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Electronic structure of organic semiconductor that is governed by the packing structure in the solid state is critically important for the transport properties of organic-semiconductor solid. Dinaphtho[2,3-b:2′,3′-f]thieno[3,2-b]thiophenes (DNTT), which has been utilized as an active semiconducting material in high-performance organic field-effect transistors (OFETs), crystalized into a herringbone packing structure that affords the two-dimensional (2D) electronic structure. Here we have investigated effects of substituents on the packing structure of a series of DNTT derivatives modified with a (trialkylsilyl)ethynyl substituents. The packing structures of the derivatives with small (trialkylsilyl)ethynyl substituents, such as (trimethylsilyl)ethynyl (TMSE) (1) and (triethylsilyl)ethynyl (TESE) groups (2), were revealed to be the herringbone packing, whereas (triisopropylsilyl)ethynyl (TIPSE)-substituted DNTT (3) crystalized into a sandwich herringbone structure, in which face-to-face dimers of molecules are packed into a herringbone array. In-depth analyses of the packing structures by means of the functional-group symmetry-adapted perturbation theory (F-SAPT) calculations showed that the size of the TESE groups is critical to determine the packing structure; intermolecular interaction between the sterically demanding TIPSE groups does not allow 3 to crystalize into the herringbone structure that is favorable for the most of DNTT derivatives including 1 and 2. Although the sandwich herringbone structure has not been regarded as a potential one for efficient carrier transport in the solid state, the OFETs based on 1−3 showed comparable high mobility of 0.34 to 1.1 cm2 V−1 s−1, indicating that the sandwich herringbone structure is not necessarily quite unsuitable for carrier transport, which was also endorsed by the transfer integrals calculated based on the packing structure elucidated by the single crystal X-ray analysis. These results imply that versatile modifications on the molecular and packing structures can be applied to the DNTT core for the development of superior organic semiconductors.

In this study, we focused on a nuclear localization signal (NLS)-based versatile peptide vector, designed by us, combined with electroporation (EP) to establish an efficient gene delivery system to non-dividing or slow growing dendritic cells. We determined the intranuclear transport, gene expression, and cell viability in JAWS II mouse dendritic cells transfected with the green fluorescent protein (GFP) expression plasmid DNA alone (naked pEGFP); positive charged complex of NLS derivative STR-CH2SV40H2C, and pEGFP (binary complex); or negative charged complex of the binary complex with a biocompatible polyanion, γ-polyglutamic acid (ternary complex) combined with or without EP application. Although the binary complex showed higher nuclear transport and GFP expression in the absence of EP than those for naked pEGFP, the combination of EP significantly decreased the cell viability and did not improve the efficiency of compared gene expression. However, in the ternary complex, the intranuclear transport and GFP expression efficiency were significantly higher than those of naked pEGFP and the binary complex when combined with EP, and there was no decrease in cell viability. The results suggest that polyanion-coated ternary complex with EP is useful for non-viral gene delivery system into non-dividing cells for ex vivo gene/cell therapy.

In this study, we examined the conformation and intermolecular interactions of benzo-12-crown-4 (B12C4) complexes with NH4+, CH3NH3+ (MeNH3+), CH3CH2NH3+ (EtNH3+), and CH3CH2CH2NH3+ (PrNH3+) using cold gas-phase spectroscopy. All of the B12C4 complexes showed sharp vibronic features in the UV photodissociation spectra, and the position of the 0-0 band was close to that of the B12C4 complex with an isotropic K+ guest. This result suggests that the conformation of B12C4 is maintained despite oriented interactions with ammonium guests via anisotropic N-H···O interactions. Further, we measured the IR-UV double-resonance spectra of these complexes in the NH stretching region. In the IR-UV spectra of the EtNH3+ and PrNH3+ complexes, two distinct IR fingerprints were observed depending on the UV probe wavelength selected, indicating the existence of another (second) conformer for these complexes. Quantum chemical calculations clarified that the second conformer of the EtNH3+ and PrNH3+ complexes was partially stabilized by the C-H···π hydrogen bond. The conformation of B12C4 complexes with ammonium ions is strongly affected by the interaction between the alkyl chain of the ion guest and the benzene ring of the B12C4 host, although the main intermolecular interaction occurs between the NH3+ group and crown cavity through the N-H···O hydrogen bonds.

This study focused on defining a quantitative disintegration index for tablet disintegrants based on a dynamic viscoelastic analysis of the complex disintegration mechanism associated with swelling and wicking. We used an oscillatory rheometer with a serrated-plate measuring system to evaluate the viscoelastic properties of three disintegrants, croscarmellose sodium (CCS), crospovidone (CPV), and corn starch (CS), which were prepared with distilled water at different liquid-to-solid ratios. The swelling and wicking disintegration indices were calculated from the obtained data. The results showed that the three disintegrants could be evaluated by the shear stress and loss tangent as representative dynamic viscoelasticity parameters that changed depending on the water content in the disintegrant preparation. Additionally, the viscoelasticity of CCS and CPV was strongly affected by swelling, whereas that of CS was mainly associated with wicking and water penetration. Furthermore, CPV had the largest swelling disintegration index value, whereas CS showed the largest wicking disintegration index value among the three disintegrants. These results suggested that the disintegration indices based on viscoelasticity established in this study could reflect the disintegration properties inherent to each disintegrant type. Our findings provide valuable guidance for selecting suitable disintegrants in the formulation design.

