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Long-term durability and safety are required to develop Li-ion batteries that can operate at high voltages. However, side reactions, including the release of O 2 from the electrode and CO 2 from the organic electrolyte, occur at the positive-electrode/electrolyte interface during charging at high voltages. In this study, universal neural network potential (UNNP)-driven molecular dynamics (MD) calculations are used to investigate the mechanism of the reaction between Li x CoO 2 (0 ≤ x ≤ 1) or Li x NiO 2 (0 ≤ x ≤ 1), as the positive-electrode material, and an ethylene-carbonate-based electrolyte, with a solid-liquid interface composed of ∼1700 atoms. Molecular CO 2 and O 2 evolve from the partially or fully Li-deintercalated Li x NiO 2 , while no gas-evolution reactions are observed for Li x CoO 2 . Hence, compared Li x NiO 2 , the LiCoO 2 electrode is more stable toward the decomposition of ethylene carbonate in the charged state. The decomposition reactions at the solid-liquid interface during charging are also analyzed using a NN force field. This study provides a robust approach involving MD simulations using UNNP to better understand the side reactions in electrochemical devices, which can guide manufacturers in selecting appropriate materials.

In this study, we have developed a smooth metal-free visible-light-induced bromo-perfluoroalkylation of unactivated olefins with the aid of 10-phenylphenothiazine (PTH) as an organic photoredox catalyst. The reaction is 100% atom-economic redox-neutral and proceeds with stoichiometric amounts of olefin and perfluoroalkyl bromide. To show the potential of these unexplored motifs, we carried out various postfunctionalizations taking advantage of the bromine atom, including gram-scale experiments.

Survivin is highly expressed in most human cancers, making it a promising target for cancer diagnosis and treatment. In this study, we developed peptide probes consisting of Bor 65-75 , a high-affinity survivin-binding peptide, and a survivin protein segment using peptide linkers as survivin-sensitive fluorescent probes (SSFPs). All conjugates were attached to 5(6)-carboxyfluorescein (FAM) at the C -terminal as a fluorophore and to 4((4(dimethylamino)phenyl)azo)benzoic acid (DABCYL) at the N -terminal as a quencher. Fluorescence (or Förster) resonance energy transfer (FRET) quenching via intramolecular binding of Bor 65-75 with survivin protein segment could be diminished by the approach of survivin to SSFPs, which dissociate Bor 65-75 from SSPF and increased the distance between FAM and DABCYL. A binding assay using recombinant human survivin protein (rSurvivin) demonstrated moderate to high affinity of SSFPs for survivin (dissociation constants ( K d ) = 121-1740 nM). Although the SSFPs (0.5 μM) had almost no fluorescence under baseline conditions, a dose-dependent increase in fluorescence intensity was observed in the presence of rSurvivin (0.1-2.0 μM). In particular, the proline-rich SSFP (SSFP5) showed the highest (2.7-fold) fluorescence induction at 2.0 μM survivin compared to the signals in the absence of survivin. Confocal fluorescence imaging demonstrated that SSFP5 exhibited clear fluorescence signals in survivin-positive MDA-MB-231 cells, whereas no marked fluorescence signals were observed in survivin-negative MCF-10A cells. Collectively, these results suggest that SSFPs can be used as survivin-specific FRET imaging probes., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Co-published by Nanjing University and American Chemical Society.)

Protein cryopreservation is important for the long-term storage of unstable proteins. Recently, we found that N -acetylglucosaminyltransferase-V (GnT-V) can be cryopreserved in a deep freezer without temperature control using a dilute binary aqueous solution of 3-(1-(2-(2-methoxyethoxy)ethyl)imidazol-3-io)butane-1-carboxylate (OE 2 imC 3 C) [10 wt %, mole fraction of solute ( x ) = 7.75 × 10 -3 ], an artificial zwitterion. However, it is unclear which solvent properties are required in these media to preserve unstable proteins, such as GnT-V. In this study, we investigated the melting phenomena and solution structure of dilute binary aqueous OE 2 imC 3 C solutions [ x = 0-2.96 × 10 -2 (0-30 wt %)] using differential scanning calorimetry (DSC) and Raman and Fourier transform infrared (FTIR) spectroscopies combined with molecular dynamics (MD) simulation to compare the cryoprotectant ability of OE 2 imC 3 C with two general cryoprotectants (CPAs), glycerol and dimethyl sulfoxide. DSC results indicated that aqueous OE 2 imC 3 C solutions can be melted at lower temperatures with less energy than the control CPA solution, with increasing x , primarily due to OE 2 imC 3 C having a higher content of unfrozen water molecules. Moreover, Raman and FTIR results showed that the high content of unfrozen water molecules in aqueous OE 2 imC 3 C solutions was due to the hydration around the ionic parts (the COO - group and imidazolium ring) and the OCH 2 CH 2 O segment. In addition, the MD simulation results showed that there were fewer structured water molecules around the OCH 2 CH 2 O segment than the hydration water molecules around the ionic parts. These solvent properties suggest that dilute aqueous OE 2 imC 3 C solutions are effective in preventing freezing, even in a deep freezer. Therefore, this medium has the potential to act as a novel cryoprotectant for proteins in biotechnology and biomedical fields.

The alignment of molecular electronic levels in a molecular multilayer is of crucial importance to realize desired functions for molecular devices. Amplitude-modulation-feedback frequency-modulation electrostatic force microscopy combined with Fowler-Nordheim tunneling spectroscopy is utilized as a probe for the energy-level alignment in an organic multilayer. Bias-dependent electrostatic force spectra were examined for bilayers including a Ru complex as a benchmark multilayer system. Electrostatic properties in the low-bias region were captured well by a single-capacitor model, which indicates weak coupling at the bilayer interface between the Ru complex and self-assembled monolayer. In contrast, in the high-bias region, significant disagreement with the expected electrostatic force was recognized for the bilayers and evaluated as the loss of electrostatic energy through the Fowler-Nordheim tunneling process. Alignment of the lowest unoccupied molecular orbital (LUMO) level of the Ru complex was determined by Fowler-Nordheim emission through resonant tunneling. These results indicate an effective method to probe level alignment at interfaces inside multilayers and to provide the partition factor β that depicts a divided electric field.

