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Vesicles are known to spontaneously adsorb onto solid-liquid interfaces and to form supported bilayers in aqueous solution. Cationic surfactants have typically been used to generate supported bilayers because solid surfaces in water are often negatively charged. The present study investigated the aggregation behavior of an anionic surfactant, hydroxy alkane sulfonate having a C18 alkyl chain (C18HAS) in aqueous CaCl 2 solutions. These assessments were performed by acquiring data related to equilibrium surface tension, the solubilization of an oil-soluble dye, UV-visible transmittance, pyrene fluorescence and dynamic light scattering together with freeze-fracture transmission electron microscopy observations. The results suggest that C18HAS can form vesicles in aqueous CaCl 2 solutions under certain surfactant concentrations. Specifically, this aggregation behavior is greatly affected by C18HAS/CaCl 2 molar ratio. At the C18HAS/CaCl 2 molar ratio is less than an equivalence point (that is, less than 2:1), phase separation occurs with the formation of a vesicle above solubility limit of the C18HAS Ca salt. On the other hand, in the case that the C18HAS/CaCl 2 molar ratio is above an equivalence point (that is, above 2:1), the Na salt of C18HAS forms micelles above the critical micelle concentration (cmc), causing solubilization of vesicles. Analyses by high-speed atomic force microscopy demonstrated that the C18HAS vesicles can spontaneously form a supported bilayer on a negatively charged mica surfaces, similar to the behavior of cationic surfactant vesicles, even though C18HAS is an anionic surfactant. These results suggest that C18HAS could serve as a detergent component but also as a surface modifier when the C18HAS/CaCl 2 molar ratio is optimized.

The development of hydrophobic poly(ethylene glycol) (PEG) hydrogels, which are typically hydrophilic, could significantly enhance their application as artificial extracellular matrices. In this study, we designed PEG hydrogels with enhanced hydrophobicity through gel-gel phase separation (GGPS), a phenomenon that uniquely enhances hydrophobicity under ambient conditions, and we elucidated the pivotal role of elasticity in this process. We hypothesized that increased elasticity would amplify GGPS, thereby improving the hydrophobicity and cell adhesion on PEG hydrogel surfaces, despite their inherent hydrophilicity. To test this hypothesis, we engineered dilute oligo-PEG gels via a two-step process, creating polymer networks from tetra-PEG clusters with multiple reaction points. These oligo-PEG gels exhibited significantly higher elasticity, turbidity, and shrinkage upon water immersion compared to dilute PEG gels. Detailed characterization through confocal laser scanning microscopy, rheological measurements, and cell adhesion assays revealed distinct biphasic structures, increased hydrophobicity, and enhanced cell attachability in the dilute oligo-PEG gels. Our findings confirm that elasticity is crucial for effective GGPS, providing a novel method for tailoring hydrogel properties without chemical modification. This research introduces a new paradigm for designing biomaterials with improved cell-scaffolding capabilities, offering significant potential for tissue engineering and regenerative medicine.

Misfolding of antibody light chains can lead to systemic light chain amyloidosis, which is associated with misfolding and aggregation. The antibody light chain may engage in 3D domain swapping within the variable region (#4V L ) through hydrogen bonding (HB) interactions, potentially forming the tetramer, as revealed in solution and crystal structures. However, the 3D-domain swapping (3D-DS) dimers could not be detected experimentally. This study investigates the absence of 3D-DS using computational approaches, focusing on structural dynamics, solvation effects, and stability relevant to the loss of 3D-DS. Microscale molecular dynamics simulations of #4V L and 3D-DS confirm that native HB interactions are essential to maintain β-sheet structures in both #4V L and 3D-DS. A flickering native HB interaction in the 3D-DS system, caused by repulsive interaction with water molecules in the hydrophobic region, leads to intramolecular breathing motions and oligomerization in another 3D-DS. Structural dynamics of the 3D-DS dimer in long-run simulations were analyzed using the newly developed integrated solvation-based principal component analysis (3D-RISM/PCA) and density-based spatial clustering of applications with noise, confirm that if the 3D-DS cannot form the tetramer within the breathing motion process, the 3D-DS will collapse. This finding provides insights into why the 3D-DS dimer is missing from the solution and can be used to design and develop 3D-DS in other antibodies.

Structural adhesives are currently applied in the assembly of automobiles, aircraft, and buildings. In particular, epoxy adhesives are widely used due to their excellent mechanical strength and durability. However, cured epoxy resins are typically rigid and inflexible; thus, they have low peel and impact strength. In this study, tough cured epoxy adhesives were developed by mixing a liquid epoxy prepolymer (EP) and polystyrene- b -polyisoprene- b -polystyrene (SIS). SIS is a block polymer-based thermoplastic elastomer (TPE) composed of polystyrene (S) soluble in liquid EP and polyisoprene (I) insoluble in liquid EP, where S and I have a glass transition temperature that is higher and lower than room temperature, respectively. In addition, cured adhesives tougher than the cured adhesives containing SIS were prepared by mixing liquid EP and SIS with hydrogen-bonding groups in the I block (h-SIS). Transmission electron microscopy (TEM) observations revealed mixed S/cured EP domains, with a d -spacing of several tens of nanometers, and cured EP domains, with diameters of one hundred to several hundred nanometers, that were macroscopically dispersed in the I or hydrogen-bonded I matrix of the cured adhesive containing SIS or h-SIS. The lap shear, peel, and impact strength of cured neat EP (EP*) were 23 MPa, 45 N/25 mm, and 0.62 kN/m, respectively. Meanwhile, the cured adhesive containing 16.5 wt % SIS exhibited the slightly lower lap shear strength of 17 MPa compared to that of cured EP*, whereas the peel and impact strength of the cured adhesive with SIS were 61 N/25 mm and 7.1 kN/m, respectively, both higher than those of EP*. Furthermore, the lap shear strength of the cured adhesive containing 15.5 wt % h-SIS was 21 MPa, which was similar to that of cured EP*. The cured adhesive with h-SIS also exhibited an excellent peel strength of 97 N/25 mm and an impact strength of 14 kN/m which was 22 times higher than that of cured EP*. Therefore, mixing liquid EP and SIS improved the cured adhesive properties and flexibility of the cured epoxy adhesives compared to the cured adhesive composed of neat EP, and further enhancement of the adhesive properties was achieved by mixing liquid EP and h-SIS with hydrogen-bonding groups instead of mixing with SIS.