A straightforward technique is presented for an interim or short-term definitive esthetic replacement of missing anterior teeth requiring no tooth preparation. Composite resins are injected into transparent silicone indices fabricated from 3-dimensional–printed casts of a digital waxing. The dentin core is formed of a durable short fiber–reinforced injectable composite resin and veneered with an enamel-shade composite resin for enhanced esthetics. Besides being noninvasive, this technique is more straightforward than traditional options, reducing chair time while providing an accurate outcome.

The question of what kinds of airborne particles, including diesel exhaust particles and their adherent chemical constituents, exacerbate the activity of allergic and inflammatory respiratory diseases has not been elucidated in detail. Therefore, chemicals that have amplifying actions on Dermatophagoides farinae (Df) body extract-induced IL-8, the inflammatory cytokines of the innate immune system, were comprehensively examined using commonly used human alveolar epithelial cells, A549, as simple screening for 17 polycyclic aromatic hydrocarbons (PAHs), which are representative organic constituents in atmospheric samples. The significant amplifying actions of two PAHs, dibenzo[a,l]pyrene (DB[a,l]P) at 50 nM and dibenzo[a,i]pyrene (DB[a,i]P) at 2 μM for 48 h, for IL-8 protein release induced by mite antigens in epithelial cells were observed for the first time. In contrast, the enhancement of IL-8 was not observed in protein levels for these PAHs without the antigens. Meanwhile, the significant synergistic amplifying effect of DB[a,l]P at 50 nM on proinflammatory actions was measured in gene expression (i.e., IL-8, IL-6, ICAM-1, and TNF-α) levels in the experimental setting; for the results, the induction of TNF-α may have been the essential factor that enhanced the amplifying activity of DB[a,l]P for IL-8 gene expression and protein release. Examining the exacerbating effect on allergic pathophysiological states for DB[a,l]P is planned for further study.

Oxygen-containing carbon materials have been studied extensively because of their excellent dispersibility, absorptivity, separability, and supportability of catalysts. However, structural control by existing top-down methods is almost impossible. Our group has demonstrated that phloroglucinol (PG, 1,3,5-trihydroxybenzene) can be a promising raw material to synthesize structurally controlled oxygen-containing carbon materials. In this study, in addition to PG, hexahydroxybenzene (HHB), which has more oxygen and high symmetry, was used as the raw material, and a Lewis acid catalyst, tris (pentafluorophenyl) borane (TPB), was used to enhance the structural control rate and the removability of catalysts from the carbonized samples. The solubility of heat-treated HHB was lower than that of heat-treated PG, but the oxygen content of heat-treated HHB was higher than that of heat-treated PG even at 673 K. By adding TPB to PG, dibenzofuran-like structures formed, and the structural control rate increased up to 93.6%. Besides, the content of fluorine in the catalyst was reduced to 0%, indicating that TPB can be a promising recyclable catalyst to promote the structural control rate of carbonized PG.

In rats, lisdexamfetamine (LDX) induces manic-like behaviors such as hyperlocomotion and increases in appetitive 50-kHz ultrasonic vocalizations (USV), which are prevented by antimanic drugs, such as lithium. Inhibition of glycogen synthase kinase 3 beta (GSK3β) and antioxidant activity have been associated with antimanic effects. Thus, the aim of the present study was to evaluate the possible antimanic-like effects of andrographolide (ANDRO), a GSK3β inhibitor, on LDX-induced hyperlocomotion and 50-kHz USV increases. In addition, the effect of ANDRO was studied on LDX-induced oxidative stress. Lithium was used as positive control. Adult Wistar rats were treated with vehicle, lithium (100 mg/kg i.p., daily) or ANDRO (2 mg/kg i.p., 3 times a week) for 21 days. On the test day, either 10 mg/kg LDX or saline was administered i.p. and USV and locomotor activity were recorded. LDX administration increased the number of 50-kHz calls, as well as locomotor activity. Repeated treatment with lithium or ANDRO prevented these effects of LDX on 50-kHz USV and locomotor activity. LDX increased lipid peroxidation (LPO) levels in rat striatum and both lithium and ANDRO prevented this effect. LPO levels in rat striatum were positively correlated with increases in 50-kHz USV emission as well as hyperlocomotion. In conclusion, the present results indicate that ANDRO has antimanic-like effects, which may be mediated by its antioxidant properties.