Magnesium rechargeable batteries (MRBs) promise to be the next post lithium-ion batteries that can help meet the increasing demand for high-energy, cost-effective, high-safety energy storage devices. Early prototype MRBs that use molybdenum-sulfide cathodes have low terminal voltages, requiring the development of oxide-based cathodes capable of overcoming the sulfide's low Mg 2+ conductivity. Here, we fabricate an ultraporous (>500 m 2 g -1 ) and ultrasmall (<2.5 nm) cubic spinel MgMn 2 O 4 (MMO) by a freeze-dry assisted room-temperature alcohol reduction process. While the as-fabricated MMO exhibits a discharge capacity of 160 mAh g -1 , the removal of its surface hydroxy groups by heat-treatment activates it without structural change, improving its discharge capacity to 270 mAh g -1 ─the theoretical capacity at room temperature. These results are made possible by the ultraporous, ultrasmall particles that stabilize the metastable cubic spinel phase, promoting both the Mg 2+ insertion/deintercalation in the MMO and the reversible transformation between the cubic spinel and cubic rock-salt phases.

Survivin is overexpressed in most cancer cells but is rarely expressed in normal adult tissues. It is associated with poor prognosis and resistance to radiation therapy and chemotherapy. In this study, we designed and synthesized borealin-derived small peptides (Bor peptides) to function as survivin-targeting agents for the diagnosis and treatment of cancers. These peptides exhibited binding affinities for recombinant human survivin ( K d = 49.6-193 nM), with Bor 65-75 showing the highest affinity ( K d = 49.6 nM). Fluorescence images of fluorescein isothiocyanate-labeled Bor 65-75 showed its co-localization with survivin expression in the human pancreatic cancer cell line, MIA PaCa-2. In the WST-1 assay, cell penetrable nona-d-arginine-conjugated Bor 65-75 (r9-Bor 65-75 ) inhibited the growth of MIA PaCa-2 cells and MDA-MB-231 cells (89 and 88% inhibition at 10 μM, respectively), whereas it had almost no effect on the human mammary epithelial cell line, MCF-10A, that inherently does not have high survivin expression. Flow cytometry with annexin V and propidium iodide staining revealed that r9-Bor 65-75 induced apoptosis in MIA PaCa-2 cells in a dose-dependent manner. An increase in cleaved poly ADP-ribose polymerase protein expression was observed in MIA PaCa-2 cells exposed to r9-Bor 65-75 by western blotting, suggesting that r9-Bor 65-75 inhibits cell proliferation by inducing apoptosis. In vivo , r9-Bor 65-75 significantly suppressed tumor growth in MIA PaCa-2 xenograft mice, without any marked weight loss. Hence, Bor peptides are promising candidates for the development of cancer imaging and anticancer agents targeting survivin.

Bioinspired organic/inorganic synthetic composites have been studied as high-performance and functional materials. In nature, biominerals such as pearls, teeth, and bones are self-organized organic/inorganic composites. The inorganic components are composed of calcium carbonate (CaCO 3 ) and hydroxyapatite (HAp), while the organic components consist of peptides and polysaccharides. These composites are used as structural materials in hard biological tissues. Biominerals do not show significantly higher performances than synthetic composites such as glass-fiber- or carbon-fiber-reinforced plastics. However, biominerals consist of environmentally friendly and biocompatible components that are prepared under mild conditions. Moreover, they form elaborate nanostructures and self-organized hierarchical structures. Much can be learned about material design from these biomineral-based hierarchical and nanostructured composites to assist in the preparation of functional materials.Inspired by these biological hard tissues, we developed nanostructured thin films and bulk hybrid crystals through the self-organization of organic polymers and inorganic crystals of CaCO 3 or HAp. In biomineralization, the combination of insoluble components and soluble acidic macromolecules controls the crystallization process. We have shown that poly(acrylic acid) (PAA) or acidic peptides called polymer additives induce the formation of thin film crystals of CaCO 3 or HAp by cooperation with insoluble organic templates such as chitin and synthetic polymers bearing the OH group. Moreover, we recently developed CaCO 3 - and HAp-based nanostructured particles with rod and disk shapes. These were obtained in aqueous media using a macromolecular acidic additive, PAA, without using insoluble polymer templates. At appropriate concentrations, the anisotropic particles self-assembled and formed colloidal liquid-crystalline (LC) phases.LC materials are generally composed of organic molecules. They show ordered and mobile states. The addition of stimuli-responsive properties to organic rod-like LC molecules led to the successful development of informational displays, which are now widely used. On the other hand, colloidal liquid crystals are colloidal self-assembled dispersions of anisotropic organic and inorganic nano- and micro-objects. For example, polysaccharide whiskers, clay nanosheets, gibbsite plate-shaped particles, and silica rod-shaped particles exhibit colloidal LC states.In this Account, we focused on the material design and hierarchical aspects of biomineral-based colloidal LC polymer/inorganic composites. We describe the design and preparation, nanostructures, and self-assembled behavior of these new bioinspired and biocompatible self-organized materials. The characterization results for these self-assembled nanostructured colloidal liquid crystals found using high-resolution transmission electron microscopy, small-angle X-ray scattering, and neutron scattering and rheological measurements are also reported. The functions of these biomineral-inspired liquid crystals are presented. Because these biomineral-based LC colloidal liquid crystals can be prepared under mild and aqueous conditions and they consist of environmentally friendly and biocompatible components, new functions are expected for these materials.

The purpose of this study is to propose a new strategy based on electrodeposition to create binder-free composites of metallic silver supported on MnO 2 . The process involves in situ reduction of the Ag + ions incorporated in the interlayer spaces of layered MnO 2 in an alkaline electrolyte without Ag + ions. The reduction process of the incorporated Ag + was monitored in situ based on the characteristic surface plasmon resonance in the visible region, and the resulting metallic Ag was identified by X-ray photoelectron spectroscopy. Because the formation of metallic Ag is only possible via electron injection into the Ag + ions between MnO 2 layers, the growth of Ag metals was inevitably limited, although the reduced Ag did not remain immobilized in the interlayers of MnO 2 . The thus-formed Ag in the MnO 2 composite functioned as an electrocatalyst for the oxygen reduction reaction in a gas diffusion electrode system, showing a much better mass activity compared to Ag particles electrodeposited from an aqueous solution containing AgNO 3 ., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Screening for small-molecule modulators targeting a particular receptor is frequently based on measurement of K d , i.e., the binding constant between the receptor and the compound of interest. However, K d values also reflect binding at receptor protein sites other than the modulatory site. We designed derivatives of retinoid X receptor (RXR) antagonist CBTF-EE ( 1 ) with modifications that altered their conformational flexibility. Compounds 6a , b and 7a , b showed quite similar K d values, but 7a , b exhibited 10-fold higher K i values than those of 6a , b . Further, 6a , b showed potent RXR-antagonistic activity, while 7a , b were inactive. These results suggest that increased conformational flexibility promotes binding at nontarget receptor sites. In this situation, conventional determination of K d is less effective for screening purposes than the determination of K i using a ligand that binds specifically to the site regulating transcriptional activity. Thus, the use of K i values for orthosteric ligands may increase the hit rate in screening active regulatory molecules., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

