NDR2‐mediated Rabin8 phosphorylation is crucial for ciliogenesis by switching binding specificity from phosphatidylserine to Sec15

Primary cilia are antenna‐like sensory organelles protruding from the plasma membrane. Defects in ciliogenesis cause diverse genetic disorders. NDR2 was identified as the causal gene for a canine ciliopathy, early retinal degeneration, but its role in ciliogenesis remains unknown. Ciliary membranes are generated by transport and fusion of Golgi‐derived vesicles to the pericentrosome, a process requiring Rab11‐mediated recruitment of Rabin8, a GDP–GTP exchange factor (GEF) for Rab8, and subsequent Rab8 activation and Rabin8 binding to Sec15, a component of the exocyst that mediates vesicle tethering. This study shows that NDR2 phosphorylates Rabin8 at Ser‐272 and defects in this phosphorylation impair preciliary membrane assembly and ciliogenesis, resulting in accumulation of Rabin8‐/Rab11‐containing vesicles at the pericentrosome. Rabin8 binds to and colocalizes with GTP‐bound Rab11 and phosphatidylserine (PS) on pericentrosomal vesicles. The phospho‐mimetic S272E mutation of Rabin8 decreases affinity for PS but increases affinity for Sec15. These results suggest that NDR2‐mediated Rabin8 phosphorylation is crucial for ciliogenesis by triggering the switch in binding specificity of Rabin8 from PS to Sec15, thereby promoting local activation of Rab8 and ciliary membrane formation.     

The introduction to Japan of the Titan barnacle,Megabalanus coccopoma (Darwin, 1854) (Cirripedia: Balanomorpha) and the role of shipping in its translocation

The Titan Acorn barnacle, Megabalanus coccopoma, a native of the tropical eastern Pacific, has become established in the western Atlantic (Brazil and the northern Gulf of Mexico to the Carolinas), northwestern Europe and the western Indian Ocean (Mauritius), and therefore its dispersal capabilities are well known. This study reports its introduction to Japan and confirms its occurrence in Australia. In an attempt to determine the source of this introduction, phylogeographic techniques, involving cytochrome c oxidase I sequences of various widely separate populations of M. rosa and M. volcano, were utilized. No significant genetic differentiation or haplotype patterns between widely separated populations of each of the three species were found. Lack of such differentiation indicates recent geographical isolation and thus negates a null hypothesis predicting that the occurrence of one of more of these species in Australia was natural.     

Probability in biology: Overview of a comprehensive theory of probability in living systems

Probability is closely related to biological organization and adaptation to the environment. Living systems need to maintain their organizational order by producing specific internal events non-randomly, and must cope with the uncertain environments. These processes involve increases in the probability of favorable events for these systems by reducing the degree of uncertainty of events. Systems with this ability will survive and reproduce more than those that have less of this ability. Probabilistic phenomena have been deeply explored using the mathematical theory of probability since Kolmogorov's axiomatization provided mathematical consistency for the theory. However, the interpretation of the concept of probability remains both unresolved and controversial, which creates problems when the mathematical theory is applied to problems in real systems. In this article, recent advances in the study of the foundations of probability from a biological viewpoint are reviewed, and a new perspective is discussed toward a comprehensive theory of probability for understanding the organization and adaptation of living systems.     

Denitrification in soil amended with thermophile-fermented compost suppresses nitrate accumulation in plants

NO ₃ ^? is a major nitrogen source for plant nutrition, and plant cells store NO ₃ ^? in their vacuoles. Here, we report that a unique compost made from marine animal resources by thermophiles represses NO ₃ ^? accumulation in plants. A decrease in the leaf NO ₃ ^? content occurred in parallel with a decrease in the soil NO ₃ ^? level, and the degree of the soil NO ₃ ^? decrease was proportional to the compost concentration in the soil. The compost-induced reduction of the soil NO ₃ ^? level was blocked by incubation with chloramphenicol, indicating that the soil NO ₃ ^? was reduced by chloramphenicol-sensitive microbes. The compost-induced denitrification activity was assessed by the acetylene block method. To eliminate denitrification by the soil bacterial habitants, soil was sterilized with γ irradiation and then compost was amended. After the 24-h incubation, the N₂O level in the compost soil with presence of acetylene was approximately fourfold higher than that in the compost soil with absence of acetylene. These results indicate that the low NO ₃ ^? levels that are often found in the leaves of organic vegetables can be explained by compost-mediated denitrification in the soil.     