Objective: The effects of 6-MSITC on cell cycle progression were investigated in quiescent mouse epidermal JB6 cells. Background: 6-Methylsulfinylhexyl isothiocyanate (6-MSITC) derived from wasabi (Wasabia japonica) has been reported to prevent tumor development in vivo. Material and methods: Treatment with epidermal growth factor (EGF) to quiescent JB6 cells, which were serum-starved for 36 h, promoted cell cycle progression from the G0/G1 phase to the S phase. Effects of pretreatment with 6-MSITC on cell cycle progression were estimated by flowcytometry and real-time RT-PCR. Results: Pretreatment with 6-MSITC at 0.25-1.0 μg/ml prior to the growth stimulation with EGF significantly inhibited cell cycle progression. Pretreatment with 6-MSITC inhibited the gene expression of DNA synthesis-related proteins cyclin A2, dumbbell former 4, and proliferating cell nuclear antigen. Conclusion: These results showed that 6-MSITC inhibits cell cycle progression in quiescent cells, accompanied by the inhibition of gene expression of DNA synthesis proteins.

The living cationic ring-opening polymerization of cyclohexene oxide (CHO) was demonstrated to proceed using cyclic ethers as Lewis basic additives that potentially form “dormant” species through a reaction with the CHO-derived propagating species. The polymers obtained under suitable conditions had molecular weights close to the theoretical values and narrow molecular weight distributions. The formation of the dormant species was strongly supported by the generation of chain ends consisting of a cyclic ether additive and a quencher fragment, which was confirmed by ¹H NMR and ESI-MS analysis of the product polymers. The use of additives with appropriate basicity, such as hexamethylene oxide and tetrahydropyran, is of considerable importance for living polymerization. In addition, the living copolymerization of CHO and 1,4-epoxycyclohexene and the synthesis of alternating-like acid-degradable polymers with aliphatic aldehydes were also achieved.

In this work, various types of chain-transfer agents (CTAs) were investigated in the reversible addition-fragmentation chain-transfer (RAFT) polymerization of isopropenyl boronate pinacol ester (IPBpin) toward not only precise synthesis of poly(IPBpin) but also elucidation of its feature as a monomer. CTAs suitable for conjugated monomers were found to be more compatible than those for nonconjugated monomers, likely due to the moderate stabilization of the growing radical by boron. This trend was supported by density functional theory-based calculations for energy balance between the growing IPBpin radical and the chain-transfer species to the CTA. The CTA-derived group at the ω-terminus of the obtained poly(IPBpin) was quantitatively converted into olefin under cobalt catalysis leading to improved stability, enabling evaluation of its well-defined structure by MALDI-TOF-MS and its thermal properties by DSC. The precise synthesis of poly(alkenyl boronate)s was achieved through RAFT polymerization of isopropenyl boronate pinacol ester (IPBpin) and subsequent terminal olefination by cobalt catalysis. Experimental and computational investigation on the compatibility of IPBpin with chain transfer agents revealed its conjugated-monomer type behavior that is ascribed to empty p-orbital of boron. Terminal olefination in post-polymerization reaction improved the stability of resulting polymers, enabling the analysis for molecular structure of poly(IPBpin) by MALDI-TOF-MS spectroscopy as well as thermal properties by DSC.

Artepillin C, 3, 5-diprenyl-4-hydroxycinnamic acid, is one of the bioactive constituents in Brazilian propolis. In the present study, the anticarcinogenic activity of this compound was investigated in human hepatoma HepG2 cells. Artepillin C inhibited the cell proliferation in a dose- and time-dependent manner accompanied by G0/G1 phase arrest in the cell cycle. This compound caused a decrease in the phosphorylation levels of the retinoblastoma protein at Ser780 and Ser807/811 and a decrease in the kinase activity of the cyclinD and CDK4 complex without any change in these protein levels. Artepillin C increased the protein level of p27Kip1, known as a CDK inhibitor. This up-regulation was regulated by both the transcriptional and post-transcriptional levels, i.e., the treatment increased the mRNA of p27Kip1 and decreased the proteosome activity. Thus, artepillin C induces cell cycle arrest at G0/G1 phase accompanied by up-regulation of p27Kip1, resulting in the inhibition of cell proliferation in HepG2 cells. This study suggested that artepillin C will be a promising anti-cancer agent against hepatoma cancer.

