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To investigate whether dantrolene (DAN), cardiac ryanodine receptor (RyR2) stabilizer, improves impaired diastolic function in an early pressure-overloaded hypertrophied heart, pressure-overload hypertrophy was induced by transverse aortic constriction (TAC) in mice. Wild-type (WT) mice were divided into four groups: sham-operated mice (Sham), sham-operated mice treated with DAN (DAN+Sham), TAC mice (TAC), and TAC mice treated with DAN (DAN+TAC). The mice were then followed up for 2 weeks. Left ventricular (LV) hypertrophy was induced in TAC, but not DAN+TAC mice, 2 weeks after TAC. There were no differences in LV fractional shortening among the four groups. Catheter tip micromanometer showed that the time constant of LV pressure decay, an index of diastolic function, was significantly prolonged in TAC but not in DAN+TAC mice. Diastolic function was significantly impaired in TAC, but not in DAN+TAC mice as determined by cell shortening and Ca^{2+} transients. An increase in diastolic Ca^{2+} leakage and a decrease in calmodulin (CaM) binding affinity to RyR2 were observed in TAC mice, while diastolic Ca^{2+} leakage improved in DAN+TAC mice. Thus, DAN prevented the progression of hypertrophy and improved the impairment of LV relaxation by inhibiting diastolic Ca^{2+} leakage through RyR2 and the dissociation of CaM from RyR2.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in the cardiac type 2 ryanodine receptor (RyR2). Using knock-in mouse (KI) model (R2474S/+), we previously reported that a single point mutation within the RyR2 sensitized the channel to agonists, primarily mediated by defective inter-domain interaction within the RyR2 and subsequent dissociation of calmodulin (CaM) from the RyR2. Here, we examined whether CPVT can be genetically rescued by enhancing the binding affinity of CaM to the RyR2. We first determined whether there was a possible amino-acid substitution within the CaM-binding domain in the RyR2 (3584-3603) that can enhance its binding affinity to CaM, and found that V3599K substitution showed the highest binding affinity of CaM to CaM-binding domain. Hence, we generated a heterozygous KI mouse model (V3599K/+) with a single amino acid substitution in the CaM-binding domain of the RyR2, and crossbred it with the heterozygous CPVT –associated R2474S/+ KI mouse to obtain a double heterozygous R2474S/V3599K KI mouse model. The CPVT phenotypes, bidirectional or polymorphic ventricular tachycardia, were inhibited in the R2474S/V3599K mice. Thus, enhancement of the CaM binding affinity of the RyR2 is essential to prevent CPVT-associated arrhythmogenesis.

McTaggart’s paradox and his A-theory and B-theory are basic notions in the contemporary philosophy of time. It is well known that the paradox was introduced by McTaggart’s paper called “The Unreality of Time” published in 1908, so that it has a one-hundred-year history. As for A-theory and B-theory, in contrast, McTaggart himself didn’t consider both of them at all. The notions of A-theory and B-theory came much later, 60 years after the paradox. Moreover, they had not been as popularized as they are today until quite recently, at least after the 1990s. This paper aims to trace the origin of the notions of A-theory and B-theory and show how the debates behind them, especially objections to “spatialising time,” form the notions.

本研究では、男性顔の時代変化とそのメカニズムを明らかにするために、日本を代表する美男子コンテストである「ジュノン・スーパーボーイ・コンテスト」のBEST30通過者の顔写真を題材として検討を行った。まず、1988年から2021年までのBEST30通過者を4つの時期ごとに分けて、それぞれの時期の美男子平均顔を作成した。次に、大学生を対象者としたアンケート調査において、ランダムに並び替えた4種類の美男子平均顔について、①印象評価と②恋愛相手・結婚相手としての魅力度を測定した。そしてさらに、美男子平均顔に対する魅力度の違い（選り好み）を説明するための変数として、対象者の③結婚観・子ども観など配偶戦略について尋ねた。 このようなアンケート調査を行った結果、①最新の美男子平均顔ほど、より「穏やか」で「女性的」、「ひ弱」と評価される傾向があり、美男子平均顔の「脱男性化」が主観的印象ではなく、客観的事実であることが確認された。そして、②最も「穏やか」な最新の美男子平均顔に対して、半数以上の女子学生が恋人・結婚相手としての魅力を感じており、その割合は男子学生の予想を大きく上回っていた。さらに、③このような女子学生の選り好みは、結婚相手の経済力を重視しない姿勢や子どもへの従順性の期待、ブレイン・フォグ頻度の低さなどとも関連していた。 これらの知見にもとづけば、美男子平均顔にみられる「脱男性化」の傾向は、女性の選り好みを反映しており、女性の選り好みは、恋愛や結婚、子育てに関する配偶戦略の変化の影響を受けていると考えられる。ただし、先行研究によれば、男性顔の「脱男性化」は、先進諸国に広く見られるだけでなく、人類史全体を通じた一貫した傾向でもあると指摘されている。これらの指摘を前提とするならば、「脱男性化」した男性顔への選り好みは、時代変化を超えた頑健な傾向であり、人類の「自己家畜化」をもたらしている大きな要因の一つとも考えられる。