In the spinel framework, copper (Cu) in two distinct coordination states exhibits catalytic activity for NO reduction through different mechanisms. However, detailed exploration of their respective catalytic properties, such as the redox behavior of Cu and substrate molecule adsorption, has been challenging due to difficulties in their separate formation. In this study, we present the controlled formation of pseudospinel CuAl 2 O 4 , containing exclusively tetrahedrally or octahedrally coordinated Cu, achieved by manipulating aging temperature and O 2 concentration. Through these materials, we observed that in the CO-NO reaction, the step primarily determining the rate differs: NO reduction dominates with octahedrally coordinated Cu, whereas carbon monoxide (CO) oxidation is prominent with tetrahedrally coordinated Cu. The lower coordination number of Cu significantly benefits NO reduction but negatively impacts the CO-NO reaction, albeit positively influencing NO reduction in three-way catalytic reactions., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

Histone deacetylase 1 and 2 (HDAC1/2) inhibitors are potentially useful as tools for probing the biological functions of the isoforms and as therapeutic agents for cancer and neurodegenerative disorders. To discover potent and selective inhibitors, we screened a focused library synthesized by using click chemistry and obtained KPZ560 as an HDAC1/2-selective inhibitor. Kinetic binding analysis revealed that KPZ560 inhibits HDAC2 through a two-step slow-binding mechanism. In cellular assays, KPZ560 induced a dose- and time-dependent increase of histone acetylation and showed potent breast cancer cell growth-inhibitory activity. In addition, gene expression analyses suggested that the two-step slow-binding inhibition by KPZ560 regulated the expression of genes associated with cell proliferation and DNA damage. KPZ560 also induced neurite outgrowth of Neuro-2a cells and an increase in the spine density of granule neuron dendrites of mice. The unique two-step slow-binding character of o -aminoanilides such as KPZ560 makes them interesting candidates as therapeutic agents.

A new cascade reaction sequence that involves alkylation, cyclization, isomerization, and 3-aza-Cope rearrangement was discovered. The stereogenic centers of the starting piperidines were transferred to the bicyclic enamine products, and a range of electron-withdrawing groups on the alkyne moieties, from ketones to amides, were tolerated under the reaction conditions. The bicyclic enamines underwent trifluoroacetic acid (TFA)-mediated cyclization to form tricyclic amines bearing tetrasubstituted carbons.

Four-armed poly(ethylene glycol) (PEG)s are essential hydrophilic polymers extensively utilized to prepare PEG hydrogels, which are valuable tissue scaffolds. When hydrogels are used in vivo , they eventually dissociate due to cleavage of the backbone structure. When the cleavage occurs at the cross-linking point, the hydrogel elutes as an original polymer unit, i.e., four-armed PEG. Although four-armed PEGs have been utilized as subcutaneously implanted biomaterials, the diffusion, biodistribution, and clearance behavior of four-armed PEG from the skin are not fully understood. This paper investigates time-wise diffusion from the skin, biodistribution to distant organs, and clearance of fluorescence-labeled four-armed PEGs with molecular weight ( M w ) ranging from 5-40 kg/mol subcutaneously injected into the back of mice. Changes over time indicated that the fate of subcutaneously injected PEGs is M w -dependent. Four-armed PEGs with M w ≤ 10 kg/mol gradually diffused to deep adipose tissue beneath the injection site and distributed dominantly to distant organs, such as the kidney. PEGs with M w ≥ 20 kg/mol stagnated in the skin and deep adipose tissue and were mainly delivered to the heart, lung, and liver. The fundamental understanding of the M w -dependent behavior of four-armed PEGs is beneficial for preparing biomaterials using PEGs, providing a reference in the field of tissue engineering.

Anticancer drug delivery by small molecules offers a number of advantages over conventional macromolecular drug delivery systems. We previously developed phenylcyclopropylamine (PCPA)-drug conjugates (PDCs) as small-molecule-based drug delivery vehicles for targeting lysine-specific demethylase 1 (LSD1)-overexpressing cancers. In this study, we applied this PDC strategy to the HDAC-inhibitory anticancer agent vorinostat. Among three synthesized PCPA or arylcyclopropylamine (ACPA)-vorinostat conjugates 1 , 9 , and 32 , conjugate 32 with a 4-oxybenzyl linker showed sufficient stability in buffer solutions, potent LSD1 inhibition, efficient LSD1-dependent vorinostat release, and potent and selective antiproliferative activity toward LSD1-expressing human breast cancer and small-cell lung cancer cell lines. These results indicate that the conjugate selectively releases vorinostat in cancer cells. A similar strategy may be applicable to other anticancer drugs., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Injectable hydrogels are biomaterials that can be administered minimally invasively in liquid form and are considered promising artificial extracellular matrix (ECM) materials. However, ordinary injectable hydrogels are synthesized from water-soluble molecules to ensure injectability, resulting in non-phase-separated structures, making them structurally different from natural ECMs with phase-separated insoluble structural proteins, such as collagen and elastin. Here, we propose a simple material design approach to impart phase-separated structures to injectable hydrogels by adding inorganic salts. Injecting a gelling solution of mutually cross-linkable tetra-arm poly(ethylene glycol)s with potassium sulfate at optimal concentrations results in the formation of a hydrogel with phase-separated structures in situ. These phase-separated structures provide up to an 8-fold increase in fracture toughness while allowing the encapsulation of live mouse chondrogenic cells without compromising their proliferative activity. Our findings highlight that the concentration of inorganic salts is an important design parameter in injectable hydrogels for artificial ECMs.

