Chromophoric water-soluble organic matter in atmospheric aerosols potentially plays an important role in aqueous reactions and light absorption by organics. The fluorescence and chemical–structural ...characteristics of the chromophoric water-soluble organic matter in submicron aerosols collected in urban, forest, and marine environments (Nagoya, Kii Peninsula, and the tropical Eastern Pacific) were investigated using excitation–emission matrices (EEMs) and a high-resolution aerosol mass spectrometer. A total of three types of water-soluble chromophores, two with fluorescence characteristics similar to those of humiclike substances (HULIS-1 and HULIS-2) and one with fluorescence characteristics similar to those of protein compounds (PLOM), were identified in atmospheric aerosols by parallel factor analysis (PARAFAC) for EEMs. We found that the chromophore components of HULIS-1 and -2 were associated with highly and less-oxygenated structures, respectively, which may provide a clue to understanding the chemical formation or loss of organic chromophores in atmospheric aerosols. Whereas HULIS-1 was ubiquitous in water-soluble chromophores over different environments, HULIS-2 was abundant only in terrestrial aerosols, and PLOM was abundant in marine aerosols. These findings are useful for further studies regarding the classification and source identification of chromophores in atmospheric aerosols.
Abstract
IgG4-related disease (IgG4-RD) is characterized by multi-organ irreversible damage resulting from tissue-specific infiltration of IgG4+ plasma cells and cytotoxic T lymphocytes (CTLs). ...However, whether IgG4 antibody contributes to the inflammation remains unclear. In this study, we established a mouse model that enabled us to evaluate the pathogenic function of IgG4 antibodies in response to a tissue-specific autoantigen using recombinant ovalbumin (OVA)-specific human IgG4 monoclonal antibody (rOVA-hIgG4 mAb) and the mice expressing OVA of the pancreatic islets (RIP-mOVA mice). We found no inflammatory effect of rOVA-hIgG4 mAb transfer alone; however, co-transfer with OVA-specific CD8 CTLs (OT-I T cells) induced tissue damage with dense lymphocytic inflammation in the pancreas of RIP-mOVA mice. rOVA-hIgG4 mAb caused accumulation of conventional DC1 cells (cDC1s) in the lymphoid tissues, and the dendritic cells (DCs) activated the OT-I T cells via cross-presentation. We also revealed that the synergistic effects of CTLs and antibodies were observed in the other subclasses including endogenous antibodies if they recognized the same antigen. The transfer of OVA-specific CD4 helper T cells (OT-II T cells) into RIP-mOVA mice induced the production of anti-OVA antibody, which had a synergistic effect, through acquisition of a T follicular helper (TFH) phenotype. Moreover, using OT-II T cells deficient in Bcl6 caused lower anti-OVA antibody production and inflammation with OT-I T cells. Our results indicated that autoreactive IgG4 antibodies play an important role of the tissue-specific CTL response in IgG4-RD.
Autoantigen-specific IgG4 synergizes with CTLs in IgG4-RD
Glycopyrronium tosylate cloth, an anticholinergic drug, has been approved for the topical treatment of primary axillary hyperhidrosis in the USA, but its effects in Japanese patients have not been ...previously investigated. This 4‐week, randomized, double‐blind, vehicle‐controlled, multicenter study was conducted to evaluate the efficacy and safety of glycopyrronium tosylate cloth for primary axillary hyperhidrosis patients in Japan. Eligible patients, who were ≥9 years of age and had primary axillary hyperhidrosis ≥6 months, with gravimetrically‐measured sweat production ≥50 mg/5 min, and Hyperhidrosis Disease Severity Scale ≥3 (moderate) were randomized 1:1:1 to once daily topical glycopyrronium tosylate 3.75%, 2.5%, or vehicle. Overall, 497 patients (163 in the glycopyrronium tosylate 3.75% group, 168 in the glycopyrronium tosylate 2.5% group, and 166 in the vehicle group, hereinafter in this order) were randomized. Statistically higher proportions of patients in the glycopyrronium tosylate groups achieved ≥2‐point improvement in Hyperhidrosis Disease Severity Scale and ≥50% reduction in sweat production from baseline versus vehicle at week 4 (51.6%, 41.1%, and 16.4%, respectively; p < 0.001 in both cases). Higher responder rates in the glycopyrronium tosylate groups compared with the vehicle group occurred as early as week 1. The most common treatment‐emergent adverse events in patients treated with glycopyrronium tosylate were photophobia, mydriasis, thirst, and dysuria. Most treatment‐emergent adverse events were mild as determined by the investigators. The incidence of treatment‐emergent adverse events leading to treatment modification was low in the three groups. The 4‐week use of topical glycopyrronium tosylate improved the patient‐reported outcome measure Hyperhidrosis Disease Severity Scale and objectively‐evaluated sweat production with a favorable benefit/risk profile.
