Melanogenic effect of dersimelagon (MT-7117), a novel oral melanocortin 1 receptor agonist.

Background: The activation of melanocortin 1 receptor (MC1R) on melanocytes stimulates the production of eumelanin. A tridecapeptide α melanocyte-stimulating hormone (αMSH) is known to induce skin pigmentation. Objectives: We characterised the properties of a novel oral MC1R agonist dersimelagon (MT-7117) with respect to its specific binding to MC1R, downstream signalling and eumelanin production in experimental models. Methods: The competitive binding and production of intracellular cyclic adenosine 3', 5'-monophosphate in cells expressing recombinant melanocortin receptors were examined. A mouse melanoma cell line B16F1 was used for the evaluation of in vitro melanin production. The in vitro activity of MT-7117 was determined with αMSH and [Nle4, D-Phe7]-αMSH (NDP-αMSH) as reference comparators. The change of coat colour and skin pigmentation were evaluated after repeat administration of MT-7117 by oral gavage to C57BL/6J-Ay/+ mice and cynomolgus monkeys, respectively. Results: MT-7117 showed the highest affinity for human MC1R compared to the other melanocortin receptors evaluated and agonistic activity for human, cynomolgus monkey and mouse MC1R, with EC50 values in the nanomolar range. In B16F1 cells, MT-7117 increased melanin production in a concentration-dependent manner. In vivo, MT-7117 (≥0.3 mg/kg/day p.o.) significantly induced coat colour darkening in mice. MT-7117 (≥1 mg/kg/day p.o.) induced significant skin pigmentation in monkeys and complete reversibility was observed after cessation of its administration. Conclusions: MT-7117 is a novel oral MC1R agonist that induces melanogenesis in vitro and in vivo, suggesting its potential application for the prevention of phototoxic reactions in patients with photodermatoses, such as erythropoietic protoporphyria and X-linked protoporphyria.

Large Seebeck coefficients of protonated titanate nanotubes for high-temperature thermoelectric conversion.

Titanate nanotubes Na(2-x)H(x)Ti(3)O(7) produced by alkali hydrothermally treated ground TiO(2) aerogels are investigated as possible materials for high-temperature thermoelectric conversion by measuring their thermoelectric properties. Strikingly, the Seebeck coefficients increased sharply in the temperature range 745 to 1032 K, reaching a maximum of 302 muV/K. The electrical resistivity of the TNNTs ranged from 325 to 525 Omegam, which is lower than that of bulk TiO(2), and thermal conductivities at room temperature were also very low, ranging from 0.55 to 0.75 Wm(-1) K(-1). The hollow structure of the titanate nanotubes, with small, uniform diameters, is thought to be responsible for the ultralow thermal conductivity. The large thermoelectric power and ultralow thermal conductivity suggest that titanate nanotubes represent a new kind of p-type oxide thermoelectric material.

Direct observation of TiO6 octahedron forming titanate nanotube by advanced transmission electron microscopy.

The nanostructure of titanate nanotubes known as a one-dimensional catalytic/electric subject is combinatorially characterized using x-ray diffraction (XRD), micro-Raman, photoluminescence (PL) and advanced electron microscopy. The micro-Raman and PL spectra prove the successful synthesis of TiO6 octahedron units in macroscopic scale. Cryo-high-angle annular dark-field (HAADF)-STEM and aberration-corrected (AC) TEM visualize in real-space the TiO6 octahedron unit formed as a TiO2-based tubular structure prepared by the alkaline hydrothermal methods. The chirality and scrolling-up mechanism of the TiO6 octahedron nanosheets in relation to an asymmetrical chemical environment and mechanical tensions are discussed.

Optical constants of V(1-x)W(x)O(2) Films.

The spectral complex optical constants in the visible and the near-infrared region of VO(2) and V(1-x)W(x)O(2) films deposited on glass substrates were determined from observed reflectance and transmittance spectra for which the least-squares method was used. In the metallic phase, the optical properties were characterized by the Drude model in wavelength regions longer than 750 nm.

[Induction of prostatic buds in the absence of androgens]. / Induction des bourgeons prostatiques en l'absence d'androgènes.

We have investigated the non-androgenic factors that induce the prostatic buds from the sinus epithelium. The buds were found to be induced in the explants cultured in the androgen-deficient medium containing 20 ng/ml rat keratinocyte growth factor (KGF) irrespective of the sex of the sinus.

[Scale induction in the chick amnionic ectoderm attached to tarsometatarsal skin dermis]. / Induction des écailles dans l'ectoderme amniotique du Poulet, associé au derme de la peau tarsométatarsienne.

Under the influence of tarsometatarsal dermis of 13-17-day chick embryos, 6.8-day amnionic ectoderm can form scales and express keratins specific for scales. In contrast, 10.5-day shank dermis can induce both feather filaments and scales in the amnionic ectoderm.

