『骨董屋』におけるネルの二つの“死の意味”: “悲劇の死”と“不滅の死”

Looking similar to Oliver Twist, Pilgrim’s Progress, and TheExhibition of Humphry Clinker in the point of view of the basicstructure, The Old Curiosity Shop has one significant difference, thedeath of the virtuous heroine Nell, far from the happy endings of the rest. It must be the most controversial point and the hardest part for us readers to understand. However, closely examining Nell’s death, we find it having two aspects and roles. One is “the tragic death” as a pathetic symbol of all children of the lower classes who were the victims of avarice at that time, to show the cruelty and injustice of the Victorian industrial society built on the sacrifice of those poor, and to evoke sympathy in the contemporaries’ mind. The other is “non-death” with eternal life as an angel, the eternal good influence of her humanity among people. Love, sympathy and all other goodness Nell embodies can be a solution to the social problem Nell’s tragic death points out and can unite all the people to establish a harmonious society based on humanistic ideals.Viewed in this light, the death of Nell takes on a new meaning, the double-layer presentation of both the social problem and its solution.論

Melville and Hawthorne : a reinterpretation of Bartleby the Scrivener

Herman Melville\u27s Bartleby, the Scrivener (1853) was composed in a period when Melville was under the strong influence of Nathaniel Hawthorne, whose friendship he valued most, sharing similar aesthetic interests and ideas. When closely examined, the story shows a revealing connection with Hawthorne\u27s The Scarlet Letter (1850) in its narrative framework and sequence of episodes. The comparison between the two works suggests that Melville\u27s original intention was to create a story that would stand in striking contrast to the other. This idea offers a new approach to the author\u27s mind, adding increased depth and insight into our understanding of his work.論

PHENOTYPIC ANALYSIS OF MICE DEFICIENT FOR Ly6C1/Ly6C2

Ly6C comprises two homologous components of Ly6C1 and Ly6C2, and the expression of either of the Ly6C molecules defines unique functional subsets of monocytes. Ly6C is also expressed by other immune cell types, including Aire-expressing medullary thymic epithelial cells. Because the role of Ly6C expression in determining the functional subsets remains unclear, we generated mice deficient for both Ly6C1 and Ly6C2 with CRISPR-Cas9–mediated deletion. Mice deficient for Ly6C1/Ly6C2 showed no major alterations in the subsets and function of monocyte and other immune cells, including the cells involved in the dextran sulfate sodium salt–induced colitis model. By generating the mice deficient for Ly6C1 alone, we have also investigated the expression pattern of Ly6C1 and Ly6C2 in immune cells. Except for medullary thymic epithelial cells and CD4 single-positive T cells, immune cells predominantly expressed Ly6C2. Thus, despite the importance as a marker with a unique differential expression pattern, the Ly6C molecules have no major impact on determining the functional subsets and maintaining immune homeostasis

Aire suppresses CTLA-4 expression from the thymic stroma to control autoimmunity

Impaired production of thymic regulatory T cells (Tregs) is implicated in the development of Aire-dependent autoimmunity. Because Tregs require agonistic T cell receptor stimuli by self-antigens to develop, reduced expression of self-antigens from medullary thymic epithelial cells (mTECs) has been considered to play a major role in the reduced Treg production in Aire deficiency. Here, we show that mTECs abnormally express co-inhibitory receptor CTLA-4 if Aire is non-functional. Upon binding with CD80/CD86 ligands expressed on thymic dendritic cells (DCs), the ectopically expressed CTLA-4 from Aire-deficient mTECs removes the CD80/CD86 ligands from the DCs. This attenuates the ability of DCs to provide co-stimulatory signals and to present self-antigens transferred from mTECs, both of which are required for Treg production. Accordingly, impaired production of Tregs and organ-specific autoimmunity in Aire-deficient mice are rescued by the depletion of CTLA-4 expression from mTECs. Our studies illuminate the significance of mTEC-DC interaction coordinated by Aire for the establishment of thymic tolerance

Amelioration of diabetes in NOD by additive Aire

Tissue-specific autoimmune diseases are assumed to arise through malfunction of two checkpoints for immune tolerance: defective elimination of autoreactive T cells in the thymus and activation of these T cells by corresponding autoantigens in the periphery. However, evidence for this model and the outcome of such alterations in each or both of the tolerance mechanisms have not been sufficiently investigated. We studied these issues by expressing human AIRE (huAIRE) as a modifier of tolerance function in NOD mice wherein the defects of thymic and peripheral tolerance together cause type I diabetes (T1D). Additive huAIRE expression in the thymic stroma had no major impact on the production of diabetogenic T cells in the thymus. In contrast, huAIRE expression in peripheral antigen-presenting cells (APCs) rendered the mice resistant to T1D, while maintaining other tissue-specific autoimmune responses and antibody production against an exogenous protein antigen, because of the loss of Xcr1+ dendritic cells, an essential component for activating diabetogenic T cells in the periphery. These results contrast with our recent demonstration that huAIRE expression in both the thymic stroma and peripheral APCs resulted in the paradoxical development of muscle-specific autoimmunity. Our results reveal that tissue-specific autoimmunity is differentially controlled by a combination of thymic function and peripheral tolerance, which can be manipulated by expression of huAIRE/Aire in each or both of the tolerance mechanisms