Background Pharmacoeconomic studies have been less performed in Japan. The objective of this study was to clarify which neuraminidase inhibitor (NI; oseltamivir, zanamivir, laninamivir, and peramivir) is most cost-effective in an adult outpatient setting in Japan. Objective To clarify which neuraminidase inhibitor (NI; oseltamivir, zanamivir, laninamivir, and peramivir) is most cost-effective in an adult outpatient setting in Japan. Methods Cost-effectiveness analysis was constructed from the healthcare payer’s perspective. A decision tree model was constructed with probabilities from relevant randomized controlled trials. Costs included medical costs and drug prices. Medical costs were obtained from the medical fee schedule table (2016 version). We also applied authorized medication costs. Outcomes of effectiveness were measured using EQ-5D-3L questionnaires for adult patients who had experienced influenza virus infections previously. Time horizon was 14 days in this study. Results Cost-effectiveness ratios for oseltamivir, zanamivir, laninamivir, and peramivir were 393 674 Yen/quality-adjusted life year (QALY; US$3883.41/QALY), 408 241 (US$4027.10), 407 980 (US$4024.53), and 444 264 (US$4382.45), respectively. The cost-effectiveness analysis base-case analysis revealed oseltamivir as the most cost-effective NI. Zanamivir was dominated. Incremental cost effectiveness ratio (ICER) for laninamivir and peramivir were 1 129 459 Yen/QALY (US$11 141.58/QALY) and 1 287 118 (US$12 696.81), respectively. One-way sensitivity analyses revealed that minimum ICERs for laninamivir based on “quality of life (QOL) values (95% confidence interval)” was −596 850 Yen/QALY (US−$5887.64/QALY) owing to high cost and less effective. Also, maximum ICER for peramivir based on“QOL values” was 14 717 518 Yen/QALY (US$145 181.32/QALY); a value more than the 5 000 000 Yen/QALY threshold. Conclusions The study results reveal oseltamivir as the most cost-effective NI for the treatment of influenza virus infection in an adult outpatient setting. Our findings may provide decision makers with scientific evidence for clinical and economic evaluation to achieve optimal therapeutic outcomes.

Novel trispirocyclotriphosphazenes with oxaphosphorine rings (DOP-PZs) were successfully synthesized by an Appel reaction with phosphoramide, which was prepared from ammonia and 10-chloro-9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide derived from 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide, generally abbreviated as DOPO. The resulting DOP-PZs were characterized by 1H, 13C{1H}, and 31P{1H} nuclear magnetic resonance spectroscopy and time-of-flight mass spectrometry and shown to consist of cis-trans isomers. Moreover, the crystal and molecular structures of the DOP-PZs were determined by X-ray diffraction; cis- and trans-DOP-PZs (C36H24N3O3P3, M = 639.49 g/mol) were refined to final R1 values of 0.0260 and 0.0463, respectively, with the SHELXL refinement package using least-squares minimization. The crystal of cis-DOP-PZ is trigonal in space group R3c and the following cell constants: a = 19.5984(5) A, c = 13.2754(4) A, V = 4415.9(3) A3, Z = 6, and Flack parameter = 0.038(8). In contrast, trans-DOP-PZ is monoclinic in space group P21/c and the following cell constants: a = 9.98647(18) A, b = 24.1737(4) A, c = 12.8472(2) A, β = 112.649(8)°, V = 2862.26(18) A3, and Z = 4. The molecular structures of these DOP-PZs were compared with those of other trispirocyclotriphosphazenes. In addition, the DOP-PZs showed high thermal stability up to 400 °C, with dielectric constants of 2.76-2.77 and dissipation factors of 0.0017-0.0031 at 10 GHz.

Cellobiohydrolase I from Trichoderma reesei ( Tr Cel7A) is one of the best-studied cellulases, exhibiting high activity towards crystalline cellulose. Tryptophan residues at subsites -7 and -4 (Trp40 and Trp38 respectively) are located at the entrance and middle of the tunnel-like active site of Tr Cel7A, and are conserved among the GH family 7 cellobiohydrolases. Trp40 of Tr Cel7A is important for the recruitment of cellulose chain ends on the substrate surface, but the role of Trp38 is less clear. Comparison of the effects of W38A and W40A mutations on the binding energies of sugar units at the two subsites indicated that the contribution of Trp38 to the binding was greater than that of Trp40. In addition, the smooth gradient of binding energy was broken in W38A mutant. To clarify the importance of Trp38, the activities of Tr Cel7A WT and W38A towards crystalline cellulose and amorphous cellulose were compared. W38A was more active than WT towards amorphous cellulose, whereas its activity towards crystalline cellulose was only one-tenth of that of WT. To quantify the effect of mutation at subsite -4, we measured kinetic parameters of Tr Cel7A WT, W40A and W38A towards cello-oligosaccharides. All combinations of enzymes and substrates showed substrate inhibition, and comparison of the inhibition constants showed that the Trp38 residue increases the velocity of substrate intake ( kon for forming productive complex) from the minus side of the subsites. These results indicate a key role of Trp38 residue in processively loading the reducing-end of cellulose chain into the catalytic tunnel.

Silylacetal was demonstrated to function as a promising cleavable moiety for preparing polymers degradable via desilylation under diverse, mild conditions. The silylacetal moieties were installed in the main chain of the polymers via the controlled cationic copolymerization of trimethylsilyl vinyl ether (TMSVE) and a cyclic acetal under appropriately designed conditions. Importantly, desilylation reactions of the silylacetal units occurred under weak acid, base, or fluoride ion conditions, which triggered the degradation of the polymer via the spontaneous cleavage of the unstable hemiacetal moieties generated by the desilylation. Moreover, silylacetal moieties were successfully incorporated at the desired positions in the main chain via the addition of a small portion of TMSVE during the controlled cationic copolymerization of a vinyl ether and cyclic acetal. The strategy devised in this study will allow the design of elaborate polymers that undergo degradation triggered by various stimuli.