Suppression of T-cell growth is an important mechanism for establishment of self-tolerance and prevention of unwanted prolonged immune responses that may cause tissue damage. Although negative ...selection of potentially self-reactive T cells in the thymus as well as in peripheral tissues has been extensively investigated and well documented, regulatory mechanisms to dampen proliferation of antigen-specific effector T cells in response to antigen stimulation remain largely unknown. Thus, in this work, we focus on the identification of growth suppression mechanisms of antigen-specific effector T cells. In order to address this issue, we investigated the cellular and molecular events in growth suppression of an ovalbumin (OVA)-specific T-cell clone after stimulation with a wide range of OVA-peptide concentrations. We observed that while an optimal dose of peptide leads to cell cycle progression and proliferation, higher doses of peptide reduced cell growth, a phenomenon that was previously termed high-dose suppression. Our analysis of this phenomenon indicated that high-dose suppression is a consequence of cell cycle arrest, but not Fas-Fas ligand-dependent apoptosis or T-cell anergy, and that this growth arrest occurs in S phase, accompanied by reduced expression of CDK2 and cyclin A. Importantly, inhibition of MEK/ERK activation eliminated this growth suppression and cell cycle arrest, while it reduced the proliferative response to optimal antigenic stimulation. These results suggest that cell cycle arrest is the major mechanism regulating antigen-specific effector T-cell expansion, and that the MEK/ERK signaling pathway has both positive and negative effects, depending on the strength of antigenic stimulation.
Periodontal tissue supports teeth in the alveolar bone socket via fibrous attachment of the periodontal ligament (PDL). The PDL contains periodontal fibroblasts and stem/progenitor cells, ...collectively known as PDL cells (PDLCs), on top of osteoblasts and cementoblasts on the surface of alveolar bone and cementum, respectively. However, the characteristics and lineage hierarchy of each cell type remain poorly defined. This study identified periodontal ligament associated protein-1 (Plap-1) as a PDL-specific extracellular matrix protein. We generated knock-in mice expressing CreERT2 and GFP specifically in Plap-1-positive PDLCs. Genetic lineage tracing confirmed the long-standing hypothesis that PDLCs differentiate into osteoblasts and cementoblasts. A PDL single-cell atlas defined cementoblasts and osteoblasts as Plap-1-Ibsp+Sparcl1+ and Plap-1-Ibsp+Col11a2+, respectively. Other populations, such as Nes+ mural cells, S100B+ Schwann cells, and other non-stromal cells, were also identified. RNA velocity analysis suggested that a Plap-1highLy6a+ cell population was the source of PDLCs. Lineage tracing of Plap-1+ PDLCs during periodontal injury showed periodontal tissue regeneration by PDLCs. Our study defines diverse cell populations in PDL and clarifies the role of PDLCs in periodontal tissue homeostasis and repair.
Previous studies (N=41) on the self-esteem of individuals with autism spectrum disorder (ASD) were reviewed, and future issues were investigated. The results of past studies examining the self-esteem ...level of ASD and typically developing individuals have been inconsistent. Individual differences in the self-esteem level of ASD individuals might be larger than those of typically developing individuals. Moreover, studies on the support for improving the self-esteem of ASD individuals have indicated that although various types of support have been provided, effective support methods have not been developed to date. For the clarification of the self-esteem of ASD individuals, the accumulation of studies on self-esteem from the perspectives of its “stability and level,” as well as its “contingency,” is required in the future. Furthermore, support for ASD children is crucial to prevent the decline in their self-esteem that starts from the upper grades of elementary school.