Conditionally expressed missense mutations: the basis for the unusual phenotype of an apparent trpD nonsense mutant of Salmonella typhimurium.

Tryptophan auxotroph trpo-28 is anomalous since preliminary mapping and suppression studies indicate the presence of a single amber nonsense mutation either late in trpE or early in trpD, but enzymological tests indicate the complete inactivation of both genes in this strain. Since the trpE and trpD genes are contiguous and encode the two subunits of a multifunctional enzyme complex, it was of interest to learn the mechanism of action of this apparent pleiotropic nonsense mutation. Our study has revealed that the phenotype of this strain derives not from a single mutation, but from the presenc and interaction of multiple mutations. Besides the recognized amber mutation (designated trpD28), this strain carries two additional, conditionally expressed missense mutations (designated trpE1651 and trpD1652). The trpD28 amber codon maps in the promoter-proximal region 1 of trpD and eliminates the glutamine amidotransferase activity of the bifunctional trpD polypeptide. The trpD1652 mutation maps in the promoter-distal region 2 of trpD and severely reduces (but does not eliminate) the phosphoribosyl transferase activity of the trpD polypeptide. The trpE1651 mutation maps in the anterior part of trpE and causes a rapid loss of activity of the trpE polypeptide, but only when it exists as an umcomplexed subunit. The existence of the two missense mutations escaped prior notice in standard recombinational tests since the nature of ech mutation is such that neither is detectable by the nutritional screens normally used in such tests unless an unsuppressed chain-terminating mutation, such as trpD28, is also present.

Suppression of a deletion mutation in the glutamine amidotransferase region of the Salmonella typhimurium trpD gene by mutations in pheA and tyrA.

Prototrophic revertants of a trpD deletion mutant that lacks the glutamine amidotransferase domain of the bifunctional component II subunit of the anthranilate synthetase-phosphoribosyltransferase complex have been found to arise by the occurrence of sublethal missense mutations in either the pheA or tyrA loci. Such suppressor mutations were obtained directly by mutation of the wild-type pheA gene as well as indirectly by partial reversion of a variety of nonleaky pheA and tyrA mutations. The suppressor strains have only a portion of the normal level of the pheA or tyrA enzyme activity and thus experience a partial limitation in the synthesis of phenylalanine or tyrosine. This limitation leads to a relaxation of end-product regulation of the phenylalanine- or tyrosine-specific enzymes of the common aromatic pathway and to the overproduction of the branch point intermediate, chorismic acid, which is one of the substrates of the anthranilate synthetase reaction. It is proposed that the high intracellular level of chorismic acid acts to elevate the non-physiological NH3-dependent anthranilate synthetase activity of the component I subunit, thereby eliminating the need for the glutamine amidotransferase activity of the component II subunit. Consistent with this is the finding that phenylalanine and tyrosine are specific inhibitors of growth of the pheA and tyrA suppressor strains, respectively, causing a shutdown of the overproduction of chorismic acid by reestablishing normal end-product control of the common pathway.

Reversion of the frameshift hisD3018 of Salmonella typhimurium.

Previous studies on histidinol dehydrogenase from His(+) revertants have shown that the frameshift mutation hisD3018 is a +1 type, resulting from inclusion of an extra cytidylate residue in messenger ribonucleic acid. Histidinol dehydrogenase from newly isolated spontaneous and N-methyl-N'-nitro-N-nitrosoguanidine (NG)-induced intragenic revertants has been examined for amino acid replacements. The results provide additional evidence that NG can delete guanine plus cytosine base pairs from deoxyribonucleic acid. One spontaneous revertant was found to result from a +2 addition of approximately 16 nucleotide residues before the +1 parent frameshift, and another by a -4 deletion about six residues before the same. Circumstantial evidence suggests the in vivo codon assignment GAG for glutamic acid. A region of histidinol dehydrogenase highly permissive of amino acid changes encoded in the minus (-) phase is now apparent.

Externally suppressible frameshift mutant of Salmonella typhimurium.

Prototrophic revertants of ICR-191A-induced frameshift mutant hisD3018 have been induced spontaneously by ICR-191A and N-methyl-N'-nitro-N-nitrosoguanidine (NG) treatment. In each case two genetically distinct prototroph classes were differentiated by transducibility into his deletion recipients: (i) transducible, generally fast-growing revertants within the hisD gene producing from 10 to 100% of normal amounts of histidinol dehydrogenase and (ii) nontransducible slow-growing prototrophs with very low levels of enzyme activity of which at least some arose by external suppression. These nontransducible revertants, whether arising spontaneously or in the presence of ICR-191A or NG, contain histidinol dehydrogenase which is electrophoretically similar to the wild-type enzyme.