Cationic copolymerization of different types of monomers, 4-hydroxybutyl vinyl ether (HBVE) and e-caprolactone (CL), was explored using EtSO3H as an acid catalyst, producing copolymers with a remar...

Lactic acid-derived 1,3-dioxolan-4-ones (DOLOs), which do not undergo cationic homopolymerization, were demonstrated to yield copolymers with oxiranes through a cationic copolymerization via frequent crossover reactions. Acetal and ester moieties were generated in the main chain of the copolymers via crossover reactions from DOLO to oxirane and from oxirane to DOLO, respectively, which is in contrast to the unsuccessful generation of hemiacetal ester moieties in the homopropagation of DOLO. In addition, the terpolymerization of DOLO, oxirane, and vinyl ether (VE) proceeded via crossover reactions, while copolymers could not be generated from VE and DOLO in the absence of oxirane. The obtained co- and terpolymers could be degraded under acidic conditions due to the acetal moieties in the main chain. The strategy devised in this study shows a promising avenue for employing plant-derived "nonhomopolymerizable" compounds as building blocks for the synthesis of degradable co- and terpolymers with general-purpose monomers.

Controlled cationic vinyl-addition polymerization of an alkyl vinyl ether (VE) and ring-opening polymerization of e-caprolactone (CL) simultaneously proceeded using HfCl4/Hf(OBu)4 as a dual-role catalyst for both mechanisms, yielding a graft copolymer consisting of a poly(VE) main chain and several poly(CL) side chains. The copolymer of conventionally incompatible monomers was generated via the unprecedented mechanisms consisting of orthogonal propagating reactions and transient merging. Specifically, the poly(CL) chains were incorporated into a poly(VE) chain through an exchange reaction between the VE-derived alkoxy group and the propagating poly(CL) chain at the acetal moiety of the propagating end of the poly(VE) chain. An appropriate ratio of HfCl4 and Hf(OBu)4 was indispensable for both the simultaneous vinyl-addition and ring-opening polymerizations and the alkoxy group exchange reaction.

Cationic terpolymerization of vinyl ether (VE), oxirane, and ketone successfully proceeded via unprecedented concurrent vinyl-addition, ring-opening, and carbonyl-addition mechanisms. In particular, the use of cyclohexene oxide as an oxirane resulted in terpolymerization via an exclusive one-way cycle, i.e., the reactions occurred only in the VE → oxirane, oxirane → ketone, and ketone → VE directions. Terpolymers that have repeating units of (VE∼2–oxirane∼2–ketone)n were obtained under appropriate conditions. In addition, no two-monomer combination achieved efficient copolymerization, which suggests that three specific types of crossover reactions are required for successful terpolymerization. The presence of a ketone, a compound that has rarely been employed as a monomer, is indispensable for a one-way cycle: terpolymerization also proceeded with an aliphatic aldehyde but resulted in two-way crossover reactions at the aldehyde-derived propagating ends.

Poly(N-isopropylacrylamide) (PNIPAAm)-based temperature-responsive fluorescence polymer probes were developed using radical polymerization, with 3-mercaptopropionic acid as the chain-transfer agent, followed by activation of terminal carboxyl groups with N-hydroxysuccinimide and reaction with 5-aminofluorescein (FL). The lower critical solution temperatures (LCSTs) of the resulting fluorescent polymer probes differed depending on the copolymer composition, and had a sharp phase-transition (hydrophilic/hydrophobic) boundary at the LCST. The cellular uptakes of the fluorescent polymer probes were effectively suppressed below the LCST, and increased greatly above the LCST. In particular, the cellular uptake of a copolymer with N,N-dimethylaminopropylacrylamide, P(NIPAAm-co-DMAPAAm2%)-FL (LCST: 37.4 °C), can be controlled within only 1 °C near body temperature, which is suitable for biological applications. These results indicated that the cellular uptakes of thermoresponsive polymers could be accurately cont...

Further advances in magnesium ion batteries (MIBs) require the development of electrolyte solutions with highly optimized properties. Here we report the design, synthesis and electrolytic properties of a new family of Mg salts of carba-closo-dodecaborate anions (CCAs). Detailed calculations suggested that modification at the boron vertices, previously considered inappropriate for MIB electrolytes, would be effective. Experimental studies showed that simple halogenation at the 12-B vertex of CCA drastically improves the solubility in low viscosity solvents without compromising the chemical and redox stability, and the ionic conductivity reached 6.2 mS/cm. The synthesized electrolytes showed low overpotential (≤200 mV) for Mg deposition and excellent reversible magnesium deposition/stripping with high Coulombic efficiency (≥95%).