Kit is a receptor-type tyrosine kinase found on the plasma membrane. It can transform mast cells through activating mutations. Here, we show that a mutant Kit from neoplastic mast cells from mice, ...Kit(D814Y), is permanently active and allows cells to proliferate autonomously. It does so by activating two signalling pathways from different intracellular compartments. Mutant Kit from the cell surface accumulates on endolysosomes through clathrin-mediated endocytosis, which requires Kit's kinase activity. Kit(D814Y) is constitutively associated with phosphatidylinositol 3-kinase, but the complex activates Akt only on the cytoplasmic surface of endolysosomes. It resists destruction because it is under-ubiquitinated. Kit(D814Y) also appears in the endoplasmic reticulum soon after biosynthesis, and there, can activate STAT5 aberrantly. These mechanisms of oncogenic signalling are also seen in rat and human mast cell leukemia cells. Thus, oncogenic Kit signalling occurs from different intracellular compartments, and the mutation acts by altering Kit trafficking as well as activation.
Abstract
It is well-established that CD28 co-stimulation is required for the development and the proliferation of thymus-derived regulatory T cells (tTregs). Meanwhile, the role of CD28 ...co-stimulation in the homeostasis of peripherally derived Tregs (pTregs) remains unclear. To clarify this issue, we analyzed Tregs in small and large intestines (SI and LI), the principle sites of pTreg development. Interestingly, and different from in the thymus, Tregs were abundant in the intestines of CD28−/− mice, and most of them were phenotypically pTregs. We showed that CD28−/− naive T cells differentiated into pTregs in the LI after oral exposure to antigens and that CD28−/− pTregs in the LI had the same highly proliferative activity as CD28+/− cells. CD28−/− pTregs acquired these Treg-specific features at transcriptional and epigenetics levels. On the other hand, some immune suppressive molecules were down-regulated in CD28−/− pTregs. Correspondingly, the suppressive activity of CD28−/− pTregs was weaker than CD28+/+ cells. These results indicate that the homeostasis of pTregs in the intestines is maintained even in the absence of CD28, whereas CD28 is required for the maximal suppressive activity of intestinal pTregs.
Lack of CD28 does not affect gut pTreg numbers but weakens their suppressive function
For hydrogen production by water electrolyzers, iridium dioxide (IrO2) works as a catalyst for oxygen evolution reaction (OER) at an anode. In this report, we aim to study the formation mechanism of ...IrO2 nanoparticles on graphene by inducing nanoscale defects artificially. The defects on graphene grown on a copper foil by chemical vapor deposition were created by UV-ozone treatment, and IrO2 nanoparticles were deposited by hydrothermal synthesis method. We investigated the amount of defects and oxygen-functional groups on graphene by Raman spectroscopy and X-ray photoelectron spectroscopy (XPS). The size and distribution of defects and IrO2 nanoparticles on graphene were analyzed by atomic force microscopy (AFM). Raman spectroscopy and XPS measurement showed that defects and oxygen-functional groups increased with the UV-ozone treatment time. The size of IrO2 nanoparticles was reduced to ca. 4.5 nm on defective graphene, whereas the nanoparticles deposited on pristine graphene is ca. 8.8 nm in diameter. It is found that the IrO2 nanoparticles were deposited and anchored on the edge of hole-like defects on graphene. In addition, the size of deposited nanoparticles can be controlled by the extent of modification in graphene.
The interfacial structures of cyano‐based room‐temperature ionic liquids play a very important role in reducing friction. However, the presence of water impairs their tribological performance. The ...interfacial structures and friction forces of 1‐ethyl‐3‐methylimidazolium dicyanamide, EMIMDCN, and the effect of water on these structures and forces were investigated using atomic force microscopy. In addition, the interaction of water and EMIMDCN was evaluated using Fourier‐transform infrared (FT‐IR) spectroscopy. Multiple repulsive layers were observed in the EMIMDCN solution. This solution showed low friction force because these repulsive layers worked as protective layers against friction. On the other hand, the specific repulsive layer characteristics of EMIMDCN could not be observed in a EMIMDCN + 2 wt% H2O solution. FT‐IR results indicated that the layer structure of EMIMDCN was disturbed by the addition of H2O. Therefore, the solution containing water exhibited a high friction force.
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