We demonstrate an experimental comparison of the bond lifetime, estimated using surface plasmon resonance (SPR), and the viscoelastic relaxation time of transient networks with well-controlled structures (dynamically cross-linked Tetra-PEG gel). SPR and viscoelastic measurements revealed that the temperature dependences of the two characteristic times are in agreement, while the viscoelastic response is delayed with respect to the lifetime by a factor of 2-3, dependent on the network strand length. Polymers cross-linked by temporary interactions form transient networks, which show fascinating viscoelasticity with a single relaxation mode. However, the molecular understanding of such simple viscoelasticity has remained incomplete because of the difficulty of experimentally evaluating bond lifetimes and heterogeneous structures in conventional transient networks. Our results suggest that bond dissociation and recombination both contribute to the macromechanical response. This report on direct bond-lifetime-viscoelastic-relaxation time comparison provides important information for the molecular design of transient network materials.

syn -2,7-Dimethyloxepane is a unique structure observed in natural ladder-shaped polycyclic ethers (LSPs), such as Caribbean ciguatoxins, gymnocin-B, and brevisulcenal-F that exhibit potent biological activities. Thus, the successful construction of this seven-membered ring is desirable, but its ring strain and the 1,3-repulsion between its two methyl groups makes this process difficult. Herein, we prepared syn -2,7-dimethyloxepanes via 7 -endo cyclizations of vinyl epoxides that break Baldwin's rules. Such a biomimetic approach to syn -2,7-dimethyloxepanes has not yet been reported; however, we achieved this challenging cyclization with the aid of a cis -olefin tether and an unsubstituted vinyl group. The NO-ring fragment of gymnocin-B was also prepared from one of these 7- endo cyclized products, demonstrating the potential application of this strategy in constructing bioactive LSPs.

The discovery of a new gold(I)-catalyzed cascade reaction involving cyclization onto a vinylammonium, 3-aza-Cope rearrangement, and Mannich cyclization is reported. A variety of fused nitrogen heterocycles were prepared from simple cyclic tertiary amines using 1-5 mol % of a AuCl(PPh 3 )/Ag[C 5 (CN) 5 ] cocatalyst system. The developed reaction was used in a study aimed at synthesizing cephalotaxine. A five-step operation from norhydrastinine provided demethylcephalotaxinone in 39.1% overall yield, which was transformed to (-)-cephalotaxine in two steps.

A diaminomethylenemalononitrile organocatalyst efficiently promotes the asymmetric direct vinylogous conjugate additions of α-angelica lactones to benzoyl acrylonitrile derivatives, resulting in the corresponding addition products bearing vicinal tertiary and quaternary stereogenic centers with excellent enantioselectivities (up to 99% ee). This report is the first successful example of the asymmetric conjugate additions of α-angelica lactone to benzoyl acrylonitriles. The chiral γ,γ-disubstituted γ-butenolides obtained can be readily transformed to the bicyclic γ-lactam derivative as a valuable synthetic intermediate.

Controlling hydrogel surface wettability is of great importance in the viewpoint of engineering biomaterials that are in contact with cells and tissues. However, studies reporting how the hydrogel bulk properties would affect the surface is scarce, and thus it has been difficult to fabricate hydrogels with the desired properties. Also, there has been no effective method to elucidate this, due to the inhomogeneity introduced in the network structure of conventional hydrogels. Here we report our approach in elucidating the relationship between hydrogel physicochemical parameters and surface wettability by using Tetra-PEG gels, which are known to have homogeneous network structure. Specifically, the polymer volume fraction (φ) and the molecular weight ( M W ) between the cross-links were controlled. The number of anions, cations, and ionic pairs introduced within the hydrogel, were also individually controlled. The surface wettability of the resulting hydrogels was then evaluated. Results showed that surface wettability is largely dependent on the concentration of charged groups that are introduced in the hydrogel bulk, especially those that are not paired and ionically stabilized. Our findings strongly support the fact that with conventional hydrogels, the correlation between surface wettability and its physicochemical properties had not been evaluated appropriately, and thus our insights will contribute significantly to accumulating further knowledge on controlling hydrogel surface wettability.

The GHIJKL fragment of gymnocin-B was synthesized using the oxiranyl anion strategy. The first highlight of the synthesis is the bromoketone cyclization reaction on the oxepane ring to construct the fused bisoxepane GH ring. The second key step is the introduction of the trans -4-hydroxy-3-methyloxepane J ring via addition of trimethylaluminum to a conjugated oxonium moiety, followed by diastereoselective epoxidation and regioselective reduction.

