Developing intuition: neural correlates of cognitive-skill learning in caudate nucleus.

The superior capability of cognitive experts largely depends on automatic, quick information processing, which is often referred to as intuition. Intuition develops following extensive long-term training. There are many cognitive models on intuition development, but its neural basis is not known. Here we trained novices for 15 weeks to learn a simple board game and measured their brain activities in early and end phases of the training while they quickly generated the best next-move to a given board pattern. We found that the activation in the head of caudate nucleus developed over the course of training, in parallel to the development of the capability to quickly generate the best next-move, and the magnitude of the caudate activity was correlated with the subject's performance. In contrast, cortical activations, which already appeared in the early phase of training, did not further change. Thus, neural activation in the caudate head, but not those in cortical areas, tracked the development of capability to quickly generate the best next-move, indicating that circuitries including the caudate head may automate cognitive computations.

Orally active zwitterionic factor Xa inhibitors with long duration of action.

We have optimized 2-aminomethylphenylamine derivative as a factor Xa inhibitor. Several polar functional groups were introduced in the central phenyl ring, and we focused on zwitter ionic compound showing continuous inhibitory activity in oral administration test. In vitro and oral activities were improved by optimization of S1 and S4 ligands. Incorporating the interaction with S1-ß pocket enhanced in vitro factor Xa inhibitory activity to less than 1 nM. Many zwitter ionic compounds showed long duration of action and potent inhibitory activity and high AUC values in oral administration tests to monkeys.

A gamma-lactone form nafuredin, nafuredin-gamma, also inhibits helminth complex I.

Nafuredin, a delta-lactone antibiotic, is a fungal metabolite showing selective helminth NADH-fumarate reductase inhibition, and whose target had been revealed as complex I. We found that nafuredin is easily converted to nafuredin-gamma by weak alkaline treatment. The structure of nafuredin-gamma was elucidated as a gamma-lactone form of nafuredin with keto-enol tautomerism. Nafuredin-gamma shows similar complex I inhibitory activity as nafuredin, and it also possesses anthelmintic activity in vivo.

Total synthesis of (-)-borrelidin.

The total synthesis of borrelidin has been achieved. The best feature of our synthetic route is SmI(2)-mediated intramolecular Reformatsky-type reaction for macrocyclization after esterification between two segments. The two key segments were synthesized through chelation-controlled carbotitanation, chelation-controlled hydrogenation, stereoselective Reformatsky reaction, and MgBr(2).Et(2)O-mediated chelation-controlled allylation. [reaction: see text]

Rice alpha-mannosidase digesting the high mannose glycopeptide of glutelin.

alpha-Mannosidase (EC 3.2.1.24) from rice dry seeds was purified to homogeneity. Optimum pH and Km for pNP-alpha-Man hydrolysis were pH 4.3-4.5 and 1.04 mM, respectively. The enzyme digested mannobioses such as Manalpha-1,2Man, Manalpha-1,6Man, Manalpha-1,3Man but Manalpha-1,4Man. Zn2+ ion was required for the activity, whereas EDTA and swainsonine inhibited the activity by 80 and 96%, respectively. The rice storage protein, glutelin was prepared and its basic subunits were shown to have high mannose-type sugar chains by two-dimensional mapping using NH2-P and C18 silica columns. They were Man9GlcNAc2, Man8GlcNAc2, Man7GlcNAc2, Man6GlcNAc2 and Man5GlcNAc2. All these oligosaccharides were digested by the purified alpha-mannosidase, and Man-GlcNAc2 and mannose were formed. Glycopeptides, having these high mannose-type sugar chains, could also be digested by the alpha-mannosidase. Subunits were prepared from glutelin basic subunit and the richest subunit among them, subunit 2 (isoform 2), was digested by the alpha-mannosidase. Isoform 2 was digested by V8 protease only partially and slowly. However, isoform 2, pre-treated with the alpha-mannosidase, was rapidly and completely digested by V8 protease.

Total synthesis of borrelidin.

The total synthesis of borrelidin has been achieved. The best feature of our synthetic route is macrocyclization at C11-C12 for the construction of an 18-membered ring after esterification between two segments. A detailed examination of the macrocyclization led us to the samarium(II) iodide-mediated intramolecular Reformatsky-type reaction as the most efficient synthetic approach. The two key segments were synthesized through regioselective methylation, directed hydrogenation, stereoselective Reformatsky-type reaction, and MgBr2.Et2O-mediated chelation-controlled allylation.