We fabricated a thin film of layered MnO 2 whose interlayer space was occupied by hydrated Ni 2+ and Cu 2+ ions. The process consisted of electrodeposition of layered MnO 2 intercalated with tetrabutylammonium cations (TBA + ) by anodic oxidation of aqueous Mn 2+ ions in the presence of TBA + , followed by ion exchange of the initially incorporated bulkier TBA + with the denser transition metals in solution. The resulting layered MnO 2 co-intercalated with Ni 2+ and Cu 2+ ions (NiCu/MnO 2 ) catalyzed the ammonia oxidation reaction (AOR) in an alkaline electrolyte with a much lower overpotential than its Ni 2+ - and Cu 2+ -intercalated single-cation counterparts. Surprisingly, the NiCu/MnO 2 electrode achieved a faradic efficiency as high as nearly 100% (97.4%) for nitrogen evolution at a constant potential of +0.6 V vs Hg/HgO. This can be ascribed to the occurrence of the AOR in the potential region where water is stable and dimerization of the partially dehydrogenated ammonia species is preferred, thereby forming an N-N bond, rather than to be further oxidized into NO x species.

To develop potent and orally bioavailable melatonin receptor (MT 1 and MT 2 ) agonists, a novel series of 5-6-5 tricyclic derivatives was designed, synthesized, and evaluated. The synthesized indeno[5,4- d ][1,3]oxazole, cyclopenta[ c ]pyrazolo[1,5- a ]pyridine, indeno[5,4- d ][1,3]thiazole, and cyclopenta[ e ]indazole derivatives showed potent binding affinities for MT 1 /MT 2 receptors. Further optimization of these derivatives based on their metabolic stability in human hepatic microsomes revealed that ( S )- 3b (( S )- N -[2-(2-methyl-7,8-dihydro-6 H -indeno[5,4- d ][1,3]oxazol-8-yl)ethyl]acetamide) was a potent MT 1 and MT 2 ligand (MT 1 , K i = 0.031 nM; MT 2 , K i = 0.070 nM) with good metabolic stability in human hepatic microsomes. Moreover, compound ( S )- 3b showed good BBB permeability in rats, and its in vivo pharmacological effects were confirmed by its sleep-promotion ability in cats.

We report the successful synthesis, crystal structure, and electrical properties of Sr 3 Re 2 O 9 , which contains Re 6+ with the 5d 1 configuration. This compound is isostructural with Ba 3 Re 2 O 9 and shows a first-order structural phase transition at ∼370 K. The low-temperature (LT) phase crystallizes in a hettotype structure of Ba 3 Re 2 O 9 , which is different from that of the LT phase of Sr 3 W 2 O 9 , suggesting that the electronic state of Re 6+ plays an important role in determining the crystal structure of the LT phase. The structural transition is accompanied by a sharp change in the electrical resistivity. This is likely a metal-insulator transition, as suggested by the electronic band calculation and magnetic susceptibility. In the LT phase, the ReO 6 octahedra are rotated in a pseudo- a 0 a 0 a + manner in Glazer notation, which corresponds to C -type orbital ordering. Paramagnetic dipole moments were confirmed to exist in the LT phase by muon spin rotation and relaxation measurements. However, the dipole moments shrink greatly because of the strong spin-orbit coupling in the Re ions. Thus, the electronic state of the LT phase corresponds to a Mott insulating state with strong spin-orbit interactions at the Re sites.

Retinoid X receptor (RXR) modulators (rexinoids) are considered to have therapeutic potential for multiple diseases, such as Alzheimer's disease and Parkinson's disease. To overcome various disadvantages of prior screening methods, we previously developed an RXR binding assay using a fluorescent RXR ligand, CU-6PMN ( 4 ). However, this ligand binds not only at the ligand-binding domain (LBD) but also at the dimer-dimer interface of hRXRα. Here, we present a new fluorescent RXR antagonist 6-[ N -ethyl- N -(5-isobutoxy-4-isopropyl-2-(11-oxo-2,3,6,7-tetrahydro-1 H ,5 H ,11 H -pyrano[2,3- f ]pyrido[3,2,1- ij ]quinoline-10-carboxamido)phenyl)amino]nicotinic acid (NEt-C343, 7 ), which emits strong fluorescence only when bound to the RXR-LBD. It allows us to perform a rapid, simple, and nonhazardous binding assay that does not require bound/free separation and uses a standard plate reader. The obtained K i values of known compounds were correlated with the K i values obtained using the standard [ 3 H]9 cis -retinoic acid assay. This assay should be useful for drug discovery as well as for research on endocrine disruptors, functional foods, and natural products.

A fluorine-doped tin oxide-coated glass electrode modified with a bilayer film of underlying α-Co(OH) 2 and overlying Mg-intercalated and Co-doped δ-type (layered) MnO 2 (Mg|Co-MnO 2 ) preferentially yielded oxygen with a Faradaic efficiency as high as 79% in the presence of chloride ions at high concentration (0.5 M). This noble metal-free electrode was fabricated by cathodic electrolysis of aqueous Co(NO 3 ) 2 followed by anodic electrolysis of a mixture of Mn 2+ , Co 2+ , and cetyltrimethylammonium (CTA + ) ions in water. The CTA + ions accommodated in the interlayer spaces of Co-doped δ-MnO 2 were replaced with Mg 2+ by ion exchange. The upper Mg|Co-MnO 2 could effectively block the permeation of Cl - ions and allow only H 2 O and O 2 , while the under α-Co(OH) 2 acted as an oxidation catalyst for the H 2 O penetrated through the upper coating. Thus, the oxygen evolution reaction (OER) was preferred to the chlorine evolution reaction (CER). In artificial seawater (pH 8.3), the blocking effect against Cl - decreased because of ion exchange of the intercalated Mg 2+ ions with Na + in solution, but the OER efficiency still remained at 57%, much higher than that (28%) without the upper Mg|Co-MnO 2 . This demonstrates that the interlayer spaces between MnO 2 layers acted as pathways for H 2 O molecules to reach the active sites of the underlying Co(OH) 2 . Density functional theory (DFT) calculations revealed that the most stable structure of hydrated Mg 2+ ion, in which a part of coordinated H 2 O molecules is hydrolyzed, has less affinity toward Cl - ion than that of hydrated Na + ion.

Li metal electrode is the ultimate choice use in Li ion batteries as high-energy storage systems. An obstacle to its practical realization is Li dendrite formation. In this study, the desolvation resistance of the Li metal electrode, which is strongly related to the inhibition of Li dendrite formation, is investigated. By applying a Laplace transform impedance technique, the desolvation/solvation resistances were successfully separated and analyzed in cells using liquid electrolytes containing different lithium salts, revealing asymmetry in the desolvation/solvation resistances of Li metal electrodes. The desolvation resistances, which supposedly require large amounts of energy derived from the strong interaction between Li + ion and solvents, were smaller than the solvation resistances. It has also been revealed that the larger resistance in the desolvation process is effective for suppressing Li dendrite formation further.