Silica-based films were prepared by radio-frequency magnetron sputtering to investigate the influence of the chemical compositions of the target glass on the structure and wettability of the sputtered films. The sputtered films were more hydrophilic than the untreated glasses. Oxygen defects formed in the silica units of the sputtered films and resulted in the formation of hydroxyl groups, regardless of the chemical composition of the glass. The three-phase contact lines were distorted by chemical heterogeneities on the surfaces of the sputtered films.

A simple isolation method for quaternary ammonium cations via ion-pair extraction using tetracyanocyclopentadienide (TCCP) was established. Separation of tetraethylammonium and carbachol cations was achieved by the selective extraction of tetraethylammonium with ethoxycarbonyl TCCP, which was moderately lipophilic. The ion-pair extraction with TCCPs was applied to the synthesis of complex quaternary ammonium salts, including a spiro vinylammonium that is a precursor of the novel 3-aza-Cope-Mannich cascade.

An organocatalyzed method for synthesizing chiral γ,γ-disubstituted γ-butenolides via direct vinylogous aldol reactions of γ-substituted β,γ-butenolides with aldehydes is reported. This reaction is catalyzed by a squaramide-sulfonamide organocatalyst to afford a range of anti-aldol adducts possessing vicinal quaternary and tertiary stereocenters with high to excellent enantioselectivities (reaching 95% ee). This is the first report of a successful stereoselective direct vinylogous aldol reaction of aldehydes with γ-substituted β,γ-butenolides.

Tools that provide absolute quantification of biomolecules, particularly of proteins and their post-translational modifications, without needing suitable specific standards, are urgently demanded nowadays. To this end, we have significantly improved the recently introduced strategy based on CH 4 addition to the plasma for absolute quantification of biomolecules using HPLC-ICP-MS. Addition of CO 2 has been optimized and finally selected as a safer, more efficient quantitative strategy that is able to provide constant (<6% error) signal response factor for the six elements assayed (S, P, As, Se, Br, I) under compromised conditions. In the particular case of absolute protein quantification, accuracy and precision attainable for S-based absolute determination of intact proteins using internal and external S-generic standards were compared. Potential for real sample analysis was demonstrated by the high-sensitivity analysis of toxins present in snake venoms. Finally, multielemental speciation capabilities of the approach have been also demonstrated through P and S simultaneous analysis in phosphoproteomics. Simultaneous accurate determination of both absolute protein amount and corresponding phosphorylation degree for intact β-casein, and even impurity traces of κ and α-s1 isoforms present, has been successfully achieved using a simple mixture of inorganic P and S standards. The lowest detection limits (<1 fmol protein) ever published for S- and P-based intact protein quantification with ICP-MS are reported.

Wet soap foam spontaneously imbibes liquid oil without defoaming when it is brought into contact. The kinetics behind this recently observed phenomenon was studied experimentally, with focus on the origin of the suction force and on the oil front dynamics. Using an aqueous foam with an air volume fraction slightly greater than the critical value ϕ C , we show that the pumping pressure of oil and/or miscible liquid into the wet foam is attributed to the interfacial distortion of the bubble surfaces. Two distinct regimes along time t were observed in the oil imbibition dynamics. The proceeding oil front evolves with t 1/2 dependency in the early imbibition time in accordance with the classical theory of penetration of a porous medium, whereas it departs into t 1/3 at late imbibition time. The latter process is attributed to the elongation of an oil branch trapped inside the foam when pumping of the exterior oil has ceased.

We have investigated high-pressure, high-temperature phase transitions of spinel (Sp)-type MgV 2 O 4 , FeV 2 O 4 , and MnCr 2 O 4 . At 1200-1800 °C, MgV 2 O 4 Sp decomposes at 4-7 GPa into a phase assemblage of MgO periclase + corundum (Cor)-type V 2 O 3 , and they react at 10-15 GPa to form a phase with a calcium titanite (CT)-type structure. FeV 2 O 4 Sp transforms to CT-type FeV 2 O 4 at 12 GPa via decomposition phases of FeO wüstite + Cor-type V 2 O 3 . MnCr 2 O 4 Sp directly transforms to the calcium ferrite (CF)-structured phase at 10 GPa and 1000-1400 °C. Rietveld refinements of CT-type MgV 2 O 4 and FeV 2 O 4 and CF-type MnCr 2 O 4 confirm that both the CT- and CF-type structures have frameworks formed by double chains of edge-shared B 3+ O 6 octahedra (B 3+ = V 3+ and Cr 3+ ) running parallel to one of orthorhombic cell axes. A relatively large A 2+ cation (A 2+ = Mg 2+ , Fe 2+ , and Mn 2+ ) occupies a tunnel-shaped space formed by corner-sharing of four double chains. Effective coordination numbers calculated from eight neighboring oxygen-A 2+ cation distances of CT-type MgV 2 O 4 and FeV 2 O 4 and CF-type MnCr 2 O 4 are 5.50, 5.16, and 7.52, respectively. This implies that the CT- and CF-type structures practically have trigonal prism (six-coordinated) and bicapped trigonal prism (eight-coordinated) sites for the A 2+ cations, respectively. A relationship between cation sizes of VIII A 2+ and VI B 3+ and crystal structures (CF- and CT-types) of A 2+ B 2 3+ O 4 is discussed using the above new data and available previous data of the postspinel phases. We found that CF-type A 2+ B 2 3+ O 4 crystallize in wide ionic radius ranges of 0.9-1.4 Å for VIII A 2+ and 0.55-1.1 Å for VI B 3+ , whereas CT-type phases crystallize in very narrow ionic radius ranges of ∼0.9 Å for VIII A 2+ and 0.6-0.65 Å for VI B 3+ . This would be attributed to the fact that the tunnel space of CT-type structure is geometrically less flexible due to the smaller coordination number for A 2+ cation than that of CF-type.