Increasing the modulation speed of semiconductor lasers has attracted much attention from the viewpoint of both physics and the applications of lasers. Here we propose a membrane distributed reflector laser on a low-refractive-index and high-thermal-conductivity silicon carbide substrate that overcomes the modulation bandwidth limit. The laser features a high modulation efficiency because of its large optical confinement in the active region and small differential gain reduction at a high injection current density. We achieve a 42 GHz relaxation oscillation frequency by using a laser with a 50-μm-long active region. The cavity, designed to have a short photon lifetime, suppresses the damping effect while keeping the threshold carrier density low, resulting in a 60 GHz intrinsic 3 dB bandwidth (f3dB). By employing the photon–photon resonance at 95 GHz due to optical feedback from an integrated output waveguide, we achieve an f3dB of 108 GHz and demonstrate 256 Gbit s−1 four-level pulse-amplitude modulations with a 475 fJ bit−1 energy cost of the direct-current electrical input. Directly modulated membrane distributed reflector lasers are fabricated on a silicon carbide platform. The 3 dB bandwidth, four-level pulse-amplitude modulation speed and operating energy for transmitting one bit are 108 GHz, 256 Gbit s−1 and 475 fJ, respectively.

Crystalline materials with intrinsically low lattice thermal conductivity (κlat) pave the way towards high performance in various energy applications, including thermoelectrics. Here we demonstrate a strategy to realize ultralow κlat using mixed-anion compounds. Our calculations reveal that locally distorted structures in chalcohalides MnPnS2Cl (Pn = Sb, Bi) derive bonding heterogeneity, which in turn causes a peak splitting of the phonon density of states. This splitting induces a large amount of scattering phase space. Consequently, the κlat of MnPnS2Cl is significantly lower than that of a single-anion sulfide CuTaS3 with a similar crystal structure. The experimental κlat of MnPnS2Cl takes an ultralow value of about 0.5 W m−1 K−1 at 300 K. Our findings will encourage the exploration of thermal transport in mixed-anion compounds, which remains a vast unexplored space, especially regarding unexpectedly low κlat in lightweight materials derived from bonding heterogeneity.

Background: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum–etoposide) showed a significant improvement in overall survival versus platinum–etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide alone. Methods: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum–etoposide, durvalumab plus platinum–etoposide, or platinum–etoposide alone. In all groups, patients received etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL/min or cisplatin 75–80 mg/m2 on day 1 of each cycle. Patients in the platinum–etoposide group received up to six cycles of platinum–etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum–etoposide versus platinum–etoposide and for durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. Findings: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum–etoposide, 268 to durvalumab plus platinum–etoposide, and 269 to platinum–etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3–27·9). Durvalumab plus tremelimumab plus platinum–etoposide was not associated with a significant improvement in overall survival versus platinum–etoposide (hazard ratio [HR] 0·82 [95% CI 0·68–1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6–12·0) versus 10·5 months (9·3–11·2). Durvalumab plus platinum–etoposide showed sustained improvement in overall survival versus platinum–etoposide (HR 0·75 [95% CI 0·62–0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3–14·7) versus 10·5 months (9·3–11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum–etoposide group, and 88 [33%] of 266 patients in the platinum–etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 85 (32%) in the durvalumab plus platinum–etoposide group, and 97 (36%) in the platinum–etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum–etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum–etoposide group (pancytopenia and thrombocytopenia [n=1 each]). Interpretation: First-line durvalumab plus platinum–etoposide showed sustained overall survival improvement versus platinum–etoposide but the addition of tremelimumab to durvalumab plus platinum–etoposide did not significantly improve outcomes versus platinum–etoposide. These results support the use of durvalumab plus platinum–etoposide as a new standard of care for the first-line treatment of ES-SCLC. Funding: AstraZeneca.

With the increasing importance of fluorine to medicinal chemistry and other areas, methods to access various fluorinated compounds are needed. Herein, we report the synthesis of difluoropropargyl vinyl ethers from ketones and aldehydes using difluoropropargyl bromide dicobalt complexes. We applied difluoropropargyl vinyl ethers to the synthesis of difluorodienone or difluoroallene under thermal conditions and trifluoro-pyran under acid-catalyzed conditions.

A subset analysis of the CA031 trial showed significant improvement in the overall response rate after administration of carboplatin plus weekly albumin-bound paclitaxel compared to carboplatin plus paclitaxel for squamous cell carcinoma of the lung (SQ). We conducted this phase II study to compare carboplatin plus weekly albumin-bound paclitaxel (CnP) to cisplatin plus gemcitabine (CG), a standard regimen for SQ. Chemotherapy-naive patients with SQ were randomly assigned to receive cisplatin (80 mg/m2) on day 1 plus gemcitabine (1000 mg/m2) on days 1 and 8 every 3 weeks or carboplatin (area under the curve: 6 mg/mL/min) on day 1 plus nab-paclitaxel (75 mg/m2) on days 1, 8, and 15 every 3 weeks. The primary endpoint was overall response rate. The secondary endpoints were progression-free survival, overall survival, disease control rate, and toxicity. Between June 2013 and October 2018, 71 patients were enrolled and assigned to either the CG arm (n = 35) or the CnP arm (n = 36) of the study. The overall response rate was 43% [95% confidence interval (CI) 27.3–58.5] in the CG arm and 47% (95% CI 31.7–62.7) in the CnP arm. Although drug combination efficacies did not differ, there were differences in toxicity: hematologic toxicities (leukopenia, neutropenia, and thrombocytopenia) were found mostly in the CG arm, whereas anemia and sensory neuropathy were more common in the CnP arm. CnP had similar response as CG despite being a carboplatin-based regimen and toxicities differed between arms. Regarding ORR, CnP was comparable to CG for SQ.

