium cromoglycate doped with water-soluble chiral additives.

We investigated the pitches of cholesteric liquid crystals prepared by mixing disodium cromoglycate (DSCG) in water with 5 different water-soluble chiral additives. The measurements are based on the Grandjean-Cano wedge cell method. Overall, the twisting effect is weak, and the shortest pitch of 2.9 ± 0.2 µm is obtained using trans-4-hydroxy-l-proline, by which the cholesteric sample is iridescent at certain viewing angles. Freeze-fracture transmission electron microscopy (FFTEM) was also performed for the first time on both the nematic and cholesteric phases, revealing that stacked chromonic aggregates are very long, up to a few hundred nm, which explains why cholesteric chromonic liquid crystals hardly have pitches in the visible wavelength region.

Unusual Electro-Optic Kerr Response in a Self-Stabilized Amorphous Blue Phase with Nanoscale Smectic Clusters.

We investigated the electro-optic response in the "foggy" amorphous blue phase (BPIII) as well as in the isotropic phase. To the best of our knowledge, such a study has not yet been performed due to the very limited thermal range of BPIII. In this study, we used a single-component chiral bent-core liquid crystal with a self-stabilized BPIII, which is stable over a wide temperature range. The results show that the response time is on the order of hundreds of microseconds in the isotropic phase and increases to 1-2 ms in the BPIII (at TI-BP -T <1), then drastically increases up to a few tens of milliseconds upon further cooling in BPIII. Such an unusual behavior was explained on the basis of the high rotational viscosity and/or the existence of nanoscale smectic (Sm) clusters. The Kerr constant was also measured and found to be ∼500 pm V(-2) , which is the largest among bent-core BP systems reported so far and comparable with that of polymer-stabilized BPs.

Ten-Gram-Scale Total Synthesis of the Anticancer Drug Candidate E7130 to Supply Clinical Trials.

E7130 is a novel drug candidate with an exceedingly complex chemical structure of the halichondrin class, discovered by a total synthesis approach through joint research between the Kishi group at Harvard University and Eisai. Only 18 months after completion of the initial milligram-scale synthesis, ten-gram-scale synthesis of E7130 was achieved, providing the first good manufacturing practice (GMP) batch to supply clinical trials. This paper highlights the challenges in developing ten-gram-scale synthesis from the milligram-scale synthesis.

Cryogenic electron ptychographic single particle analysis with wide bandwidth information transfer.

Advances in cryogenic transmission electron microscopy have revolutionised the determination of many macromolecular structures at atomic or near-atomic resolution. This method is based on conventional defocused phase contrast imaging. However, it has limitations of weaker contrast for small biological molecules embedded in vitreous ice, in comparison with cryo-ptychography, which shows increased contrast. Here we report a single-particle analysis based on the use of ptychographic reconstruction data, demonstrating that three dimensional reconstructions with a wide information transfer bandwidth can be recovered by Fourier domain synthesis. Our work suggests future applications in otherwise challenging single particle analyses, including small macromolecules and heterogeneous or flexible particles. In addition structure determination in situ within cells without the requirement for protein purification and expression may be possible.

Performance of low-voltage STEM/TEM with delta corrector and cold field emission gun.

To reduce radiation damage caused by the electron beam and to obtain high-contrast images of specimens, we have developed a highly stabilized transmission electron microscope equipped with a cold field emission gun and spherical aberration correctors for image- and probe-forming systems, which operates at lower acceleration voltages than conventional transmission electron microscopes. A delta-type aberration corrector is designed to simultaneously compensate for third-order spherical aberration and fifth-order 6-fold astigmatism. Both were successfully compensated in both scanning transmission electron microscopy (STEM) and transmission electron microscopy (TEM) modes in the range 30-60 kV. The Fourier transforms of raw high-angle annular dark field (HAADF) images of a Si[110] sample revealed spots corresponding to lattice spacings of 111 and 96 pm at 30 and 60 kV, respectively, and those of raw TEM images of an amorphous Ge film with gold particles showed spots corresponding to spacings of 91 and 79 pm at 30 and 60 kV, respectively. Er@C(82)-doped single-walled carbon nanotubes, which are carbon-based samples, were successfully observed by HAADF-STEM imaging with an atomic-level resolution.