Glucagon-like peptide-1 (GLP-1) is an incretin peptide that plays a crucial role in lowering blood glucose levels and holds promise for treating type II diabetes. In this study, we synthesized GLP-1 derivatives that were conjugated with glycosaminoglycans (GAGs), i.e., chondroitin (CH) or heparosan (HPN), to address the major limitation in their clinical use of GLP-1, which is its short half-life in the body. After exploring a variety of CHs with different molecular sizes and heterobifunctional linkers having different alkyl chains, we obtained CH-conjugated GLP-1 derivatives that stayed in blood circulation much longer ( T 1/2 elim > 25 h) than unconjugated GLP-1 and showed blood glucose-lowering efficacy up to 120 h after subcutaneous injection in mice. By using the same optimized linker design, we eventually obtained a HPN-conjugated GLP-1 derivative with efficacy lasting 144 h. These results demonstrate that conjugation with GAG is a promising strategy for improving the duration of peptide drugs., Competing Interests: The authors declare no competing financial interest.

The dispersion stabilization of colloidal particles and subsequent construction of functional materials are of great interest in areas ranging from colloid chemistry to materials science. A promising strategy is the spatial immobilization of colloidal particles within gel scaffolds. However, conventional gels readily deform and even collapse when changes in environmental conditions occur. Herein, we describe the enzyme-catalyzed bottom-up synthesis of mechanically and physicochemically stable nanoribbon network hydrogels composed of crystalline cellulose oligomers in which cellulose nanocrystals (CNCs) as model colloidal particles are immobilized spatially. The stiffness of the hydrogels increased with the amount of CNCs incorporated. Filling the void space of the hydrogels with hydrophobic polymers resulted in polymer nanocomposites with excellent mechanical properties. The nanoribbon networks will be useful for demonstrating the potential functions of colloidal particles.

A simple device structure composed of an interfacial Eu 2+/3+ complex on a mesoporous TiO 2 film is developed by a solution process and acts as the high-performance photodetector with photomultiplication phenomena. The electron transfer from the photoexcited organic ligand, 2,2':6',2″-terpyridine (terpy), as a photosensitizer to TiO 2 is accelerated by the reduction level of Eu 3+/2+ ions chemically bonding among terpy and TiO 2 , resulting in the generation of a large photocurrent. It is worth noting that its external quantum efficiency is in excess of 10 5 % under applied reverse bias. The corresponding responsivity of the device is also determined to be 464 A/W at an irradiation light intensity of 0.7 mW/cm 2 (365 nm), which is more than 3 orders of magnitude larger than those of inorganic photodetectors. A dark current of the device can be reduced to 10 -9 A/cm 2 by introducing a Eu oxide thin-film layer as a carrier blocking layer at the interface between transparent conducting oxide (TCO) and the TiO 2 layer, and the specific detectivity reaches 5.2 × 10 15 jones at 365 nm with -3 V. The performance of our organic-inorganic hybrid photodetector surpasses those of existing ultraviolet photodetectors.

Thermal changes in the association behavior of poly(ethylene oxide)-poly(propylene oxide) alternating multiblock (PEO-PPO AMB) copolymers in water are investigated by the use of transmittance and light scattering measurements. Two PEO-PPO AMB copolymers with a different weight fraction of PEO, (EO 220 PO 33 ) 8 and (EO 68 PO 33 ) 9 , are prepared. The weight-average molecular weights of (EO 220 PO 33 ) 8 and (EO 68 PO 33 ) 9 estimated by static light scattering measurements are 1.3 × 10 5 and 4.1 × 10 4 g mol -1 , respectively. The number of PEO-PPO repeating pairs is over 8. It is found that the aqueous solution of (EO 220 PO 33 ) 8 undergoes phase separation with a lower critical solution temperature (LCST) of around 58 °C at 0.3 wt %. For the aqueous (EO 68 PO 33 ) 9 solution, the LCST is estimated to be ca. 42 °C. The critical solution concentration for (EO 68 PO 33 ) 9 is not clear because of a small concentration dependence of T c at a higher concentration range. Dynamic light scattering measurements indicate that a micellelike aggregate is formed below the LCST. From the Debye plot, it is elucidated that the second virial coefficient, A 2 , starts going down at around 32 °C for (EO 220 PO 33 ) 8 and below 15 °C for (EO 68 PO 33 ) 9 . The A 2 value of (EO 220 PO 33 ) 8 approaches 0 near 50 °C, whereas that of (EO 68 PO 33 ) 9 approaches 0 at around 35 °C. At a high temperature, the attractive interaction among the copolymers becomes dominant, thereby inducing the formation of micellelike aggregates.

Fabrication of nanographene shows a promising route for production of designed porous carbons, which is indispensable for highly efficient molecular separation and energy storage applications. This process requires a better understanding of the mechanical properties of nanographene in their aggregated structure. We studied the structural and mechanical properties of nanographene monoliths compressed at 43 MPa over different times from 3 to 25 h. While in monoliths compressed over shorter time adsorption isotherms of Ar at 87 K or N 2 at 77 K exhibited a prominent hysteresis due to presence of predominant mesopores, compression for long time induces a low pressure hysteresis. On the other hand, compression for 25 h increases the microporosity evaluated by Ar adsorption, not by N 2 adsorption, indicating that 25 h compression rearranges the nanographene stacking structure to produce ultramicropores that can be accessible only for Ar. TEM, X-ray diffraction, and Raman spectroscopic studies indicated that the compression for 25 h unfolds double-bent-like structures, relaxing the unstable nanographene stacked structure formed on the initial compression without nanographene sheets collapse. This behavior stems from the highly elastic nature of the nanographenes.

