BackgroundHuman T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus associated with both HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is a chronic neuroinflammatory disease, and adult T-cell leukemia (ATL). The pathogenesis of HAM/TSP is known to be as follows: HTLV-1-infected T cells trigger a hyperimmune response leading to neuroinflammation. However, the HTLV-1-infected T cell subset that plays a major role in the accelerated immune response has not yet been identified.Principal FindingsHere, we demonstrate that CD4+CD25+CCR4+ T cells are the predominant viral reservoir, and their levels are increased in HAM/TSP patients. While CCR4 is known to be selectively expressed on T helper type 2 (Th2), Th17, and regulatory T (Treg) cells in healthy individuals, we demonstrate that IFN-γ production is extraordinarily increased and IL-4, IL-10, IL-17, and Foxp3 expression is decreased in the CD4+CD25+CCR4+ T cells of HAM/TSP patients as compared to those in healthy individuals, and the alteration in function is specific to this cell subtype. Notably, the frequency of IFN-γ-producing CD4+CD25+CCR4+Foxp3− T cells is dramatically increased in HAM/TSP patients, and this was found to be correlated with disease activity and severity.ConclusionsWe have defined a unique T cell subset—IFN-γ+CCR4+CD4+CD25+ T cells—that is abnormally increased and functionally altered in this retrovirus-associated inflammatory disorder of the central nervous system.

Invariant natural killer T (iNKT) cells are unique T cells that regulate the immune response to microbes, cancers, and autoimmunity. We assessed the characteristics of iNKT cells from persons infected with human T-lymphotropic virus type 1 (HTLV-1). Whereas most infected persons remain asymptomatic carriers (ACs IntroductionHuman T-cell lymphotropic virus type 1 (HTLV-1) causes persistent infection. Whereas most infected persons remain asymptomatic carriers (ACs), 3% to 5% develop a T-cell malignancy termed adult T-cell leukemia (ATL), and another 0.25% to 3% develop a chronic progressive inflammatory neurologic disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/ TSP). [1][2][3] One of the most important pathogenic factors in HAM/ TSP is an increased HTLV-1 load in the peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid, 4-6 which suggests that in affected persons, virus control is inadequate. A higher HTLV-1 load increases the risk of HAM/TSP and ATL. 4,7 Therefore, the precise mechanisms controlling HTLV-1-infected cells must be better understood. With regard to the host defense mechanisms involved in HTLV-1 infection, the role of HTLV-1-specific CD8 ϩ cytotoxic T lymphocytes (CTLs) has been studied. [8][9][10] The HTLV-1-specific CTL response is critical for a low viral load to be maintained. [9][10][11] Despite the high frequency of HTLV-1-specific CTLs, the number of HTLV-1-infected T cells is surprisingly high in HAM/TSP patients. 5,6 We and others have reported that the maturation and functioning of HTLV-1-specific CTLs are inadequate in HAM/TSP patients, although in vitro studies have shown that these CTLs exert cytolytic activity against HTLV-1-expressing target cells. 12,13 Therefore, we hypothesize that there may be another cell population without CTLs that contributes to the control of HTLV-1-infected T cells.A unique T-cell subpopulation, natural killer T (NKT) cells, constitute a subset of lymphocytes that share the features of both innate and adaptive immune cells. Unlike conventional T cells, NKT cells express a T-cell receptor (TCR) that recognizes glycolipids instead of protein antigens. Moreover, these cells share properties and receptors with NK cells. They rapidly produce granzymes and perforins on stimulation. Among the CD3 ϩ T cells in human blood, 10% to 25% express NK cell-surface molecules, such as CD161, and these can be classified as NKT cells. 14,15 A small population of T cells within this NKT cell subset expresses a highly conserved V␣24J␣18 TCR chain that associates preferentially with V␤11. [16][17][18] These T cells are referred to as invariant NKT (iNKT) cells. Very recently, a novel clonotypic monoclonal antibody 6B11 specific for the V␣24J␣18 TCR chain has been shown to selectively stain human iNKT cells. 18,19 Activation of human iNKT cells requires the presentation of glycolipids, such as ␣-galactosylceramide (␣-GalCer) on the major histocompatibility complex class I-like molecule CD1d. 20 ␣-GalCer stimulation induces rapid cytoki...

Synoviolin is an E3 ubiquitin ligase localized in the endoplasmic reticulum (ER) and serving as ERassociated degradation system. Analysis of transgenic mice suggested that synoviolin gene dosage is implicated in the pathogenesis of arthropathy. Complete deficiency of synoviolin is fatal embryonically. Thus, alternation of Synoviolin could cause breakdown of ER homeostasis and consequently lead to disturbance of cellular homeostasis. Hence, the expression level of Synoviolin appears to be important for its biological role in cellular homeostasis under physiological and pathological conditions. To examine the control of protein level, we performed promoter analysis to determine transcriptional regulation. Here we characterize the role of synoviolin transcription in cellular homeostasis. The Ets binding site (EBS), termed EBS-1, from position ؊76 to ؊69 of the proximal promoter, is responsible for synoviolin expression in vivo and in vitro. Interestingly, transfer of EBS-1 decoy into NIH 3T3 cells conferred not only the repression of synoviolin gene expression but also a decrease in cell number. Fluorescence-activated cell sorter analysis using annexin V staining confirmed the induction of apoptosis by EBS-1 decoy and demonstrated recovery of apoptosis by overexpression of Synoviolin. Our results suggest that transcriptional regulation of synoviolin via EBS-1 plays an important role in cellular homeostasis. Our study provides novel insight into the transcriptional regulation for cellular homeostasis.