Skyrmion, a concept originally proposed in particle physics half a century ago, can now find the most fertile field for its applicability, that is, the magnetic skyrmion realized in helimagnetic materials. The spin swirling vortex-like texture of the magnetic skyrmion can define the particle nature by topology; that is, all the constituent spin moments within the two-dimensional sheet wrap the sphere just one time. Such a topological nature of the magnetic skyrmion can lead to extraordinary metastability via topological protection and the driven motion with low electric-current excitation, which may promise future application to spintronics. The skyrmions in the magnetic materials frequently show up as the crystal lattice form, e.g., hexagonal lattice, but sometimes as isolated or independent particles. These skyrmions in magnets were initially found in acentric magnets, such as chiral, polar, and bilayered magnets endowed with antisymmetric spin exchange interaction, while the skyrmion host materials have been explored in a broader family of compounds including centrosymmetric magnets. This review describes the materials science and materials chemistry of magnetic skyrmions using the classification scheme of the skyrmion forming microscopic mechanisms. The emergent phenomena and functions mediated by skyrmions are described, including the generation of emergent magnetic and electric field by statics and dynamics of skrymions and the inherent magnetoelectric effect. The other important magnetic topological defects in two or three dimensions, such as biskyrmions, antiskyrmions, merons, and hedgehogs, are also reviewed in light of their interplay with the skyrmions.

Ion-beam irradiation serves as a powerful tool of mutagenesis that engineers novel traits in a wide range of plants. A previous study indicated that coincidental changes of multiple traits are frequently induced by ion-beam irradiation in soybean, a paleopolyploid plant whose genome comprises a large number of duplicated genes. Here we analyzed the levels of isoflavones, the major secondary compounds accumulated in soybean seeds, in a population of mutants having chlorophyll deficiency of various degrees obtained by the mutagenesis. Significant reduction in the levels of four isoflavones, namely, daidzin, genistin, and their malonylglucosides, was detected in 4–9 plant lines among 28 lines analyzed. The average levels of chlorophyll in the leaf tissues and isoflavones in seeds are correlated with each other. In selected mutant lines, the levels of isoflavones were lower than the wild-type plants throughout seed development. Gene expression profiles indicated that the mRNA levels of multiple genes involved in the isoflavone synthesis pathway reduced during seed development, which suggests that the observed reduction in the levels of isoflavones may be attributable to gene expression changes. Along with the possibility that multiple and independent mutations that reduce the levels of chlorophyll and isoflavones occurred simultaneously, these observations suggest the presence of an unrecognized physiological link between the synthesis and/or accumulation of these compounds in soybean.

In recent decades, in addition to existing small-molecule drug therapies, biomedical technology has also rapidly progressed, leading to the development of various therapies based on biopharmaceuticals and therapeutic cells. However, these materials require effective separation methods for their analysis and production. A representative separation method, which has been extensively studied, is the temperature-responsive chromatography system using poly(N-isopropylacrylamide) and its copolymers. Over the last 20 years, various temperature-responsive chromatographic techniques have been developed for the separation of different types of analytes by changing the copolymer composition, the polymer graft configuration, and the base materials of the stationary phase. The developed methods have been successfully applied for the separation of small-molecule drugs, peptides, and proteins, without affecting their biological activity, simply by changing the column temperature. Furthermore, temperature-modulated cell separation columns have been investigated for the separation of cells without changing their properties. Therefore, the developed methods can serve as effective tools for the current and future bioseparation of various biological compounds, biopharmaceutical proteins, and therapeutic cells that are currently used in therapies.

Oxygen-containing carbon materials such as graphene oxide have been extensively studied because of their high dispersibility. However, the oxygen-containing functional groups in most carbon materials are not controlled. Uncontrollability of the synthesis is also one of factors that prevent industrialization. Carbon materials derived from phloroglucinol (PG), which show high solubility/dispersibility and controllability of functional groups, have been developed recently by our group. The high performance of carbonized PG originates from the thermally stable backbone structure of the benzene ring with hydroxy groups of PG. However, the degree of carbonization was low. In this study, five heteropoly acids (HPAs), which are thermally stable homogeneous strong acid catalysts, were used to promote carbonization of PG without losing the controllability of functional groups and the dispersibility. HPAs promoted etherification of hydroxy groups followed by C=C coupling reactions (furan cyclization) at 523 K. Furthermore, it was confirmed that particularly furan structures, which contribute to solubility/dispersibility in solvents, and thermal stability in air, could be maintained at 673 K as suggested by spectroscopies and thermogravimetric-differential thermal analysis. Among five HPAs, phosphotungstic acid worked as the excellent catalyst to promote carbonization of PG containing furan structures, exhibiting high solubility/dispersibility and high thermal stability in air.