Metal-free, formal [2 + 2 + 2] cycloaddition strategies for the synthesis of polycyclic pyridine derivatives are described. The overall transformation proceeds via a two-stage pericyclic cascade mechanism. In the first step, an intramolecular propargylic ene reaction generates a vinylallene that is necessarily locked in the s-cis conformation. This vinylallene exhibits exceptional reactivity as a Diels-Alder reaction partner and engages in [4 + 2] cycloadditions with normally unreactive azadienophiles including unactivated cyano groups and heterosubstituted imine derivatives such as dimethylhydrazones and oximino ethers. Few examples of oximino ether Diels-Alder reactions have been reported previously, and normal electron-demand [4 + 2] cycloadditions of unactivated dialkylhydrazones are unprecedented. Overall, this metal-free formal [2 + 2 + 2] cycloaddition provides access to polycyclic pyridine derivatives and complements transition-metal-catalyzed [2 + 2 + 2] strategies.

Small, "doll"-shaped tetracyanocyclopentadienide bearing a 1,3-dioxane acetal "head" and cyano "hands" and "feet" was synthesized. Its pyridinium salt, which was named NanoGoblin, exhibited catalytic activity in the methanolysis of acetals, as demonstrated by the reaction with NanoKid in methanol- d 4 , where the acetal head of NanoKid was converted to a deuterated dimethyl acetal moiety., Competing Interests: The authors declare no competing financial interest.

The detonation nanodiamonds form the aggregate having interparticle voids, giving a marked hygroscopic property. As the relationship between pore structure and water adsorption of aggregated nanodiamonds is not well understood yet, adsorption isotherms of N 2 at 77 K and of water vapor at 298 K of the well-characterized aggregated nanodiamonds were measured. HR-TEM and X-ray diffraction showed that the nanodiamonds were highly crystalline and their average crystallite size was 4.5 nm. The presence of the graphitic layers on the nanodiamond particle surface was confirmed by the EELS examination. The pore size distribution analysis showed that nanodiamonds had a few ultramicropores with predominant mesopores of 4.5 nm in average size. The water vapor adsorption isotherm of IUPAC Type V indicates the hydrophobicity of the nanodiamond aggregates, with the presence of hydrophilic sites. Then the hygroscopic nature of nanodiamonds should be associated with the surface functionalities of the graphitic shell and the ultramicropores on the mesopore walls.

Plant hormones act as important signaling molecules that regulate responses to abiotic stress as well as plant growth and development. Because their concentrations of hormones control the physiological responses in the target tissue, it is important to know the distributions and concentrations in the tissues. However, it is difficult to determine the hormone concentration on the plant tissue as a result of the limitations of conventional methods. Here, we report the first multi-imaging of two plant hormones, one of cytokinin [i.e., trans-zeatin (tZ)] and abscisic acid (ABA) using a new technology, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) imaging. Protonated signals of tZ (m/z 220.1) and ABA (m/z 265.3) were chosen on longitudinal sections of rice roots for MS imaging. tZ was broadly distributed about 40 mm behind the root apex but was barely detectable at the apex, whereas ABA was mainly detected at the root apex. Multi-imaging using MALDI-TOF-MS enabled the visualization of the localization and quantification of plant hormones. Thus, this tool is applicable to a wide range of plant species growing under various environmental conditions.

Native silk fibers are known to demonstrate excellent mechanical properties such as high strength and ductility. However, regenerated silk material has not yet been used as a tough structural material in our everyday life. To recreate the mechanical properties with regenerated silk material, the network structure and hydration state of silk materials are studied and optimized in this study. This is the first to demonstrate the effect of chemical and physical cross-links in hydrated and dehydrated silk materials, namely, silk hydrogels and resins. Mild hydration conditions (relative humidity 20-60%) realizes tough and strong silk materials with chemical and physical cross-links. In the case of relatively high concentrations of silk molecules, contributions to the high strength and toughness of silk-based materials are considered to come not only from β-sheet cross-links and chemical dityrosine links but also from entanglements and assembly via the hydrophobic interactions of silk molecules. In addition, dehydration treatment does not disturb the biodegradability of the silk resins in natural environments. Based on the overall results, the silk resins with controlled network structures and hydration state have successfully achieved the highest toughness possible for a bulk silk material while maintaining favorable biodegradability.

Asymmetric direct vinylogous aldol reactions of furan-2(5H)-one with aldehydes in the presence of a catalytic amount of novel squaramide-sulfonamide organocatalyst resulted in the corresponding addition products with high to excellent enantioselectivities. This is the first successful report illustrating an example of highly stereoselective reactions using a squaramide-sulfonamide organocatalyst.

An improved route for the synthesis of the KLMN fragment of gymnocin-A was developed through the oxiranyl anion coupling of the FGH fragment with a chiral C 3 epoxy sulfone, followed by 6-endo cyclization. This straightforward approach reduced the number of synthetic steps by 14 compared with a previous route using alternative building blocks.

Rotamers around the C Ar -O bond were disclosed in 3,3'-disubstituted BINOL esters by NMR spectroscopy. A bulky R 1 group increased the rotational barrier. The pivalate showed two rotamers at 2 °C, and broad signals were observed close to room temperature when R 2 = Ph. The highest rotational barrier was recorded for the (tetracyanocyclopentadienyl)carboxylate, and C-O rotamers were present at room temperature. DFT calculations indicated the presence of repulsion between R 1 and R 2 during rotation of the C Ar -O bond.

