Discovery and structure–activity relationships of 4-aminoquinazoline derivatives,a novel class of opioid receptor like-1 (ORL1) antagonists

Synthesis and structure–activity relationship studies of a series of 4-aminoquinazoline derivatives led to the identification of (1R,2S)-17, N-[(1R,2S)-2-({2-[(4-chlorophenyl)carbonyl]amino-6-methylquinazolin-4-yl}amino)cyclohexyl]guanidine dihydrochloride, as a highly potent ORL1 antagonist with up to 3000-fold selectivity over the μ, δ, and κ opioid receptors. Molecular modeling clarified the structural factors contributing to the high affinity and selectivity of (1R,2S)-17.     

Molecular mechanisms of generation for nitric oxide and reactive oxygen species, and role of the radical burst in plant immunity

Rapid production of nitric oxide (NO) and reactive oxygen species (ROS) has been implicated in the regulation of innate immunity in plants. A potato calcium-dependent protein kinase (StCDPK5) activates an NADPH oxidase StRBOHA to D by direct phosphorylation of N-terminal regions, and heterologous expression of StCDPK5 and StRBOHs in Nicotiana benthamiana results in oxidative burst. The transgenic potato plants that carry a constitutively active StCDPK5 driven by a pathogen-inducible promoter of the potato showed high resistance to late blight pathogen Phytophthora infestans accompanied by HR-like cell death and H₂O₂ accumulation in the attacked cells. In contrast, these plants showed high susceptibility to early blight necrotrophic pathogen Alternaria solani, suggesting that oxidative burst confers high resistance to biotrophic pathogen, but high susceptibility to necrotrophic pathogen. NO and ROS synergistically function in defense responses. Two MAPK cascades, MEK2-SIPK and cytokinesis-related MEK1-NTF6, are involved in the induction of NbRBOHB gene in N. benthamiana. On the other hand, NO burst is regulated by the MEK2-SIPK cascade. Conditional activation of SIPK in potato plants induces oxidative and NO bursts, and confers resistance to both biotrophic and necrotrophic pathogens, indicating the plants may have obtained during evolution the signaling pathway which regulates both NO and ROS production to adapt to wide-spectrum pathogens.     

Disorganized Innervation and Neuronal Loss in the Inner Ear of Slitrk6-Deficient Mice

Slitrks are type I transmembrane proteins that share conserved leucine-rich repeat domains similar to those in the secreted axonal guidance molecule Slit. They also show similarities to Ntrk neurotrophin receptors in their carboxy-termini, sharing a conserved tyrosine residue. Among 6 Slitrk family genes in mammals, Slitrk6 has a unique expression pattern, with strong expression in the sensory epithelia of the inner ear. We generated Slitrk6-knockout mice and investigated the development of their auditory and vestibular sensory organs. Slitrk6-deficient mice showed pronounced reduction in the cochlear innervation. In the vestibule, the innervation to the posterior crista was often lost, reduced, or sometimes misguided. These defects were accompanied by the loss of neurons in the spiral and vestibular ganglia. Cochlear sensory epithelia from Slitrk6-knockout mice have reduced ability in promoting neurite outgrowth of spiral ganglion neurons. Indeed the Slitrk6-deficient inner ear showed a mild but significant decrease in the expression of Bdnf and Ntf3, both of which are essential for the innervation and survival of sensory neurons. In addition, the expression of Ntrk receptors, including their phosphorylated forms was decreased in Slitrk6-knockout cochlea. These results suggest that Slitrk6 promotes innervation and survival of inner ear sensory neurons by regulating the expression of trophic and/or tropic factors including neurotrophins from sensory epithelia.     

Different effects of novel mtDNA G3242A and G3244A base changes adjacent to a common A3243G mutation in patients with mitochondrial disorders

Two novel mitochondrial DNA base changes were identified at both sides of the 3243A > G mutation, the most common mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). One was a 3244G > A transition in a girl with MELAS. The other was a 3242G > A transition in a girl with a mitochondrial disorder without a MELAS phenotype. Although the two base changes were adjacent to the 3243A > G mutation, they had different effects on the clinical phenotype, muscle pathology, and respiratory chain enzyme activity. Investigations of the different effects of the 3244G > A and 3242G > A base changes may provide a better understanding of tRNA dysfunction in mitochondrial disorders.     

Spatio-temporal variation in Lepidopteran larval assemblages associated with oak, Quercus crispula: the importance of leaf quality

Abstract.  1. Lepidoptera larval abundance and diversity in the canopies of oak ( Quercus crispula ) trees and saplings were surveyed in a cool-temperate, deciduous broadleaf forest in northern Japan.
2. In general, newly developed leaves were soft, rich in water and nitrogen, and low in tannin, whereas they became tough, poor in water and nitrogen, and high in tannin as the season proceeded. Leaf quality also varied among forest strata, such variations resulting in seasonal and among-strata differences in the structure of the Lepidoptera larval assemblage.
3. The greater Lepidoptera larval abundance and species richness may related to the higher leaf quality on spring foliage compared with summer foliage. On the other hand, diversity (Shannon's H' ) and evenness (Pielou's J' ) were greater on summer foliage than on spring foliage. Strengthened defences of the host plants against herbivory may cause these differences by filtering the larvae of Lepidoptera species and by constraining the super-dominance of a few species on summer foliage.
4. Canonical Correspondence Analysis (CCA) ordination also revealed a stratified structure of the Lepidoptera larval assemblage in the forest. In both spring and summer, the assemblage composition was more similar between sunlit and shaded canopies than between canopies and saplings. Such assemblage stratification was highly correlated with toughness and tannin content (in spring and summer) or water content (in summer).
5. This study emphasised the importance of spatio-temporal variations in leaf quality, even within the same host plant species, for promoting herbivore diversity in forests.     

Cognitive behavioral therapy for psychosomatic problems in dental settings

Cognitive behavioral therapy (CBT) has been applied for various problems, including psychiatric diseases such as depression and anxiety, and for physical symptoms such as pain. It has also been applied for dental problems. Although the effect of CBTs on temporomandibular disorders and dental anxiety are well documented, its effectiveness on other types of oral symptoms remain unclear. Little information comparing the different types of CBTs in the dental setting is currently available. Because dental professionals are often expected to conduct CBTs in the dental setting, it is important to develop proper training programs for dental professionals.In this review article, we demonstrate and discuss the application of CBTs for psychosomatic problems, including temporomandibular disorders, dental anxiety, burning mouth syndrome, and other oral complaints in dental settings.     

Plant growth regulators from the fruiting bodies of Tricholoma flavovirens

A novel indole derivative (1) and three known compounds (2–4) were isolated from the fruiting bodies of Tricholoma flavovirens. Their structures were determined or identified by the interpretation of spectroscopic data. Compounds 1 and 2 promoted root growth of lettuce and inhibited hypocotyl growth at 1 μmol/paper. Compound 3 inhibited hypocotyl and root growth at 100 nmol/paper.