MeCP2 Functions Largely Cell-Autonomously, but Also Non-Cell-Autonomously, in Neuronal Maturation and Dendritic Arborization of Cortical Pyramidal Neurons

Rett syndrome is a human neurodevelopmental disorder presenting almost exclusively in female infants; it is the second most common cause of mental retardation in girls, after Down’s syndrome. The identification in 1999 that mutation of the methyl-CpG-binding protein 2 (MECP2) gene on the X chromosome causes Rett syndrome has led to a rapid increase in understanding of the neurobiological basis of the disorder. However, much about the functional role of MeCP2, and the cellular phenotype of both patients with Rett syndrome and mutant Mecp2 mouse models, remains unclear. Building on prior work in which we demonstrated that cortical layer 2/3 pyramidal neurons (primarily interhemispheric “callosal projection neurons” (CPN)) have reduced dendritic complexity and smaller somata in Mecp2-null mice, here we investigate whether Mecp2 loss-of-function affects neuronal maturation cell-autonomously and/or non-cell-autonomously by creating physical chimeras. We transplanted Mecp2-null or wild-type (wt) E17-18 cortical neuroblasts and immature neurons from mice constitutively expressing enhanced green fluorescent protein (eGFP) into wt P2-3 mouse cortices to generate chimeric cortices. Mecp2-null layer 2/3 pyramidal neurons in both Mecp2-null and wt neonatal cortices exhibit equivalent reduction in dendritic complexity, and are smaller than transplanted wt neurons, independent of recipient environment. These results indicate that the phenotype of Mecp2-null pyramidal neurons results largely from cell-autonomous mechanisms, with additional non-cell-autonomous effects. Dysregulation of MeCP2 target genes in individual neuronal populations such as CPN is likely centrally involved in Rett syndrome pathogenesis. Our results indicating MeCP2 function in the centrally affected projection neuron population of CPN themselves provide a foundation and motivation for identification of transcriptionally regulated MeCP2 target genes in developing CPN.Stem Cell and Regenerative Biolog

日向薬事始め(その9) : 日向出身の、華岡青洲および賀川玄悦(賀川流・産科)門下生とその周辺

This paper deals with eight young men, Ryusuke Yuge, Toshihide Nakamura, Shunkei Yuchi, Mototatsu Inoue, Shouhei Odate, Michitaka Kiwaki and Doukei Iida studied under Seishu Hanaoka (Wakayama or Osaka), and Korechika Kuwahara also studied under Genetsu Kagawa (Kyoto) in Edolate period from Hyuga (Miyazaki)

Effects of demethylating agent 5-aza-2 '-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

Maspin, which belongs to the serine protease inhibitor (serpin) superfamily, has been proposed as a potent tumor suppressor that inhibits cell motility, invasion, angiogenesis, and metastasis. In the present study, we examined the effects of 5-aza-2'-deoxycytidine (5-aza-dC), a demethylating agent, and FR901228, a histone deacetylase (HDAC) inhibitor, on maspin expression in oral cancer cell tines. The expression levels of maspin mRNA were divided into two groups, which was the maspin tow-expressed and high-expressed cell lines in the 12 oral cancer cell lines. The maspin promoter contained only a few methylated CpG sites in the maspin low-expressed cell lines. Moreover, the methylation status was not altered after 5-aza-dC treatment. However, the transcription of the maspin gene was clearly increased following 5-aza-dC treatment in a number of oral cancer cell tines. These results imply that an action of 5-aza-dC is separate from induction of promoter demethylation. Treatment with FR901228 resulted in a time-dependent stimulation of the re-expression of maspin mRNA as early as 4 h after treatment in the maspin downregulated cells. The re-expression of the maspin gene may contribute to the recuperation of biological functions linked to FR901228 such as an inhibitory effect on tumor angiogenesis and cell invasion. These results indicate that maspin and its target genes may be excellent leads for future studies on the potential benefits of FR901228, a HDAC inhibitor, in cancer therapy.</p

日向薬(くすり)事始め (その5) : 日向出身の緒方洪庵・適塾と広瀬淡窓・咸宜園に学んだ人々

This paper is a historical review of Edo period students from Hyuga, and their influence on medicinal and pharmaceutical sciences in the Hyuga area, which is now Miyazaki-ken. These students studied in Osaka and Oita. Seven of these students studied with Mr. Kouan Ogata at Tekijuku in Osaka. Fifty-four of these students studied with Mr. Tansou Hirose at Kangien in Hita-Bungo, in modern day Oita

日向薬事始め(その7)延岡における医学所「明道館」の設立と藩士教育

This paper concerns the foundation of medical school,"Meidou-kan"in Nobeoka, Hyuga during the Edo period. Activities and personal histories of both Kanao Niizuma and Zusho Hayakawa parcipated in the foundation of the school were described. Furthermore, it was also discussed on the educational system in Nobeoka, Hyuga for young people (Han-shi) in the Naito-han and others

日向薬(くすり)事始め (その11) 日向における蘭方医術の嚆矢者、岩切芳哲とその周辺

This paper deals with Houtetsu Iwakiri who developed the Dutch medicine in Hyuga (Nobeoka), Miyazaki during the Edo-period. Houtetsu Iwakiri was born at Ifukugata, Nobeoka in 1730 as the third boy among three brothers. When eighteen years old, he went to Nagasaki to learn Dutch-medicine under the first, Eitetsu Narabayashi for four years. In 1752, Houtetsu Iwakiri came back to Nobeoka and became to be a medicinal doctor of the Naito clan, Masaki Naito. It was called that Houtetsu Iwakiri was the pioneer who spreaded the Dutch-medicine into Hyuga (Miyazaki) during the Edo-period. He was dead as 71 years old in 1800

Oral intake of Lactobacillus pentosus strain b240 accelerates salivary immunoglobulin A secretion in the elderly: A randomized, placebo-controlled, double-blind trial

<p>Abstract</p> <p>Background</p> <p>Immunoglobulin A (IgA) secretion in saliva decreases with age and may be the cause of increased vulnerability of the elderly to respiratory infections. The effect of oral intake of lactic acid bacteria on salivary secretory IgA (SIgA) in the elderly has not been reported. The objective of this study was to demonstrate the acceleration of salivary SIgA secretion by oral intake of <it>Lactobacillus pentosus </it>strain b240 (b240) in the elderly.</p> <p>Results</p> <p>A total of 80 healthy elderly individuals were randomly allocated to either an intervention (i.e., b240) or a control (i.e., placebo) group. The elderly individuals in the b240 group were given a sterile water beverage (125 mL) containing heat-killed b240 (4 × 10⁹cells), while those in the placebo group were given only a sterile water beverage (125 mL); both groups received their respective beverages once daily for 12 weeks. Saliva was collected before initiation of the study and every 2 weeks thereafter. Saliva flow rate and SIgA concentration were determined, and the SIgA secretion rate was calculated. The mean salivary SIgA secretion rate in the b240 group steadily increased until week 4 (exhibiting a 20% elevation relative to that at week 0), and then remained stable until week 12. Changes in SIgA secretion rate over the intervention period were significantly greater in the b240 group than in the placebo group. The treatment groups exhibited no significant differences in adverse events.</p> <p>Conclusions</p> <p>Oral intake of <it>L. pentosus </it>strain b240 for 12 weeks significantly accelerated salivary SIgA secretion, thereby indicating its potential utility in the improvement of mucosal immunity and resistance against infection in the elderly.</p

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target