Efficient and large-scale removal of humic acid (HA) from aqueous environments is required since HA causes human health and esthetic issues. Hydro-garnet compounds, Ca 3 Al 2 (SiO 4 ) 3- x (OH) 4 x , have recently been suggested as HA adsorbents not only due to their superior adsorption behaviors but also because they are ubiquitous element-derived compounds. In this study, the adsorption behavior of formic acid to hydro-garnets was investigated by means of first-principles density functional theory (DFT) computations. Formic acid was chosen owing to its reasonable computational cost and inclusion of carboxylic acid as HA. Comparisons of adsorption energies for formic acid among various compounds (including platinum and kaolinite) indicate that hydro-garnet compounds are promising due to their lower (more stable) adsorption energies. Also, the optimization of composition x enables selective adsorption of formic acid against solvent water molecules. Relationships between surface electronic/atomistic structures and adsorption properties are discussed., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Recently, we found that self-organization of hydroxyapatite (HAp) with poly(acrylic acid) (PAA) leads to the formation of liquid-crystalline (LC) nanorod hybrids that form aligned films and show stimuli-responsive properties. Here, we demonstrate that these biocompatible HAp/PAA hybrid nanorods represent a platform technology as drug nanocarriers for photodynamic cancer therapy and as bioscaffolds for the control of cellular alignment and growth. To use hybrid nanorods as a drug nanocarrier, we introduced methylene blue (MB), a typical photosensitizer for photodynamic therapy, into the PAA nanolayer covering the surface of the HAp nanocrystals through electrostatic interactions. The stable MB-loaded HAp/PAA hybrid nanorods efficiently produced singlet oxygen from MB upon light irradiation and showed remarkable photodynamic therapeutic effects in cancer cells. Moreover, taking advantage of the mechanically responsive LC alignment properties of the HAp/PAA hybrid nanorods, macroscopically oriented bioscaffolds were prepared through a spin-coating process. The cells cultured on the oriented scaffolds showed cellular alignment and elongation along the oriented direction of the hybrid nanorods. The HAp/PAA hybrid nanorods demonstrate potential in drug delivery and tissue engineering. These unique LC HAp/PAA hybrid nanorods have significant potential as a platform for the development of various types of biomaterial.

Research has recently been focused on high-performance next-generation batteries to replace secondary batteries due to capacity limitations and safety concerns. The Mg secondary battery is one candidate to realize high energy density storage batteries for practical applications. Ni and Co typically exhibit desirable electrochemical characteristics; therefore, we have attempted to synthesize new rock-salt compositions, Mg x Ni y Co z O 2 ( x + y + z ≤ 2.0), as cathode materials for Mg rechargeable batteries, and investigated their crystal structures and electrochemical characteristics. The materials were synthesized by the reverse coprecipitation method. Powder X-ray diffraction and transmission electron microscopy analyses showed the obtained samples were a single phase of the rock-salt structure with the space group Fm3̅ m. The vacancies at the metal sites were estimated by Rietveld analysis to determine the new chemical composition of Mg x Ni y Co z□2- x- y- z O 2 (0.41 < x < 0.64, 0.82 < y < 1.23, 0.24 < z < 0.61). Charge-discharge tests indicated the discharge characteristics varied according to the Mg composition and the Ni/Co ratio. The Co and Mg compositions were considered to facilitate the insertion/deinsertion of Mg 2+ . The present new material has the potential to be a superior cathode material for Mg secondary batteries by first-principles calculations.

A polar LiNbO 3 (LN)-type oxide LiSbO 3 was synthesized by a high-temperature heat treatment under a pressure of 7.7 GPa and found to exhibit ferroelectricity. The crystal structural refinement using the data of synchrotron powder X-ray diffraction and neutron diffraction and the electronic structure calculation of LN-type LiSbO 3 suggest a covalent-bonding character between Sb and O. When comparing the distortion of BO 6 in LN-type ABO 3 , the distortions of SbO 6 in LiSbO 3 and SnO 6 in ZnSnO 3 , which included a B cation with a d 10 electronic configuration, were smaller than those of BO 6 in LN-type oxides having the second-order Jahn-Teller active B cation, e.g., LiNbO 3 and ZnTiO 3 . The temperature dependence of the lattice parameters, second harmonic generation, dielectric permittivity, and differential scanning calorimetry made it clear that a second-order ferroelectric-paraelectric phase transition occurs at a Curie temperature of T c = 605 ± 10 K in LN-type LiSbO 3 . Further, first-principles density functional theory calculation suggested that perovskite-type LiSbO 3 is less stable than LN-type LiSbO 3 under even high pressure, and the ambient phase of LiSbO 3 directly transforms to LN-type LiSbO 3 under high pressure. The phase stability of LN-type LiSbO 3 and the polar and ferroelectric properties are rationalized by the covalent bonding of Sb-O and the relatively weak Coulomb repulsion between Li + and Sb 5+ .

It is an urgent challenge to develop low-cost and high-performance catalysts for the oxygen evolution reaction (OER). We synthesized nanoparticulate electrocatalysts consisting of cobalt-doped goethite-type iron oxyhydroxide (α-FeOOH) with controlled Co/Fe ratios [Co x Fe 1- x OOH ( x ≤ 0.20)] based on our own wet process. A Co 0.20 Fe 0.80 OOH-coated glassy carbon electrode generated a current density ( j ) of 10 mA cm -2 at an overpotential (η) as small as 383 mV (1.61 V vs the reversible hydrogen electrode) in an alkaline electrolyte, with a small Tafel slope of 40 mV dec -1 and excellent durability, whereas pure α-FeOOH required η = 580 mV to reach the same current density. This can be ascribed to the effect of Co doping, which resulted in an increase in electrochemically active surface area and a decrease in charge-transfer resistance. The content of cobalt, a scarce resource, in the catalyst is much smaller than those in most of the other Fe-based catalysts reported so far. Thus, this study will provide a new strategy of designing cost-effective and high-performance catalysts for the OER in alkaline solution., Competing Interests: The authors declare no competing financial interest.

A new semiconducting 3D coordination polymer, [Cu 2 Br 2 (ttz)] n (1), with an acceptor bridging ligand, 1,2,4,5-tetrazine (ttz), was synthesized. The complex shows large absorption bands extending to the near-IR region, indicating a small band gap in the coordination polymer. This complex shows higher conductivity than those of [CuBr(pyz)] n (2), including pyrazine (pyz) with a higher lowest unoccupied molecular orbital level. We performed density functional theory band calculations using the VASP program to understand the electronic states and conducting paths of the coordination polymer.