Dramatic improvement in catalyst loadings and molar ratios of coupling partners for Ni/Cr-mediated coupling reactions: heterobimetallic catalysts.

Two new ligands 1a,b are reported. Upon treatment with 1 equiv of NiCl(2) x (MeOCH(2))(2), 1a,b give the corresponding Ni complexes. X-ray analysis of 1a x NiCl(2) established that the NiCl(2) is selectively coordinated to the phenanthroline nitrogens. Ni/Cr heterobimetallic catalysts 1a,b x CrCl(2)/NiCl(2), prepared from 1a,b x NiCl(2), have been shown to behave exceptionally well in catalytic asymmetric Ni/Cr-mediated couplings, with highlights including the following: (1) 1-2 mol % catalyst is sufficient to complete the coupling; (2) only negligible amounts of the dimers, byproducts formed through the alkenyl Ni species, are observed; (3) the coupling goes to completion even with a 1:1 molar ratio of the coupling partners; and (4) the asymmetric induction is practically identical with that obtained from the coupling with the Cr catalysts prepared from (S)-sulfonamides 2a,b. The scope of the new Ni/Cr heterobimetallic catalysts was briefly studied using four additional aldehydes. The applicability of the new catalysts to polyfunctional substrates was demonstrated by two C-C bond formations chosen from the halichondrin/E7389 synthesis as examples.

Toolbox approach to the search for effective ligands for catalytic asymmetric Cr-mediated coupling reactions.

Chromium catalysts derived from chiral sulfonamides represented by A effect the couplings of aldehydes with vinyl, allyl, or alkyl halides. With three distinct sites for structural modification, A affords access to a structurally diverse pool of chiral sulfonamides. The Cr catalysts derived from these sulfonamides exhibit a broad range of catalyst-substrate matching profiles. A strategy is presented to search for a satisfactory chiral sulfonamide for a given substrate. In order to demonstrate the generality and effectiveness of this approach, five diverse C-C bond-forming cases have been selected from the halichondrin synthesis. For each of the cases, two ligands have been deliberately searched for, to induce the formation of (R)- and (S)-alcohols, respectively, at the arbitrarily chosen efficiency level of ">or=80% yield with >or=20:1 stereoselectivity in the presence of

New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: reductive cyclization and oxy-Michael cyclization approaches.

Cr-mediated coupling reactions are usually achieved with a slight excess of a given nucleophile. To develop a cost-effective use of this process, two different approaches have been studied. The first approach depends on two consecutive catalytic asymmetric Cr-mediated couplings, with use of coupling partners purposely being of unbalanced molecular size and complexity. The second approach rests on the success in identifying the nucleophile, which allows us to achieve the coupling satisfactorily with a 1:1 molar ratio of the coupling partners. The C23-O bond is stereospecifically constructed via reductive cyclization of the oxonium ion, or oxy-Michael cyclization. Both syntheses have a high overall efficiency: E7389 C14-C35 and halichondrin C14-C38 building blocks have been synthesized from the corresponding C27-C35 and C27-C38 aldehydes, respectively, in high overall yields with an excellent stereoselectivity. Because of operational simplicity, the synthesis outlined herein appears to be well suited for scaling.

A landmark in drug discovery based on complex natural product synthesis.

Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery/development even for the cases of complex natural products.

Dismantlable Thermosetting Adhesives Composed of a Cross-Linkable Poly(olefin sulfone) with a Photobase Generator.