Macromolecular crowding, a solution state with high macromolecular concentrations, was used to promote the crystallization-driven self-assembly of enzymatically synthesized cellulose oligomers. Cellulose oligomers were synthesized via cellodextrin phosphorylase-catalyzed enzymatic reactions in the concentrated solutions of water-soluble polymers, such as dextran, poly(ethylene glycol), and poly( N -vinylpyrrolidone). The reaction mixtures were transformed into cellulose oligomer hydrogels composed of well-grown crystalline nanoribbon networks irrespective of the polymer species. This method was successfully applied in the one-pot preparation of double network hydrogels composed of the nanoribbons and physically cross-linked gelatin molecules through the simple control of reaction temperatures, demonstrating the superior mechanical properties of the composite hydrogels. Our concept that promotes the growth of self-assembled architectures under macromolecular crowding conditions demonstrates a new avenue into developing novel hydrogel materials.

Connective tissues such as tendon, ligament and cartilage are mostly composed of extracellular matrix (ECM). These tissues are insoluble, mainly due to the highly cross-linked ECM proteins such as collagens. Difficulties obtaining suitable samples for mass spectrometric analysis render the application of modern proteomic technologies difficult. Complete solubilization of them would not only elucidate protein composition of normal tissues but also reveal pathophysiology of pathological tissues. Here we report complete solubilization of human Achilles tendon and yellow ligament, which is achieved by chemical digestion combined with successive protease treatment including elastase. The digestion mixture was subjected to liquid chromatography-mass spectrometry. The low specificity of elastase was overcome by accurate mass analysis achieved using FT-ICR-MS. In addition to the detailed proteome of both tissues, we also quantitatively determine the major protein composition of samples, by measuring peak area of some characteristic peptides detected in tissue samples and in purified proteins. As a result, differences between human Achilles tendon and yellow ligament were elucidated at molecular level.

In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical shortcoming is revealed. Thus, an early evaluation of structure-activity relationships (SARs) can mitigate unforeseen outcomes within a series of multiple compounds, although there have been very few examples to follow such a policy. PI4KIIIα is one of four mammalian phosphatidylinositol-4 kinases and has recently drawn significant attention as an emerging target for hepatitis C virus (HCV) treatment. In this letter, a novel "head-to-tail" approach to discover a diverse set of PI4KIIIα inhibitors is reported. We believe this method will generate distinct core scaffolds, a rational strategy to circumvent potential risks in general kinase programs.

Newly developed inorganic single-wall carbon nanotube (SWCNT) inks of the Zn/Al complex and colloidal silica give a quite homogeneous SWCNT film on the polyethylene terephthalate (PET) substrate by the bar-coating method, whereas the surfactant-based SWCNT inks of sodium dodecyl sulfonate (SDS) and sodium dodecyl benzene sulfonate (SDBS) cannot give a homogeneous film. The key properties of SWCNT inks were studied for the production of homogeneous SWCNT films. The contact angle and surface tension of the inorganic dispersant-based SWCNT inks were 70° and 72 mN m(-1), respectively, being close to those of water (71.5° and 71 mN m(-1)). The viscosity was significantly higher than that of water (0.90 mPa·s), consequently, providing sufficient wettability, spreadability, and slow drying of the ink on the substrate, leading to homogeneous film formation. On the other hand, the surfactant dispersant-aided SWCNT inks have the contact angle and surface tension twice lower than the inorganic dispersant-based SWCNT inks, guaranteeing better wettability and spreadability than the inorganic dispersant-based inks. However, the small viscosity close to that of water induces a heterogeneous flow of SWCNT ink on rapid drying, leading to inhomogeneous film formation.

A total synthesis of brevisamide, a marine monocyclic ether amide isolated from the dinoflagellate Karenia brevis, has been achieved in 18 steps starting from 4-(benzyloxy)butanol. The synthesis involves oxiranyl anion coupling between an epoxy sulfone and a triflate, intramolecular etherification of a hydroxy-bromoketone, diastereoselective introduction of the axial methyl group by hydroxyl-directed hydrogenation of an exocyclic olefin, and installation of an acetamide side chain by nucleophilic substitution of an N-acetyl carbamate. The dienal side chain is assembled using a Horner-Wadsworth-Emmons reaction to complete the synthesis.

A convergent total synthesis of cytotoxic marine natural polycyclic ether, gymnocin-A (1), is described. The synthesis features three iterations of an oxiranyl anion strategy, involving base-mediated cycloetherification, ring expansion, and reductive etherification, for the construction of the FGH fragment and for its coupling with the ABC and KLMN fragments.

A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduction of CYP inhibition was observed, which finally led to discovery of a selective and orally efficacious RORγ inhibitor 3z.

In recent years, research utilizing micro- and nanoscale geometries and structures on biomaterials to manipulate cellular behaviors, such as differentiation, proliferation, survival, and motility, have gained much popularity; however, how the surface microtopography of 3D objects, such as implantable devices, can affect these various cell behaviors still remains largely unknown. In this study, we discuss how the walls of microgroove topography can influence the morphology and the motility of unrestrained cells, in a different fashion from 2D line micropatterns. Here adhesive substrates made of tetra(polyethylene glycol) (tetra-PEG) hydrogels with microgroove structures or 2D line micropatterns were fabricated, and cell motility on these substrates was evaluated. Interestingly, despite being unconstrained, the cells exhibited drastically different migration behaviors at the edges of the 2D micropatterns and the walls of microgroove structures. In addition to acquiring a unilamellar morphology, the cells increased their motility by roughly 3-fold on the microgroove structures, compared with the 2D counterpart or the nonpatterned surface. Immunostaining revealed that this behavior was dependent on the alignment and the aggregation of the actin filaments, and by varying the slope of the microgroove walls, it was found that relatively upright walls are necessary for this cell morphology alterations. Further progress in this research will not only deepen our understanding of topography-assisted biological phenomena like cancer metastasis but also enable precise, topography-guided manipulation of cell motility for applications such as cancer diagnosis and cell sorting.

