Review Intracellular Glutathione in Cellular Immunology

Glutathione is the most abundant intracellular tripeptide thiol and acts as a reducing agent and an antioxidant. Glutathione may regulate many enzymatic and pharmacological activities by changing the intracellular redox condition. Recent studies have accumulated evidence for important roles of glutathione in full competence of lymphocytes for such as activation, proliferation and induction of cytotoxicity. A decrease in intracellular glutathione may cause malfunction of lymphocytes, immunosuppression and apoptosis. A variety of immunological functions are determined on the basis of the balance between synthesis and con-sumption of intracellular glutathione

Regulation of Antitumor Immune Responses by the IL-12 Family Cytokines, IL-12, IL-23, and IL-27

The interleukin (IL)-12 family, which is composed of heterodimeric cytokines including IL-12, IL-23, and IL-27, is produced by antigen-presenting cells such as macrophages and dendritic cells and plays critical roles in the regulation of helper T (Th) cell differentiation. IL-12 induces IFN-γ production by NK and T cells and differentiation to Th1 cells. IL-23 induces IL-17 production by memory T cells and expands and maintains inflammatory Th17 cells. IL-27 induces the early Th1 differentiation and generation of IL-10-producing regulatory T cells. In addition, these cytokines induce distinct immune responses to tumors. IL-12 activates signal transducers and activator of transcription (STAT)4 and enhances antitumor cellular immunity through interferon (IFN)-γ production. IL-27 activates STAT1, as does IFN-γ and STAT3 as well, and enhances antitumor immunity by augmenting cellular and humoral immunities. In contrast, although exogenously overexpressed IL-23 enhances antitumor immunity via memory T cells, endogenous IL-23 promotes protumor immunity through STAT3 activation by inducing inflammatory responses including IL-17 production

A Pivotal Role for Interleukin-27 in CD8+ T Cell Functions and Generation of Cytotoxic T Lymphocytes

Cytotoxic T lymphocytes (CTLs) play a critical role in the control of various cancers and infections, and therefore the molecular mechanisms of CTL generation are a critical issue in designing antitumor immunotherapy and vaccines which augment the development of functional and long-lasting memory CTLs. Interleukin (IL)-27, a member of the IL-6/IL-12 heterodimeric cytokine family, acts on naive CD4+ T cells and plays pivotal roles as a proinflammatory cytokine to promote the early initiation of type-1 helper differentiation and also as an antiinflammatory cytokine to limit the T cell hyperactivity and production of pro-inflammatory cytokines. Recent studies revealed that IL-27 plays an important role in CD8+ T cells as well. Therefore, this article reviews current understanding of the role of IL-27 in CD8+ T cell functions and generation of CTLs

Origin of highly rr-process-enhanced stars in a cosmological zoom-in simulation of a Milky Way-like galaxy

The $r$-process-enhanced (RPE) stars provide fossil records of the assembly history of the Milky Way and the nucleosynthesis of the heaviest elements. Observations by the $R$-Process Alliance (RPA) and others have confirmed that many RPE stars are associated with chemo-dynamically tagged groups, which likely came from accreted dwarf galaxies of the Milky Way (MW). However, we do not know how RPE stars are formed. Here, we present the result of a cosmological zoom-in simulation of an MW-like galaxy with $r$-process enrichment, performed with the highest resolution in both time and mass. Thanks to this advancement, unlike previous simulations, we find that most highly RPE ($r$-II; [Eu/Fe] $> +0.7$) stars are formed in low-mass dwarf galaxies that have been enriched in $r$-process elements for [Fe/H] $\,<-2.5$, while those with higher metallicity are formed in situ, in locally enhanced gas clumps that were not necessarily members of dwarf galaxies. This result suggests that low-mass accreted dwarf galaxies are the main formation site of $r$-II stars with [Fe/H] $\,<-2.5$. We also find that most low-metallicity $r$-II stars exhibit halo-like kinematics. Some $r$-II stars formed in the same halo show low dispersions in [Fe/H] and somewhat larger dispersions of [Eu/Fe], similar to the observations. The fraction of simulated $r$-II stars is commensurate with observations from the RPA, and the distribution of the predicted [Eu/Fe] for halo $r$-II stars matches that observed. These results demonstrate that RPE stars can be valuable probes of the accretion of dwarf galaxies in the early stages of their formation.Comment: 20 pages, 15 figures, published in MNRA

Voltage-assisted Magnetization Switching in Ultrathin Fe80Co20 Alloy Layers

Growing demands for the voltage-driven spintronic applications with ultralow-power consumption have led to new interest in exploring the voltage-induced magnetization switching in ferromagnetic metals. In this study, we observed a large perpendicular magnetic anisotropy change in Au(001) / ultrathin Fe80Co20(001) / MgO(001) / Polyimide / ITO junctions, and succeeded in realizing a clear switching of magnetic easy axis between in-plane and perpendicular directions. Furthermore, employing a perpendicularly magnetized film, voltage-induced magnetization switching in the perpendicular direction under the assistance of magnetic fields was demonstrated. These pioneering results may open a new window of electric-field controlled spintronics devices

Precipitation during γ-ε Phase Transformation in Biomedical Co-Cr-Mo Alloys Fabricated by Electron Beam Melting