Use of a Caco-2 permeability assay to evaluate the effects of several Kampo medicines on the drug transporter P-glycoprotein

In modern medical care in which Kampo and Western drugs are often combined, it is extremely important to clarify drug–drug interaction (DDI) to ensure safety and efficacy. However, there is little evidence of DDI in Kampo medicines. Therefore, as part of our studies to clarify the DDI risk for Kampo medicines, we evaluated the effects of five Kampo medicines [yokukansan (YKS), rikkunshito (RKT), shakuyakukanzoto (SKT), hangeshashinto (HST), and goshajinkigan (GJG)] that are widely used in Japan, on drug transporter P-glycoprotein (P-gp) using a Caco-2 permeability assay. These Kampo medicines inhibited the P-gp transport of digoxin through a Caco-2 cell monolayer. The IC50 values were 1.94–10.80 mg/ml. Of the five Kampo medicines, YKS showed the strongest inhibition (IC50 = 1.94 mg/ml), which was attributed to Uncariae Uncis Cum Ramulus. Unfortunately, we could not find the active ingredients responsible for its action. Finally, the Igut/IC50 values for the five Kampo medicines were calculated, and the DDI risk was objectively evaluated according to the criteria in the DDI guidance issued by the Japanese Ministry of Health, Labor, and Welfare and the US Food and Drug Administration. The Igut/IC50 values for the five Kampo medicines were ≤3.4. As these values were <10, they were evaluated as having a weak P-gp inhibitory effect that does not require further verification in humans, suggesting that the DDI risk due to P-gp inhibition for these Kampo medicines is low. The results should provide useful clinical information on the safety and efficacy of the combined use of Kampo and Western medicines

A NEW LOOK AT TRANSCRIPTIONAL REGULATION BY AIRE IN mTECs

The deficiency of Aire, a transcriptional regulator whose defect results in the development of autoimmunity, is associated with reduced expression of tissue-restricted self-Ags (TRAs) in medullary thymic epithelial cells (mTECs). Although the mechanisms underlying Aire-dependent expression of TRAs need to be explored, the physical identification of the target(s) of Aire has been hampered by the low and promiscuous expression of TRAs. We have tackled this issue by engineering mice with augmented Aire expression. Integration of the transcriptomic data from Aire-augmented and Aire-deficient mTECs revealed that a large proportion of so-called Aire-dependent genes, including those of TRAs, may not be direct transcriptional targets downstream of Aire. Rather, Aire induces TRA expression indirectly through controlling the heterogeneity of mTECs, as revealed by single-cell analyses. In contrast, Ccl25 emerged as a canonical target of Aire, and we verified this both in vitro and in vivo. Our approach has illuminated the Aire’s primary targets while distinguishing them from the secondary targets

Relationship of Physical Activity to Self-Care Agency and Physical Condition Among Older Adults in a Rural Area

[Background] Maintaining physical activity is important for older adults. “Self-care agency” is the ability to perform self-care, which is defined as people following their own will, managing themselves, and maintaining activities. We investigated the relationship among physical activity and self-care agency, demographic factors and physical condition in older adults. [Methods] Self-care agency was assessed by using the Self-Care Agency Questionnaire developed for Japanese patients with chronic diseases. Among 175 older adults aged 65 years or older living in a rural area, responses from 83 who performed physical activities were analyzed. Correspondence analysis was conducted to characterize demographic factors and self-care agency. [Results] A higher proportion of women than men were engaged in physical activity. Irrespective of age and sex, many of the participants performed stretching exercises, walking, radio exercises, TV exercises, and participated in community circles. Participants who engaged in physical activities had significantly higher self-care agency scores than inactive participants. Among the active participants, the self-care agency score was significantly higher for women than men (P = .04) and was also significantly higher for participants aged ≥ 75 years compared to those aged < 75 years. Individuals with a high self-care agency tended to participate in local programs and perform brief physical activities at home. [Conclusion] Physically active older adults demonstrated high self-care agency. Their activities were easily carried out in their daily lives, with activities varying by age and sex. Support from community health experts is needed to promote suitable physical activity among older adults tailored for age and sex, especially among older adults who have low self-care agency