Pore opening, not voltage sensor movement, underpins the voltage-dependence of facilitation by a hERG blocker.

A drug that blocks the cardiac myocyte voltage-gated K+ channels encoded by the human Ether-à-go-go-Related Gene (hERG) carries a potential risk of long QT syndrome and life-threatening cardiac arrhythmia, including Torsade de Points Interestingly, certain hERG blockers can also facilitate hERG activation to increase hERG currents, which may reduce proarrhythmic potential. However, the molecular mechanism involved in the facilitation effect of hERG blockers remains unclear. The hallmark feature of the facilitation effect by hERG blockers is that a depolarizing preconditioning pulse shifts voltage-dependence of hERG activation to more negative voltages. Here we utilize a D540K hERG mutant to study the mechanism of the facilitation effect. D540K hERG is activated by not only depolarization but also hyperpolarization. This unusual gating property enables tests of the mechanism by which voltage induces facilitation of hERG by blockers. With D540K hERG, we find that nifekalant, a hERG blocker and Class III antiarrhythmic agent, blocks and facilitates not only current activation by depolarization but also current activation by hyperpolarization, suggesting a shared gating process upon depolarization and hyperpolarization. Moreover, in response to hyperpolarizing conditioning pulses, nifekalant facilitates D540K hERG currents but not wild-type currents. Our results indicate that induction of facilitation is coupled to pore opening, not voltage per se We propose that gated access to the hERG central cavity underlies the voltage-dependence of induction of facilitation. This study identifies hERG channel pore gate opening as the conformational change facilitated by nifekalant, a clinically important antiarrhythmic agent. Significance Statement Nifekalant is a clinically important antiarrhythmic agent and a hERG blocker which can also facilitate voltage-dependent activation of hERG channels after a preconditioning pulse. Here we show that the mechanism of action of the preconditioning pulse is to open a conductance gate to enable drug access to a facilitation site. Moreover, we find that facilitation increases hERG currents by altering pore dynamics, rather than acting through voltage sensors.

Good appearance of food gives an appetizing impression and increases cerebral blood flow of frontal pole in healthy subjects.

We investigated the effect of food appearance on appetite and on left-frontal pole blood flow in healthy young subjects. The iEat, a new form of foods with good appearance and greater softness was hypothesized to have the better effects to the subjects than blender-processed foods. The effect on appetite and left-frontal pole blood flow using hemoencephalography was assessed while participants were viewing the slideshows of two kinds of foods respectively. The slideshows were used to control the showing time and other variables. The pictures of iEat foods stimulated both of them more than the blender-processed ones. The measurement of cerebral blood flow could be a useful method to monitor the cognitive and emotional aspects of feeding behavior that are important for humans. Like iEat, the foods that look as good as ordinary food yet are softer can be used for people with poor appetite and eating difficulties to ordinary food.

Amphos-Mediated Conversion of Alkyl Azides to Diazo Compounds and One-Pot Azide-Site Selective Transient Protection, Click Conjugation, and Deprotective Transformation.

A one-pot conversion of alkyl azides to diazo compounds is outlined. After the reaction of α-azidocarbonyl compounds with Amphos, treatment of the resulting phosphazides with silica gel in a wet solvent afforded α-diazo carbonyl products. Through the azido group protection property of Amphos, inter- and intramolecular azide-site selective reactions of azido group protection, click functionalization, and deprotection of the diazo group have been demonstrated in one pot.

Supramolecular linear coordination polymers of human serum albumin and haemoglobin.

We describe the synthesis, structure, and functionalities of water-soluble linear coordination polymers of human serum albumin and haemoglobin, which are connected via a bis(terpyridyl)-Fe2+ complex. These protein fibres were self-assembled by lyophilisation and were transformed into single-wall nanotubes. The biological activities of the protein units were perfectly preserved in the long fibres.

Stratiform Protein Microtube Reactors Containing Glucose Oxidase Layer.

This paper describes the synthesis and catalytic activities of stratiform protein microtube reactors containing a glucose oxidase (GOD) enzyme layer. The microtubes were fabricated by layer-by-layer assembly using a microporous polycarbonate membrane with human serum albumin (HSA), poly(l-arginine) (PLA), and GOD. The GOD component was introduced into the tube wall as the innermost layer, the intermediate layer, or all internal protein layers. SEM observations revealed the formation of uniform hollow cylinders with ca. 1.17 µm outer diameter and ca. 135 nm wall thickness. In aqueous medium, each microtube catalyzed ß-d-glucose oxidation with high efficiency. We first ascertained the enzyme parameters (Km and kcat ) of these microtube reactors. Different catalytic activities that have dependent on the GOD layer position in the cylindrical wall have been elucidated.

Neural substrates of social facilitation effects on incentive-based performance.

Throughout our lives we must perform tasks while being observed by others. Previous studies have shown that the presence of an audience can cause increases in an individual's performance as compared to when they are not being observed-a phenomenon called 'social facilitation'. However, the neural mechanisms underlying this effect, in the context of skilled-task performance for monetary incentives, are not well understood. We used functional magnetic resonance imaging to monitor brain activity while healthy human participants performed a skilled-task during conditions in which they were paid based on their performance and observed and not observed by an audience. We found that during social facilitation, social signals represented in the dorsomedial prefrontal cortex (dmPFC) enhanced reward value computations in ventromedial prefrontal cortex (vmPFC). We also found that functional connectivity between dmPFC and ventral striatum was enhanced when participants exhibited social facilitation effects, indicative of a means by which social signals serve to modulate brain regions involved in regulating behavioral motivation. These findings illustrate how neural processing of social judgments gives rise to the enhanced motivational state that results in social facilitation of incentive-based performance.

Neural mechanisms underlying human consensus decision-making.

Consensus building in a group is a hallmark of animal societies, yet little is known about its underlying computational and neural mechanisms. Here, we applied a computational framework to behavioral and fMRI data from human participants performing a consensus decision-making task with up to five other participants. We found that participants reached consensus decisions through integrating their own preferences with information about the majority group members' prior choices, as well as inferences about how much each option was stuck to by the other people. These distinct decision variables were separately encoded in distinct brain areas-the ventromedial prefrontal cortex, posterior superior temporal sulcus/temporoparietal junction, and intraparietal sulcus-and were integrated in the dorsal anterior cingulate cortex. Our findings provide support for a theoretical account in which collective decisions are made through integrating multiple types of inference about oneself, others, and environments, processed in distinct brain modules.