A novel photodetachable adhesive was prepared using a photodepolymerizable cross-linked poly(olefin sulfone). A mixture of a cross-linkable poly(olefin sulfone), a cross-linking reagent, and a photobase generator functioned as a thermosetting adhesive and exhibited high adhesive strength on quartz plates comparable to that obtained for commercially available epoxy adhesives. The cured resin was stable in the absence of UV light irradiation but completely lost its adhesive strength upon exposure of glued quartz plates to UV light in conjunction with heating to 100 °C.

Reading aloud and arithmetic calculation improve frontal function of people with dementia.

BACKGROUND: Recent findings of neuroimaging studies indicate that reading aloud and arithmetic calculation activate bilateral dorsolateral prefrontal cortex of humans. The purpose of this study was to measure the effect of reading aloud and arithmetic calculation, by elderly people who were clinically diagnosed with dementia Alzheimer type, on their brain functions and activities of daily living. METHODS: Sixteen experimental and 16 age- and Mini-Mental State Examination score-matched control subjects participated. The participants in the experimental group were asked to perform a training program using learning tasks in reading and arithmetic for 2-6 days a week. The function of the frontal cortex of the subjects was assessed by FAB at bedside (Frontal Assessment Battery). RESULTS: After 6 months of training, the FAB score of the experimental group showed a statistically significant improvement. The FAB score of the control group decreased slightly over the 6-month period, and the difference between the scores of the experimental and control groups was statistically significant. We also observed the restoration of communication and independence in the experimental group. CONCLUSION: Our results indicate that learning tasks of reading aloud and arithmetic calculation can be used for cognitive rehabilitation of dementia patients.

Multiparametric Phenotypic Screening System for Profiling Bioactive Compounds Using Human Fetal Hippocampal Neural Stem/Progenitor Cells.

Stem cell research has been progressing rapidly, contributing to regenerative biology and regenerative medicine. In this field, small-molecule compounds affecting stem cell proliferation/differentiation have been explored to understand stem cell biology and support regenerative medicine. In this study, we established a multiparametric screening system to detect bioactive compounds affecting the cell fate of human neural stem/progenitor cells (NSCs/NPCs), using human fetal hippocampal NSCs/NPCs, HIP-009 cells. We examined effects of 410 compounds, which were collected based on mechanisms of action (MOAs) and chemotypes, on HIP-009's cell fate (self-renewal, neuronal and astrocytic differentiation) and morphology by automated multiparametric assays and profiled induced cellular phenotypes. We found that this screening classified compounds with the same MOAs into subgroups according to additional pharmacological effects (e.g., mammalian target of rapamycin complex 1 [mTORC1] inhibitors and mTORC1/mTORC2 dual inhibitors among mTOR inhibitors). Moreover, it identified compounds that have off-target effects under matrix analyses of MOAs and structure similarities (e.g., neurotropic effects of amitriptyline among tri- and tetracyclic compounds). Therefore, this automated, medium-throughput and multiparametric screening system is useful for finding compounds that affect the cell fate of human NSCs/NPCs for supporting regenerative medicine and to fingerprint compounds based on human stem cells' multipotency, leading to understanding of stem cell biology.

Synthesis of the bicyclo[7.3.0]dodecatrienediyne core of the C-1027 chromophore.

[reaction: see text] C-1027, an extremely potent antitumor agent, is composed of chromophore 1 and an apoprotein. Here we report a general and efficient route to the exceedingly reactive bicyclo[7.3.0]dodecatrienediyne core of 1, utilizing selenoxide elimination and epoxide deoxygenation to build the cyclopentadiene and enediyne structures, respectively.

A functional MRI study of simple arithmetic--a comparison between children and adults.