Aqueous Mn 2+ ions were anodized at 70 °C with Co 2+ in the presence of cationic surfactant, cetyltrimethylammonium (CTA). X-ray diffraction (XRD) analysis revealed that the deposited film possesses a layered structure of MnO 2 , the interlayer of which is occupied with the assembled CTA molecules. Inclusion of Co ions in the MnO 2 film was evidenced by X-ray photoelectron spectroscopy (XPS). They were located in the MnO 2 framework, not in the interlayer. The thus-obtained film, CTA-intercalated Co-framework-doped layered MnO 2 (CTA/Co-MnO 2 ), was applied as an electrochemical sensor toward iodide (I - ), a hydrophobic anion. The organic phase between MnO 2 layers could extract I - ions from solution, providing a better sensitivity than a film consisting of layered MnO 2 with hydrated alkali metals. On the other hand, the Co-doped layers of MnO 2 achieved faster electron transfer kinetics for the oxidation of I - , which resulted in a drastic reduction in response time compared to the nondoped CTA/MnO 2 .

Gallium-68 ( 68 Ga) is a positron emitter for clinical positron emission tomography (PET) applications that can be produced by a 68 Ge/ 68 Ga generator without cyclotron. However, commercially available 68 Ge/ 68 Ga generator systems require multiple steps for the preparation of 68 Ga radiopharmaceuticals and are sometimes plagued by metallic impurities in the 68 Ga eluent. We developed a 68 Ge/ 68 Ga generator system using polysaccharide-based adsorbents and direct application of the generator-eluted 68 Ga-citrate to PET imaging of tropical infectious diseases. N -Methylglucamine (MG) as a 68 Ge-adsorbing unit (Sepha-MGs) was introduced to a series of Sephadex G-10, G-15, G-25, G-50, and G-75. In the batch method, over 97% of the 68 Ge in the solution was adsorbed onto the Sepha-MG series within 15 min. In particular, 68 Ge was effectively adsorbed on the Sepha(15)-MG packed columns and 70-80% of the 68 Ga was eluted by 1 mL of 0.1 M trisodium citrate with low 68 Ge contamination (<0.001%). The chemical form of the generator-eluted 68 Ga solution was identified as 68 Ga-citrate. In PET studies, affected regions in mice infected with Leishmania and severe fever with thrombocytopenia syndrome virus were clearly visualized using the 68 Ga-citrate. Sepha-MGs are useful adsorbents for 68 Ge/ 68 Ga generator systems with high 68 Ga elution efficiency and minimal 68 Ge breakthrough. These results indicated that eluted 68 Ga-citrate can be directly used for PET imaging of infectious sites in mice. This novel generator system may be useful for straightforward PET imaging of infection in clinical practice., Competing Interests: The authors declare no competing financial interest.

A facile method for the fabrication of a highly sensitive surface relief is demonstrated, which operates on the principle of spatially patterned photopolymerization-induced mass transport in the amorphous films of a series of bisanthracene compounds. The stability of the resultant colorless transparent relief structure is dramatically improved owing to the polymerization of the bisanthracene.

In this article, we describe the development of a nanosized-glutathione peroxidase (GPx) mimic based on liposomes of which the amphiphilic selenenylsulfide derivative (R-Se-S-R') was incorporated into a lipid membrane. A lipid membrane-compatible selenenylsulfide derivative, 1-oxo-headecyl-seleno-l-cysteine-methyl- Se -yl- S -l-penicillamine methyl ester (OHSeP), was synthesized. X-ray photoelectron spectroscopy revealed that the sulfur and selenium atoms of the OHSeP molecule formed a selenenylsulfide linkage. The use of OHSeP easily allowed the introduction of the seleno-l-cysteine (SeCys) moiety into the liposomal membranes by mixing with the phosphatidylcholines (PCs), which gave rise to the GPx-like catalytic activity because of the selenium atom in the SeCys moiety. The penicillamine moiety of the OHSeP molecule incorporated into the OHSeP/PC liposomes was thought to orient toward the outer water phase. The OHSeP/PC liposomes generated the GPx-like catalytic activity, which was ascribed to the SeCys moiety that was introduced into the PC-based liposomes. Consequently, the lipid/water interface of the liposomal membranes could possibly provide an effective colloidal platform for the development of water-soluble nanosized GPx mimics., Competing Interests: The authors declare no competing financial interest.

The majority of nanoparticles designed for cellular delivery of drugs and imaging agents enter the cell via endocytotic pathways leading to their entrapment in endosomes that present a robust barrier to further trafficking of the nanoparticles within the cells. A few materials, such as the cell penetrating peptides (CPPs), are known to enter cells not only via endocytosis, but also via translocation through the cell membrane into the cytoplasm, successfully bypassing the endosomes. We report here that random copolymers of 3-dimethyl(methacryloyloxyethyl)ammonium propanesulfonate and poly(ethylene glycol) methacrylate, p(DMAPS-ran-PEGMA), are internalized in cells primarily via translocation through the cell membrane rather than endocytosis. The properties of the polymers and their modes of uptake were investigated systematically by dynamic light scattering, confocal fluorescence microscopy, and flow cytometry. Using specific inhibitors of the cellular uptake machinery in a human cervical carcinoma cell line (HeLa), we show that these nontoxic synthetic polyzwitterions exist in cell media as self-assembled nanospheres that unravel as they adsorb on the plasma membrane and translocate through it. Conjugates of p(DMAPS-ran-PEGMA) with rhodamine B were delivered selectively to the mitochondria, whereas doxorubicin (Dox)-p(DMAPS-ran-PEGMA) conjugates were accumulated in both the nucleus and the mitochondria, effectively inducing apoptosis in HeLa cells. These findings suggest that the noncytotoxic and readily synthesized p(DMAPS-ran-PEGMA) can find applications as bioimaging tools and drug nanocarriers.

Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of pK(a) < 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo[1,2-a]pyridine ring (represented in compounds 6a and 6b), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)oxy]-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one 10a. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats.

