(R)-ketamine restores anterior insular cortex activity and cognitive deficits in social isolation-reared mice

Yokoyama R., Ago Y., Igarashi H., et al. (R)-ketamine restores anterior insular cortex activity and cognitive deficits in social isolation-reared mice. Molecular Psychiatry , (2024); https://doi.org/10.1038/s41380-024-02419-6.Chronic social isolation increases the risk of mental health problems, including cognitive impairments and depression. While subanesthetic ketamine is considered effective for cognitive impairments in patients with depression, the neural mechanisms underlying its effects are not well understood. Here we identified unique activation of the anterior insular cortex (aIC) as a characteristic feature in brain-wide regions of mice reared in social isolation and treated with (R)-ketamine, a ketamine enantiomer. Using fiber photometry recording on freely moving mice, we found that social isolation attenuates aIC neuronal activation upon social contact and that (R)-ketamine, but not (S)-ketamine, is able to counteracts this reduction. (R)-ketamine facilitated social cognition in social isolation-reared mice during the social memory test. aIC inactivation offset the effect of (R)-ketamine on social memory. Our results suggest that (R)-ketamine has promising potential as an effective intervention for social cognitive deficits by restoring aIC function

地域在住高齢者の趣味の有無と認知機能の関連

高齢者の趣味の有無が認知機能と関連しているとの報告が多くなされている。今回、地域在住一般高齢者272名（平均年齢72.3歳）を対象に趣味の有無と認知機能の関連を検討した。趣味を有する群（186名）と無趣味群（86名）では、主観的幸福感、抑うつ程度、 日常生活動作には有意差は見られなかったが、認知機能においては、趣味を有する群では無趣味群に比して有意に高値であった。また、趣味を有する群では、無趣味群に比して、物事に好奇心があり、社交的な性格であった。認知症予防において、趣味を持つことを積極的に勧めることは重要と思われる

地域在住高齢者の認知機能とビタミンEの関連

抗酸化ビタミンの１つであるビタミンEと認知機能の関連について検討した。対象は地域在住一般高齢者254名（73.1±5.2歳、男性101名、女性153名）で、認知機能はミニメンタルテスト（MMSE）で測定し、また、MMSE特典の1年間の変化により、改善群（MMSEにて2-6ポイント増加）24名（平均年齢72.9歳）、不変群（1ポイント以内）45名（73.5歳）、悪化群（2-6ポイント減少）25名（73.9歳）の3群に分け検討した。年齢、主観的幸福感、抑うつ程度、日常生活動作と血漿ビタミンE値の間には相関はみられなかったが、MMSEとビタミンE値とは弱いながらも正相関が認められた（p=0.046）。MMSE改善群、不変群、悪化群の血漿ビタミンE値は、それぞれ10.5±2.5μg/mL、11.1±4.3μg/mL、10.5±3.9μg/mLと各群間には有意差は認められなかった。ビタミンEは認知機能の程度とは関連している可能性があるが、認知機能低下の進行とは関連が見られなかった

Loss of connectin novex-3 leads to heart dysfunction associated with impaired cardiomyocyte proliferation and abnormal nuclear mechanics

Abstract Connectin (also known as titin) is a giant striated muscle protein that functions as a molecular spring by providing elasticity to the sarcomere. Novex-3 is a short splice variant of connectin whose physiological function remains unknown. We have recently demonstrated using in vitro analyses that in addition to sarcomere expression, novex-3 was also expressed in cardiomyocyte nuclei exclusively during fetal life, where it provides elasticity/compliance to cardiomyocyte nuclei and promotes cardiomyocyte proliferation in the fetus, suggesting a non-sarcomeric function. Here, we analyzed novex-3 knockout mice to assess the involvement of this function in cardiac pathophysiology in vivo. Deficiency of novex-3 compromised fetal cardiomyocyte proliferation and induced the enlargement of individual cardiomyocytes in neonates. In adults, novex-3 deficiency resulted in chamber dilation and systolic dysfunction, associated with Ca2+ dysregulation, resulting in a reduced life span. Mechanistic analyses revealed a possible association between impaired proliferation and abnormal nuclear mechanics, including stiffer nuclei positioned peripherally with stabilized circumnuclear microtubules in knockout cardiomyocytes. Although the underlying causal relationships were not fully elucidated, these data show that novex-3 has a vital non-sarcomeric function in cardiac pathophysiology and serves as an early contributor to cardiomyocyte proliferation

Macropinocytosis-Inducible Extracellular Vesicles Modified with Antimicrobial Protein CAP18-Derived Cell-Penetrating Peptides for Efficient Intracellular Delivery

The antimicrobial protein CAP18 (approximate molecular weight: 18 000), which was first isolated from rabbit granulocytes, comprises a C-terminal fragment that has negatively charged lipopolysaccharide binding activity. In this study, we found that CAP18 (106-121)-derived (sC18)(2) peptides have macropinocytosis-inducible biological functions. In addition, we found that these peptides are highly applicable for use as extracellular vesicle (exosomes, EV)-based intracellular delivery, which is expected to be a next-generation drug delivery carrier. Here, we demonstrate that dimerized (sC18)(2) peptides can be easily introduced on EV membranes when modified with a hydrophobic moiety, and that they show high potential for enhanced cellular uptake of EVs. By glycosaminoglycan-dependent induction of macropinocytosis, cellular EV uptake in targeted cells was strongly increased by the peptide modification made to EVs, and intriguingly, our herein presented technique is efficiently applicable for the cytosolic delivery of the biologically cell-killing functional toxin protein, saporin, which was artificially encapsulated in the EVs by electroporation, suggesting a useful technique for EV-based intracellular delivery of biofunctional molecules