The purpose of this study was to examine brain areas involved in simple arithmetic, and to compare these areas between adults and children. Eight children (four girls and four boys; age, 9-14 years) and eight adults (four women and four men; age, 40-49 years) were subjected to this study. Functional magnetic resonance imaging (fMRI) was performed during mental calculation of addition, subtraction, and multiplication of single digits. In each group, the left middle frontal, bilateral inferior temporal and bilateral lateral occipital cortices were activated during each task. The adult group showed activation of the right frontal cortex during addition and multiplication tasks, but the children group did not. Activation of the intraparietal cortex was observed in the adult group during each task. Although, activation patterns were slightly different among tasks, as well as between groups, only a small number of areas showed statistically significant differences. The results indicate that cortical networks involved in simple arithmetic are similar among arithmetic operations, and may not show significant changes in the structure during the second decade of life.

Dynamic amplification of light signals in photorefractive ferroelectric liquid crystalline mixtures.

The photorefractive effect in photoconductive ferroelectric liquid crystals that contain photoconductive chiral compounds was investigated. Terthiophene compounds with chiral structures were chosen as the photoconductive chiral compounds, and they were mixed with an achiral smectic C liquid crystal. The mixtures exhibit the ferroelectric chiral smectic C phase. The photorefractivity of the mixtures was investigated by two-beam coupling experiments. It was found that the ferroelectric liquid crystals containing the photoconductive chiral compound exhibit a large gain coefficient of over 1200 cm(-1) and a fast response time of 1 ms. Real-time dynamic amplification of an optical image signal of over 30 fps using the photorefractive ferroelectric liquid crystal was demonstrated.

Resolution enhancement at a large convergence angle by a delta corrector with a CFEG in a low-accelerating-voltage STEM.

Resolution reduction by a diffraction limit becomes severe with an increase in the wavelength of an electron at a relatively low accelerating voltage. For maintaining atomic resolution at a low accelerating voltage, a larger convergence angle with aberration correction is required. The developed aberration corrector, which compensates for higher-order aberration, can expand the uniform phase angle. Sub-angstrom imaging of a Ge [112] specimen with a narrow energy spread obtained by a cold field emission gun at 60 kV was performed using the aberration corrector. We achieved a resolution of 82 pm for a Ge-Ge dumbbell structure image by high angle annular dark-field imaging.

Aberration-corrected STEM/TEM imaging at 15kV.

The performance of aberration-corrected (scanning) transmission electron microscopy (S/TEM) at an accelerating voltage of 15kV was evaluated in a low-voltage microscope equipped with a cold-field emission gun and a higher-order aberration corrector. Aberrations up to the fifth order were corrected by the aberration measurement and auto-correction system using the diffractogram tableau method in TEM and Ronchigram analysis in STEM. TEM observation of nanometer-sized particles demonstrated that aberrations up to an angle of 50mrad were compensated. A TEM image of Si[110] exhibited lattice fringes with a spacing of 0.192nm, and the power spectrum of the image showed spots corresponding to distances of 0.111nm. An annular dark-field STEM image of Si[110] showed lattice fringes of (111) and (22¯0) planes corresponding to lattice distances of 0.314nm and 0.192nm, respectively. At an accelerating voltage of 15kV, the developed low-voltage microscope achieved atomic-resolution imaging with a small chromatic aberration and a large uniform phase.

Quantitative evaluation of temporal partial coherence using 3D Fourier transforms of through-focus TEM images.

We evaluate the temporal partial coherence of transmission electron microscopy (TEM) using the three-dimensional (3D) Fourier transform (FT) of through-focus images. Young's fringe method often indicates the unexpected high-frequency information due to non-linear imaging terms. We have already used the 3D FT of axial (non-tilted) through-focus images to reduce the effect of non-linear terms on the linear imaging term, and demonstrated the improvement of monochromated lower-voltage TEM performance [Kimoto et al., Ultramicroscopy 121 (2012) 31-39]. Here we apply the 3D FT method with intentionally tilted incidence to normalize various factors associated with a TEM specimen and an imaging device. The temporal partial coherence of two microscopes operated at 30, 60 and 80 kV is evaluated. Our method is applicable to such cases where the non-linear terms become more significant in lower acceleration voltage or aberration-corrected high spatial resolution TEM.