The ongoing search for fast Li-ion conducting solid electrolytes has driven the deployment surge on density functional theory (DFT) computation and materials informatics for exploring novel chemistries before actual experimental testing. Existing structure prototypes can now be readily evaluated beforehand not only to map out trends on target properties or for candidate composition selection but also for gaining insights on structure-property relationships. Recently, the tavorite structure has been determined to be capable of a fast Li ion insertion rate for battery cathode applications. Taking this inspiration, we surveyed the LiMTO4F tavorite system (M(3+)-T(5+) and M(2+)-T(6+) pairs; M is nontransition metals) for solid electrolyte use, identifying promising compositions with enormously low Li migration energy (ME) and understanding how structure parameters affect or modulate ME. We employed a combination of DFT computation, variable interaction analysis, graph theory, and a neural network for building a crystal structure-based ME prediction model. Candidate compositions that were predicted include LiGaPO4F (0.25 eV), LiGdPO4F (0.30 eV), LiDyPO4F (0.30 eV), LiMgSO4F (0.21 eV), and LiMgSeO4F (0.11 eV). With chemical substitutions at M and T sites, competing effects among Li pathway bottleneck size, polyanion covalency, and local lattice distortion were determined to be crucial for controlling ME. A way to predict ME for multiple structure types within the neural network framework was also explored.

We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: 5, EC50 = 143 nM, Emax = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: 8b, EC50 = 169 nM, Emax = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: 7b, EC50 = 19 nM). NEt-4IB (8b) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to 5.

Thermoresponsive poly(N-isopropylacrylamide) (PIPAAm)-immobilized surfaces for controlling cell adhesion and detachment were fabricated by the Langmuir-Schaefer method. Block copolymers composed of polystyrene and PIPAAm (St-IPAAms) having various chain lengths and compositions were synthesized by reversible addition-fragmentation chain transfer radical polymerization. The St-IPAAm Langmuir film at an air-water interface was horizontally transferred onto a hydrophobically modified glass substrate while regulating its density. Atomic force microscopy images clearly visualized nanoscaled sea-island structures on the surface. By adjusting both the composition of St-IPAAms and the density of immobilized PIPAAms, a series of thermoresponsive surfaces was prepared to control the strength, rate, and quality of cell adhesion and detachment through changes in temperature across the lower critical solution temperature range of PIPAAm molecules. In addition, a two-dimensional cell structure (cell sheet) was more rapidly recovered on the optimized surfaces than on conventional PIPAAm surfaces. These unique PIPAAm surfaces are suggested to be useful for controlling the strength of cell adhesion and detachment.

Modifications of metastin(45-54) produced peptide analogues with higher metabolic stability than metastin(45-54). N-terminally truncated nonapeptide 4 ([D-Tyr46,D-Pya(4)47,azaGly51,Arg(Me)53]metastin(46-54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained KISS1 receptor agonistic activity. Furthermore, [D-Tyr46,D-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46-54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than metastin(45-54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[D-Tyr46,D-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46-54)). With continuous administration, 22 possessed 10-50-fold more potent testosterone-suppressive activity in rats than 4. These results suggested that a controlled release of short-length KISS1 receptor agonists can suppress the hypothalamic-pituitary-gonadal axis and reduce testosterone levels. Compound 22 was selected for further preclinical evaluation for hormone-dependent diseases.

Deposition of amyloid aggregates has been regarded as an early stage of amyloidosis progression. An imaging probe that can image amyloid aggregates enables the early diagnosis of amyloidosis and contributes to the development of new medical therapies. High binding affinity for amyloid aggregates is essential to develop a useful molecular imaging probe. This article describes a new strategy to enhance the binding affinity of imaging agents targeting amyloid aggregates. We designed and synthesized novel (99m)Tc-hydroxamamide ((99m)Tc-Ham) complexes with a bivalent amyloid ligand and evaluated their binding affinity for amyloid aggregates by using β-amyloid peptide (Aβ(1-42)) aggregates as a model. In vitro inhibition assay indicated that bivalent (99m)Tc-Ham complexes had much higher binding affinity for amyloid aggregates than monovalent complexes. In vitro autoradiography using Tg2576 mice showed the specific binding of bivalent (99m)Tc-Ham complexes to Aβ plaques in the mouse brain, as reflected in the results of the inhibition assay. The preliminary results suggest that a new molecular design based on bivalent (99m)Tc-Ham complexes may be reasonable to develop an imaging probe targeting amyloid aggregates.

A polar LiNbO3-type (LN-type) titanate ZnTiO3 has been successfully synthesized using ilmenite-type (IL-type) ZnTiO3 under high pressure and high temperature. The first principles calculation indicates that LN-type ZnTiO3 is a metastable phase obtained by the transformation in the decompression process from the perovskite-type phase, which is stable at high pressure and high temperature. The Rietveld structural refinement using synchrotron powder X-ray diffraction data reveals that LN-type ZnTiO3 crystallizes into a hexagonal structure with a polar space group R3c and exhibits greater intradistortion of the TiO6 octahedron in LN-type ZnTiO3 than that of the SnO6 octahedron in LN-type ZnSnO3. The estimated spontaneous polarization (75 μC/cm(2), 88 μC/cm(2)) using the nominal charge and the Born effective charge (BEC) derived from density functional perturbation theory, respectively, are greater than those of ZnSnO3 (59 μC/cm(2), 65 μC/cm(2)), which is strongly attributed to the great displacement of Ti from the centrosymmetric position along the c-axis and the fact that the BEC of Ti (+6.1) is greater than that of Sn (+4.1). Furthermore, the spontaneous polarization of LN-type ZnTiO3 is greater than that of LiNbO3 (62 μC/cm(2), 76 μC/cm(2)), indicating that LN-type ZnTiO3, like LiNbO3, is a candidate ferroelectric material with high performance. The second harmonic generation (SHG) response of LN-type ZnTiO3 is 24 times greater than that of LN-type ZnSnO3. The findings indicate that the intraoctahedral distortion, spontaneous polarization, and the accompanying SHG response are caused by the stabilization of the polar LiNbO3-type structure and reinforced by the second-order Jahn-Teller effect attributable to the orbital interaction between oxygen ions and d(0) ions such as Ti(4+).

Metastin/kisspeptin is a 54 amino acid peptide ligand of the KISS1R receptor and is a critical regulator of GnRH secretion. The N-terminally truncated peptide, metastin(45-54), possesses a 10-fold higher receptor-binding affinity than full-length metastin and agonistic KISS1R activity but is rapidly inactivated in rodent plasma. We have developed a decapeptide analog [D-Tyr(45),D-Trp(47),azaGly(51),Arg(Me)(53)]metastin(45-54) with improved serum stability compared with metastin(45-54) but with decreased KISS1R agonistic activity. Amino acid replacements at positions 45-47 led to an enhancement of KISS1R agonistic activity and metabolic stability. N-terminal truncation resulted in a stable nonapeptide, [D-Tyr(46),D-Pya(4)(47),azaGly(51),Arg(Me)(53)]metastin(46-54), compound 26, which displayed KISS1R binding affinities comparable to metastin(45-54) and had improved serum stability. Compound 26 reduced plasma testosterone in male rats and is the first short-length metastin analog to possess testosterone suppressive activities. Compound 26 has led to the elucidation of investigational analogs TAK-683 and TAK-448, both of which have undergone clinical evaluation for hormone-dependent diseases such as prostate cancer.