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Several studies have investigated neural correlates of aesthetic appreciation for paintings but to date the findings have been heterogeneous. This heterogeneity may be attributed to previous studies’ measurement of aesthetic appreciation of not only the beauty of paintings but also the beauty of motifs of the paintings. In order to better elucidate the beauty of paintings, it seems necessary to compare aesthetic appreciation of paintings and photographic analogs which included corresponding real images. We prepared for famous painters’ pictures and their photographic analogs which were set up to resemble each painting in order to investigate the hypothesis that there exist specific neural correlates associated with the aesthetic appreciation for paintings. Forty-four subjects participated in functional magnetic resonance study which required comparisons of aesthetic appreciation of paintings of still life and landscape versus photographic analogs including corresponding real images of still life and landscape. Bilateral cuneus and the left lingual gyrus were activated in the comparison of aesthetic appreciation of paintings versus photographic analogs. In conclusion, the present findings suggest a possibility of the existence of specific neural correlates associated with the aesthetic appreciation for paintings and that bilateral cuneus and the left lingual gyrus may be involved.

Background and AimChronic hepatic damage leads to liver fibrosis, which is characterized by the accumulation of collagen-rich extracellular matrix. However, the mechanism by which E3 ubiquitin ligase is involved in collagen synthesis in liver fibrosis is incompletely understood. This study aimed to explore the involvement of the E3 ubiquitin ligase synoviolin (Syno) in liver fibrosis.MethodsThe expression and localization of synoviolin in the liver were analyzed in CCl4-induced hepatic injury models and human cirrhosis tissues. The degree of liver fibrosis and the number of activated hepatic stellate cells (HSCs) was compared between wild type (wt) and Syno+/− mice in the chronic hepatic injury model. We compared the ratio of apoptosis in activated HSCs between wt and Syno+/− mice. We also analyzed the effect of synoviolin on collagen synthesis in the cell line from HSCs (LX-2) using siRNA-synoviolin and a mutant synoviolin in which E3 ligase activity was abolished. Furthermore, we compared collagen synthesis between wt and Syno−/− mice embryonic fibroblasts (MEF) using quantitative RT-PCR, western blotting, and collagen assay; then, we immunohistochemically analyzed the localization of collagen in Syno−/− MEF cells.ResultsIn the hepatic injury model as well as in cirrhosis, synoviolin was upregulated in the activated HSCs, while Syno+/− mice developed significantly less liver fibrosis than in wt mice. The number of activated HSCs was decreased in Syno+/− mice, and some of these cells showed apoptosis. Furthermore, collagen expression in LX-2 cells was upregulated by synoviolin overexpression, while synoviolin knockdown led to reduced collagen expression. Moreover, in Syno−/− MEF cells, the amounts of intracellular and secreted mature collagen were significantly decreased, and procollagen was abnormally accumulated in the endoplasmic reticulum.ConclusionOur findings demonstrate the importance of the E3 ubiquitin ligase synoviolin in liver fibrosis.

BackgroundThe suture-bridge (SB) method has recently become the mainstream means of repairing full-thickness rotator cuff tears. However, in some patients the deep and superficial layers have moved in different directions because of delamination of their rotator cuffs. In such cases, a simple suture (double-layer, double-row [DD] method) is used to repair the superficial and deep layers separately. The purpose of this study was to analyze the clinical outcomes and re-tear rates of the DD and SB methods, with patients selected according to the condition of their torn cuffs.MethodsWe retrospectively registered 74 patients with full-thickness rotator cuff tears that had been repaired arthroscopically, 35 shoulders by the DD and 39 by the SB method. Mean ages were 66.1 years in the DD and 62.9 years in the SB group. We evaluated clinical status before and after surgery (Japanese Orthopedic Association [JOA] scores) and re-tear rate. The Wilcoxon signed-ranks test was used to compare JOA scores and active ROM between before and after surgery in each group. Mann–Whitney’s U test was used for comparing JOA scores, active ROM, re-tear rates, size of tear, duration of follow-up, sex, and presence of subscapular muscle repair between the DD and SB groups. A hazard ratio of less than 5% was considered to denote significance.ResultsJOA scores improved significantly in the DD and SB groups from preoperative means of 63.4 and 63.3 points, respectively, to postoperative means of 91.8 and 92.1 points, respectively. The active flexural ROM improved significantly from means of 110.1° and 100.0°, respectively, to postoperative means of 142.3° and 142.7°, respectively; the differences between groups were not significant. Re-tear occurred in 5.9% of the DD (two of 34 shoulders) and 7.9% of the SB group (three of 38 shoulders); its incidence did not differ significantly between the two groups.ConclusionsBoth the DD and SB methods achieve satisfactory clinical outcomes that do not differ significantly. Our results suggest that careful selection of operative method on the basis of the delamination pattern in patients undergoing RCT may reduce the re-tear rate after utilizing the SB method.