We studied the precipitates that were induced during γ-ε phase transformation in biomedical Co-28Cr-6Mo (mass%) alloys that were fabricated by electron beam melting with carbon contents of 0.184 and 0.018 mass%. In the high-C as-built alloy, M23X6-type, π-phase (M3T2X-type), and η-phase (M6X-M12X-type) precipitates were observed (M and T: metallic elements, X: C and/or N). σ-phase (Co(Cr,Mo)), π-phase, and Co3Mo2Si-type precipitates were observed in the low-C as-built alloy. This is the first report that shows the presence and chemical composition of this precipitate, as the Co3Mo2Si-type precipitate has not been detected in biomedical Co-Cr-Mo alloys before. After aging in the ε-phase stability region, the high-C and low-C alloys both contained a single ε-phase matrix, and the amount of π-phase precipitates increased. Conversely, the amount of π-phase precipitates in both alloys decreased when a reverse transformation treatment was applied in the γ-phase stability region after aging. In the low-C alloy, the amount of Co3Mo2Si-type precipitates increased after reverse transformation treatment. These results indicate that the dissolution of π-phase precipitates and the formation of Co3Mo2Si-type precipitates during reverse transformation promote the formation of fine γ-phase grains at the precipitate/ε-phase matrix interface, because the formation and dissolution of these precipitates affect the γ-phase stability of the matrix

Superb Microvascular Imaging Ultrasound for Cervical Carotid Artery Stenosis for Prediction of the Development of Microembolic Signals on Transcranial Doppler during Carotid Exposure in Endarterectomy

Introduction: During exposure of the carotid arteries, embolism from the surgical site is recognized as a primary cause of neurological deficits or new cerebral ischemic lesions following carotid endarterectomy (CEA), and associations have been reported between histological neovascularization in the carotid plaque and both plaque vulnerability and the development of artery-to-artery embolism. Superb microvascular imaging (SMI) enables accurate visualization of neovessels in the carotid plaque without the use of intravenous contrast. This study aimed to determine whether preoperative SMI ultrasound for cervical carotid artery stenosis predicts the development of microembolic signals (MES) on transcranial Doppler (TCD) during exposure of the carotid arteries in CEA. Methods: Preoperative cervical carotid artery SMI ultrasound followed by CEA under TCD monitoring of MES in the ipsilateral middle cerebral artery was conducted in 70 patients previously diagnosed with internal carotid artery stenosis (defined as ≥70%). First, observers visually identified intraplaque microvascular flow (IMVF) signals as moving enhancements located near the surface of the carotid plaque within the plaque on SMI ultrasonograms. Next, regions of interest (ROI) were manually placed at the identified IMVF signals (or at arbitrary places within the plaque when no IMVF signals were identified within the carotid plaque) and the carotid lumen, and time-intensity curves of the IMVF signal and lumen ROI were generated. Ten heartbeat cycles of both time-intensity curves were segmented into each heartbeat cycle based on gated electrocardiogram findings and averaged with respect to the IMVF signal and lumen ROI. The difference between the maximum and minimum intensities (ID) was calculated based on the averaged IMVF signal (IDIMVF) and lumen (IDl) curves. Finally, the ratio of IDIMVF to IDl was calculated. Results: MES during exposure of the carotid arteries were detected in 17 patients (24%). The incidence of identification of IMVF signals was significantly greater in patients with MES (94%) than in those without (57%; p = 0.0067). The IDIMVF/IDl ratio was significantly greater in patients with MES (0.108 ± 0.120) than in those without (0.017 ± 0.042; p &#x3c; 0.0001). The specificity and positive predictive value for the IDIMVF/IDl ratio for prediction of the development of MES were significantly higher than those for the identification of IMVF signals. Logistic regression analysis revealed that only the IDIMVF/IDl ratio was significantly associated with the development of MES (95% CI 101.1–3,628.9; p = 0.0048). Conclusion: Preoperative cervical carotid artery SMI ultrasound predicts the development of MES on TCD during exposure of the carotid arteries in CEA

Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis

クローン性造血の臨床予後への影響を解明 --遺伝子変異とコピー数異常の統合的な知見--. 京都大学プレスリリース. 2021-07-09.Clonal hematopoiesis (CH) in apparently healthy individuals is implicated in the development of hematological malignancies (HM) and cardiovascular diseases. Previous studies of CH analyzed either single-nucleotide variants and indels (SNVs/indels) or copy number alterations (CNAs), but not both. Here, using a combination of targeted sequencing of 23 CH-related genes and array-based CNA detection of blood-derived DNA, we have delineated the landscape of CH-related SNVs/indels and CNAs in 11, 234 individuals without HM from the BioBank Japan cohort, including 672 individuals with subsequent HM development, and studied the effects of these somatic alterations on mortality from HM and cardiovascular disease, as well as on hematological and cardiovascular phenotypes. The total number of both types of CH-related lesions and their clone size positively correlated with blood count abnormalities and mortality from HM. CH-related SNVs/indels and CNAs exhibited statistically significant co-occurrence in the same individuals. In particular, co-occurrence of SNVs/indels and CNAs affecting DNMT3A, TET2, JAK2 and TP53 resulted in biallelic alterations of these genes and was associated with higher HM mortality. Co-occurrence of SNVs/indels and CNAs also modulated risks for cardiovascular mortality. These findings highlight the importance of detecting both SNVs/indels and CNAs in the evaluation of CH