In recent years, free-electron lasers operating in the true X-ray regime have opened up access to the femtosecond-scale dynamics induced by deep inner-shell ionization. We have investigated charge creation and transfer dynamics in the context of molecular Coulomb explosion of a single molecule, exposed to sequential deep inner-shell ionization within an ultrashort (10 fs) X-ray pulse. The target molecule was CH3I, methane sensitized to X-rays by halogenization with a heavy element, iodine. Time-of-flight ion spectroscopy and coincident ion analysis was employed to investigate, via the properties of the atomic fragments, single-molecule charge states of up to +22. Experimental findings have been compared with a parametric model of simultaneous Coulomb explosion and charge transfer in the molecule. The study demonstrates that including realistic charge dynamics is imperative when molecular Coulomb explosion experiments using short-pulse facilities are performed.

Semiconductor quantum dot (QD) superlattices, which are periodically ordered three-dimensional (3D) array structures of QDs, are expected to exhibit novel photo-optical properties arising from the resonant interactions between adjacent QDs. Since the resonant interactions such as long-range dipole-dipole Coulomb coupling and short-range quantum resonance strongly depend on inter-QD nano space, precise control of the nano space is essential for physical understanding of the superlattice, which includes both of nano and bulk scales. Here, we study the pure quantum resonance in the 3D CdTe QD superlattice deposited by a layer-by-layer assembly of positively charged polyelectrolytes and negatively charged CdTe QDs. From XRD measurements, existence of the periodical ordering of QDs both in the lamination and in-plane directions, that is, the formation of the 3D periodic QD superlattice, was confirmed. The lowest excitation energy decreases exponentially with decreasing the nano space between the CdTe QD layers and also with decreasing the QD size, which is apparently indicative of the quantum resonance between the QDs rather than a dipole-dipole Coulomb coupling. The quantum resonance was also computationally demonstrated and rationalized by the orbital delocalization to neighboring CdTe QDs in the superlattice.

We report the gelation mechanism of tetra-armed prepolymer chains in typical aprotic ionic liquid (aIL), i.e., A-B type cross-end coupling reaction of tetra-armed poly(ethylene glycol)s with amine and activated ester terminals (TetraPEG-NH2 and TetraPEG-NHS, respectively) in 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)amide ([C2mIm][TFSA]). In the ion gel system, we focused on the pH (or H(+) concentration) dependence of the gelation reaction. We thus applied the protic ionic liquid (pIL), 1-ethylimidazolium TFSA ([C2ImH][TFSA]), as a nonvolatile H(+) source, and added it into the solvent aIL. It was found that the gelation time of TetraPEG ion gel can be successfully controlled from 1 min to 3 h depending on the concentration of pIL (cpIL = 0-3 mM). This suggests that the acid-base properties of TetraPEG-NH2 showing acid-base equilibrium (-NH2 + H(+) ⇆ -NH3(+)) in the solutions play a key role in the gelation process. The acid dissociation constants, pKa's of TetraPEG-NH3(+) and C2ImH(+) (cation of pIL) in aIL were directly determined by potentiometric titration to be 16.4 and 13.7, respectively. This indicates that most of the H(+) ions bind to TetraPEG-NH2 and then C2ImH(+) exists as neutral C2Im. The reaction efficiency of amide bond (cross-linked point) systematically decreased with increasing cpIL, which was reflected to the mechanical strength of the ion gels. From these results, we discuss the gelation mechanism of TetraPEG in aIL to point out the relationship between polymer network structure and [H(+)] in the solutions.

Motor activity of myosin III is regulated by autophosphorylation. To investigate the role of the kinase activity on the transporter function of myosin IIIA (Myo3A), we identified the phosphorylation sites of kinase domain (KD), which is responsible for the regulation of kinase activity and thus motor function. Using mass spectrometry, we identified six phosphorylation sites in the KD, which are highly conserved among class III myosins and Ste20-related misshapen (Msn) kinases. Two predominant sites, Thr¹⁸⁴ and Thr¹⁸⁸, in KD are important for phosphorylation of the KD as well as the motor domain, which regulates the affinity for actin. In the Caco2 cells, the full-length human Myo3A (hMyo3AFull) markedly enlarged the microvilli, although it did not show discrete localization within the microvilli. On the other hand, hMyo3AFull(T184A) and hMyo3AFull(T188A) both showed clear localization at the microvilli tips. Our results suggest that Myo3A induces large actin bundle formation to form microvilli, and phosphorylation of KD at Thr¹⁸⁴ and Thr¹⁸⁸ is critical for the kinase activity of Myo3A, and regulation of Myo3A translocation to the tip of microvilli. Retinal extracts potently dephosphorylate both KD and motor domain without IQ motifs (MDIQo), which was inhibited by okadaic acid (OA) with nanomolar range and by tautomycetin (TMC) with micromolar range. The results suggest that Myo3A phosphatase is protein phosphatase type 2A (PP2A). Supporting this result, recombinant PP2Ac potently dephosphorylates both KD and MDIQo. We propose that the phosphorylation-dephosphorylation mechanism plays an essential role in mediating the transport and actin bundle formation and stability functions of hMyo3A.