Ammonia decomposition on Ru/MgO was strongly affected by the pore structure of the MgO support. We found that highly active Ru/MgO catalysts were successfully prepared by using Ru hydroxide and hyd...

Lolitrems are tremorgenic indole diterpenes that exhibit a unique 5/6 bicyclic system of the indole moiety. Although genetic analysis has indicated that the prenyltransferase LtmE and the cytochrome P450 LtmJ are involved in the construction of this unique structure, the detailed mechanism remains to be elucidated. Herein, we report the reconstitution of the biosynthetic pathway for lolitrems employing a recently established genome-editing technique for the expression host Aspergillus oryzae. Heterologous expression and bioconversion of the various intermediates revealed that LtmJ catalyzes multistep oxidation to furnish the lolitrem core. We also isolated the key reaction intermediate with an epoxyalcohol moiety. This observation allowed us to establish the mechanism of radical-induced cyclization, which was firmly supported by density functional theory calculations and a model experiment with a synthetic analogue.

Heavy metal ions are among the most dangerous contaminants, which can cause serious health problems. In this work, ion-exchange resin beads were used as supports for magnetite (Fe3O4) synthesis to produce heavy metal adsorbents which can be easily separated by magnetic field. The first step of the magnetite preparation was the replacement of hydrogen ions with Fe2+ and Fe3+ ions on the sulfonic acid groups of the resin. In the second step, magnetite particle formation was induced by coprecipitating the iron ions with sodium hydroxide. The regeneration of the ion-exchange resin was also carried out by using sodium hydroxide. SEM images verified that relatively large magnetite crystal particles (diameter = 100–150 nm) were created. The ion-exchange effect of the prepared magnetic adsorbent was also confirmed by applying Cu2+, Ni2+, Pb2+ and Cd2+ ions in adsorption experiments.

The cationic polymerization of phenyl vinyl ether (PhVE) was investigated to elucidate the reason it is much more difficult to obtain high-molecular-weight polymers of PhVE than with alkyl vinyl et...

Purpose Collagen IV is a component of the basement membrane (BM) that provides mechanical support for muscle fibers. In addition, transcription factor 4 (TCF4) is highly expressed in muscle connective tissue fibroblasts and regulates muscle regeneration. However, the expression of collagen IV and TCF4 (+) cells in response to exercise-induced muscle injury is not well known. Here, we investigated the expression and localization of collagen IV and TCF4 (+) cells during the recovery process after muscle injury induced by different exercise loads. Materials and methods Muscle injury was observed in the soleus muscle of young Wistar rats after 12 or 18 sets-downhill running (DR) on a treadmill. After running, the rats were permitted to recover for a period of 0.5 days, 2 days, or 7 days. Results Ectopic localization of collagen IV in injured muscle fibers was observed after DR, and the number increased at 0.5 days after 18 sets DR and at 2 days after 12 or 18 sets DR as compared to the number observed at baseline. BM disruption was observed after DR. TCF4 (+) cells appeared in the inside and around injured muscle fibers at 0.5 day of recovery. After 18 sets DR, TCF4 (+) cells were more abundant for a longer period than that observed after 12 sets DR. Conclusions DR induces BM disruption accompanied by muscle fiber damage. It is possible that BM destruction may be accompanied by muscle damage and that TCF4 (+) cells contribute to muscle fiber and BM recovery.

Antibody drugs play an important role in biopharmaceuticals, because of the specificity for target biomolecules and reduction of side effects. Thus, separation and analysis techniques for these antibody drugs have increased in importance. In the present study, we develop functional chromatography matrices for antibody drug separation and analysis. Three types of polymers, poly(N-isopropylacrylamide (NIPAAm)-co-2-acrylamido-2-methylpropanesulfonic acid (AMPS)-co-N-phenyl acrylamide (PhAAm)), P(NIPAAm-co-AMPS-co-n-butyl methacrylate (BMA)), and P(NIPAAm-co-AMPS-co-tert-butylacrylamide (tBAAm)), were modified on silica beads through atom transfer radical polymerisation. Rituximab elution profiles were observed using the prepared beads-packed column. Rituximab adsorption at high temperature and elution at low temperature from the column were observed, as a result of the temperature-modulated electrostatic and hydrophobic interactions. Using the column, rituximab purification from contaminants was performed simply by changing the temperature. Additionally, three types of antibody drugs were separated using the column through temperature-modulated hydrophobic and electrostatic interactions. These results demonstrate that the temperature-responsive column can be applied for the separation and analysis of biopharmaceuticals through a simple control of the column temperature.

Styrene derivatives were demonstrated to cationically copolymerize with 2,2-disubstituted oxiranes, which can generate a tertiary carbocation by the ring opening of the oxonium ion, through crossov...