ADAPTATION FROM RESTRICTED GEOMETRIES: THE SHELL INCLINATION OF TERRESTRIAL GASTROPODS

The adaptations that occur for support and protection can be studied with regard to the optimal structure that balances these objectives with any imposed constraints. The shell inclination of terrestrial gastropods is an appropriate model to address this problem. In this study, we examined how gastropods improve shell angles to well‐balanced ones from geometrically constrained shapes. Our geometric analysis and physical analysis showed that constantly coiled shells are constrained from adopting a well‐balanced angle; the shell angle of such basic shells tends to increase as the spire index (shell height/width) increases, although the optimum angle for stability is 90° for flat shells and 0° for tall shells. Furthermore, we estimated the influences of the geometric rule and the functional demands on actual shells by measuring the shell angles of both resting and active snails. We found that terrestrial gastropods have shell angles that are suited for balance. The growth lines of the shells indicated that this adaptation depends on the deflection of the last whorl: the apertures of flat shells are deflected downward, whereas those of tall shells are deflected upward. Our observations of active snails demonstrated that the animals hold their shells at better balanced angles than inactive snails.     

Identification of a novel benzimidazole derivative as a highly potent NPY Y5 receptor antagonist with an anti-obesity profile

Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain.     

A novel,potent, and orally active VLA-4 antagonist with good aqueous solubility: trans-4-[1-[[2-(5-Fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl]acetyl]-(5S)-[methoxy(methyl)amino]methyl-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid

We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl)amino]methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5 mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 μg/mL; JP2, 462 μg/mL). Furthermore, this compound showed good oral bioavailability (F = 54%) in monkeys.     

Lead optimization of 5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxyhexanamides to reduce a cardiac safety issue: Discovery of DS-8108b,an orally active renin inhibitor

With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure–activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h.     

Excitotoxicity-induced immediate surge in hippocampal prostanoid production has latent effects that promote chronic progressive neuronal death

Excitotoxicity is involved in neurodegenerative conditions. We investigated the pathological significance of a surge in prostaglandin production immediately after kainic acid (KA) administration [initial phase], followed by a sustained moderate elevation in prostaglandin level [late phase] in the hippocampus of juvenile rats. Numerous pyknotic hippocampal neurons were observed 72 h after KA treatment; this number remained elevated on days 10 and 30. Gross hippocampal atrophy was observed on days 10 and 30. Pre-treatment with indomethacin ameliorated neuronal death on days 10 and 30, and prevented hippocampal atrophy on day 30. Microglial response was moderated by the indomethacin pre-treatment. Blockade of only late-phase prostaglandin production by post-treatment with indomethacin ameliorated neuronal death on day 30. These findings suggest a role for initial-phase prostaglandin production in chronic progressive neuronal death, which is exacerbated by late-phase prostaglandin production. Blockade of prostaglandin production has therapeutic implications in preventing long-term neurological sequelae following excitotoxic brain damage.     

Ester Synthesis in Various Organic Solvents by Three Kinds of Lipase Preparations Derived from Pseudomonas fragi 22.39 B

DNA-synthesis stimulatory activity was found in some tryptic fragments of human /¡-casein by using BALB/c3T3 cells, and two of them were identified as the /¡-casein fragments of Arg[l] to Lys[18] (/¡-CN(f 1 -18)) and of Gln[105] to Lys[l 17] (/¡-CN(fl05 -117)).