In prostate cancer diagnosis, PSA test has greatly contributed to the early detection of prostate cancer; however, expanding overdiagnosis and unnecessary biopsies have emerged as serious issues. To explore plasma biomarkers complementing the specificity of PSA test, we developed a unique proteomic technology QUEST-MS (Quick Enrichment of Small Targets for Mass Spectrometry). The QUEST-MS method based on 96-well formatted sequential reversed-phase chromatography allowing efficient enrichment of <20 kDa proteins quickly and reproducibly. Plasma from 24 healthy controls, 19 benign prostate hypertrophy patients, and 73 prostate cancer patients were purified with QUEST-MS and analyzed by LC/MS/MS. Among 153 057 nonredundant peptides, 189 peptides showed prostate cancer specific detection pattern, which included a neurotransmitter polypeptide neuropeptide-Y (NPY). We further validated the screening results by targeted multiple reaction monitoring technology using independent sample set (n = 110). The ROC curve analysis revealed that logistic regression-based combination of NPY, and PSA showed 81.5% sensitivity and 82.2% specificity for prostate cancer diagnosis. Thus QUEST-MS technology allowed comprehensive and high-throughput profiling of plasma polypeptides and had potential to effectively uncover very low abundant tumor-derived small molecules, such as neurotransmitters, peptide hormones, or cytokines.

Terminally functionalized poly(N-isopropylacrylamide) (PIPAAm) brush grafted glass surfaces were prepared by a surface-initiated reversible addition-fragmentation chain transfer radical (SI-RAFT) polymerization. SI-RAFT mediated PIPAAm chains possessed terminal dodecyl trithiocarbonate groups which can be substituted with various functional groups. In this study, dodecyl groups were substituted with hydrophilic maleimide groups for controlling the thermoresponsive character of PIPAAm brushes. PIPAAm brushes exhibited reversible temperature-dependent surface wettability changes around PIPAAm's lower critical solution temperature. Phase transition of dodecyl-terminated PIPAAm brushes clearly shifted to lower temperature than that of maleimide-terminated PIPAAm brushes, and this shift was attributed to promoted PIPAAm dehydration via terminal hydrophobes. By using this feature, the specific adhesion temperatures of bovine carotid artery endothelial cells (BAECs) on the PIPAAm brush surfaces were successfully controlled. BAECs were initiated to adhere on dodecyl-PIPAAm surfaces at 31 °C, while their adhesion was significantly suppressed on maleimide-PIPAAm surfaces under 33 °C. In contrast, terminal functionality scarcely affected the thermoresponsive behavior of PIPAAm brushes in the polymer rehydration process by reducing temperatures, and thus, the difference in spontaneous cell detachment from different PIPAAm-brush surface was negligible. Consequently, confluently cultured cells were able to be harvested as contiguous cell sheets from individual surfaces with comparable periods at 20 °C.

Ureido-derivatized polymers, such as poly(allylurea) (PU) and poly(L-citrulline) derivatives, exhibited upper critical solution temperature (UCST) behavior under physiological buffer conditions as we previously reported. The PU derivatives having amino groups (PU-Am) also showed UCST behavior. In this study, we modified the amino groups of the polymer with succinyl anhydride (PU-Su) or acetyl anhydride (PU-Ac) to determine the effects of these ionic groups on the UCST behavior and to control interactions between the PU derivatives and biocomponents such as proteins and cells. Succinylation of PU-Am resulted in a significant decrease in phase separation temperature (Tp), whereas acetylation of PU-Am resulted in an increase in Tp. As expected, the Tp of PU-Am and PU-Su changed when the pH of the solution was changed. The Tp of PU-Am increased at higher pH, whereas that of PU-Su increased at lower pH, indicating that ionic charge decreases Tp of PU derivatives by increasing osmotic pressure and by increasing hydrophilicity of the polymer chains. Interestingly, these groups did not significantly change UCST when these groups were nonionic. We then examined capture and separation of particular proteins from a protein mixture by cooling-induced phase separation. Selective and rapid capture of particular proteins from protein mixture by PU derivatives was shown, indicating that the ureido-derivatized polymers are potential media for bioseparation under biofriendly conditions.

We have reported that retinoid X receptor (RXR) partial agonist 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid (CBt-PMN, 4a) shows a significant antidiabetes effect in the KK-A(y) type 2 diabetes model mice, with reduced side effects compared to RXR full agonists. To elucidate the mechanism of the RXR partial agonist activity of 4a, we synthesized derivatives of 4a, evaluated their RXR agonist activity, and performed structure-activity relationship analysis. Reporter gene assay revealed that though 6b, which possesses an amino group at the 2-position of 5-carboxybenzimidazole, showed RXR full-agonist activity, compounds 6d and 6e, which possess an oxygen atom and a sulfur atom at the corresponding position, respectively, showed weak RXR agonist activity. On the other hand, 6c, which has a trifluoromethyl group at the corresponding position, acts as an RXR partial agonist, having similar Emax (67 ± 2%) and lower EC50 (15 ± 0 nM) compared to those of 4a (Emax = 75 ± 4%, EC50 = 143 ± 2 nM). A fluorescence polarization assay of cofactor recruitment confirmed that fluorescein-labeled D22 coactivator peptide was less efficiently recruited to RXR by 4a and 6c than by LGD1069 (1), a known RXR full agonist. Electrostatic potential field calculations and computational docking studies suggested that full agonists show an electrostatic attraction, which stabilizes the holo structure and favors coactivator recruitment, between the side chain at the benzimidazole 2-position and the α-carbonyl oxygen of asparagine-306 in helix 4 (H4) of the RXR receptor. However, RXR partial agonists 4a and 6c lack this interaction. Like 4a, 6c showed a significant antidiabetes effect in KK-A(y) type 2 diabetes model mice with reduced levels of the side effects associated with RXR full agonists. These findings should aid the design of new RXR partial agonists as antitype 2 diabetes drug candidates.

Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K(+) channel inhibition in a patch-clamp study. To decrease hERG K(+) channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K(+) channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration.

Treating insulin resistance and type 2 diabetes in rodents, currently known retinoid X receptor (RXR) agonists induce significant adverse effects. Here we introduce a novel RXR partial agonist CBt-PMN (11b), which shows a potent glucose-lowering effect and improvements of insulin secretion and glucose tolerance without the serious adverse effects caused by RXR full agonists. We suggest that RXR partial agonists may be a new class of antitype 2 diabetes drug candidates.

The behavior of C(60) molecules deposited onto 11-phenoxyundecanethiol (phenoxy) self-assembled monolayers (SAMs) is studied using ultrahigh vacuum scanning tunneling microscopy (UHV-STM) and spectroscopy. We observe that after thermally annealing between 350 and 400 K in vacuum a combination of hexagonally close-packed islands, rectangularly packed islands, and isolated single lines of C(60) is observed when the C(60) is initially deposited on an unannealed phenoxy SAM. However, only rectangularly packed islands are found when they are deposited on a preannealed phenoxy SAM. We determine the rectangular packing to have a (2√3 × 4) rectangular unit cell with respect to the underlying Au(111) substrate. This type of C(60) structure has not been observed previously for multicomponent self-assemblies on a surface. We discuss the possible causes for the formation of this structure as well as the differences between starting on an unannealed SAM and an annealed one. This study demonstrates the capability of functionalized alkanethiol SAMs to control the growth and structure of C(60) islands during annealing depending on the structural changes of the SAM itself; by preannealing the SAM, the motion of the C(60) can be confined and unique structures resulting from interactions between the SAM molecules and C(60) can be produced.

Chirality switching is intriguing for the dynamic control of the electronic and optical properties in nanoscale materials. The ability to photochemically switch the chirality in liquid crystals (LCs) is especially attractive given their potential applications in electro-optic displays, optical data storage, and the asymmetric synthesis of organic molecules and polymers. Here, we present a dynamic photoswitching of the helical inversion in chiral nematic LCs (N*-LCs) that contain photoresponsive axially chiral dopants. Novel photoresponsive chiral dithienylethene derivatives bearing two axially chiral binaphthyl moieties are synthesized. The dihedral angle of the binaphthyl rings changes via the photoisomerization between the open and closed forms of the dithienylethene moiety. The N*-LCs induced by the dithienylethene derivatives that are used as chiral dopants exhibit reversible photoswitching behaviors, including a helical inversion in the N*-LC and a phase transition between the N*-LC and the nematic LC. The present compounds are the first chiral dopants that induce a helical inversion in N*-LC via the photoisomerization between open and closed forms of the dithienylethene moiety., (© 2012 American Chemical Society)

For preparing cell sheets effectively for cell sheet-based regenerative medicine, cell-adhesion strength to thermoresponsive cell culture surfaces need to be controlled precisely. To design new thermoresponsive surfaces via a terminal modification method, thermoresponsive polymer brush surfaces were fabricated through the surface-initiated reversible addition-fragmentation chain transfer (RAFT) radical polymerization of N-isopropylacrylamide (IPAAm) on glass substrates. The RAFT-mediated grafting method gave dithiobenzoate (DTB) groups to grafted PIPAAm termini, which can be converted to various functional groups. In this study, the terminal carboxylation of PIPAAm chains provided high cell adhesive property to thermoresponsive surfaces. Although cell adhesion is generally promoted by a decrease in the grafted PIPAAm amount, the decrease also decelerated thermally-induced cell detachment, whereas the influence of terminal modification was negligible on the cell detachment. Consequently, the terminally modified PIPAAm brush surfaces allowed smooth muscle cells (SMCs) to simultaneously adhere strongly and detach themselves rapidly. In this study, SMCs were unable to reach a confluent monolayer on as-prepared PIPAAm brush surfaces (grafted amount: 0.41 μg/cm(2)) without terminal carboxylation due to their insufficient cell-adhesion strength. On the other hand, though a decrease in the PIPAAm amount allowed SMCs to form a confluent cell monolayer on the PIPAAm brush surface, the SMCs were unable to be harvested as a monolithic cell sheet by low-temperature culture at 20 °C. Because of their unique property, only terminal-carboxylated PIPAAm brush surfaces achieved rapid harvesting of complete cell sheets by low-temperature culturing.

There are few examples of polymers that exhibit upper critical solution temperature (UCST) behavior under physiological conditions of temperature, pH, and ionic strength. In this study, we demonstrated that polymers with ureido groups undergo UCST-type phase transitions under physiologically relevant conditions. Poly(allylurea) copolymers showed UCST behavior at pH 7.5 in 150 mM NaCl even at the low polymer concentration of 0.13 mg/mL. Their phase separation temperatures (T(p)) could be controlled up to 65 °C. Similar thermosensitivity was observed with copolypeptides consisting of L-citrulline having an ureido group. This is the first demonstration of a non-vinyl polymer that shows UCST behavior under physiologically relevant conditions. We suggest that the ureido modification will be useful for production of polymer materials with UCST behavior in aqueous media.

We discovered a potent retinoid X receptor (RXR) antagonist, 6-[N-ethyl-N-(5-isobutoxy-4-isopropyl-2-(E)-styrylphenyl)amino]nicotinic acid (13e), that is structurally closely related to the RXR full agonist 6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB) (4). Compound 13e was synthesized via a simple route from 11, a methyl ester precursor of 4. Because 11 possesses high electrophilic reactivity because of the amino and alkoxy groups, it was readily transformed to 12 by iodization, and the iodine atom of 12 was converted to a C-C or C-N bond by means of palladium-catalyzed reaction to afford 13. Transcriptional activation assay revealed that 13g (in which the iodine atom was replaced with an amino group) is a weak RXR agonist, while 13d (a phenyl group), 13e (a styryl group), and 13f (an anilino group) are RXR antagonists. Among them, 13e was found to be more potent than the known RXR antagonist PA452 (9).

Novel tricyclic dihydrofuran derivatives were designed, synthesized, and evaluated as melatonin receptor (MT(1)/MT(2)) ligands based on the previously reported 1,6-dihydro-2H-indeno[5,4-b]furan 1a. By screening the central tricyclic cores, we identified 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine as a potent scaffold with a high ligand-lipophilicity efficiency (LLE) value. Subsequent optimization of the side chains led to identification of the potent MT(1)/MT(2) agonist 4d (MT(1), K(i) = 0.062 nM; MT(2), K(i) = 0.420 nM) with good oral absorption and blood-brain barrier (BBB) penetration in rats. The oral administration of compound 4d exhibited a sleep-promoting action in freely moving cats at 0.1 mg/kg.

A novel series of 1,6-dihydro-2H-indeno[5,4-b]furan derivatives were designed and synthesized as MT(2)-selective ligands. This scaffold was identified as a potent mimic of the 5-methoxy indole core of melatonin, and introduction of a cyclohexylmethyl group at the 7-position of this scaffold afforded an MT(2)-selective ligand 15 (K(i) = 0.012 nM) with high MT(1)/MT(2) selectivity (799). Compound 15 was identified as a potent full agonist for the MT(2) subtype and exhibited reentrainment effects to a new light/dark cycle in ICR mice at 3-30 mg/kg. This result demonstrated the involvement of the MT(2) receptors in chronobiotic activity.