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Severe fever with thrombocytopenia syndrome (SFTS) has a high mortality rate compared to other infectious diseases. SFTS is particularly associated with a high risk of mortality in immunocompromised individuals, while most patients who die of SFTS exhibit symptoms of severe encephalitis before death. However, the region of brain damage and mechanisms by which the SFTS virus (SFTSV) causes encephalitis remains unknown. Here, we revealed that SFTSV infects the brainstem and spinal cord, which are regions of the brain associated with respiratory function, and motor nerves in IFNAR1‐/‐ mice. Further, we show that A1‐reactive astrocytes are activated, causing nerve cell death, in infected mice. Primary astrocytes of SFTSV‐infected IFNAR1‐/‐ mice also induced neuronal cell death through the activation of A1‐reactive astrocytes. Herein, we showed that SFTSV induces fatal neuroinflammation in the brain regions important for respiratory function and motor nerve, which may underlie mortality in SFTS patients. This study provides new insights for the treatment of SFTS, for which there is currently no therapeutic approach. [ABSTRACT FROM AUTHOR]

In a diffusion Monte Carlo simulation, when diffusion starts between two parallel planes, the "walks‐on‐spheres" (WOS) algorithm is usually used. In this case, an absorption ε‐layer is used to terminate the diffusion. Here, based on isomorphism between the electrostatic Poisson problem and the corresponding diffusion motion expectation of the first passage, a new parallel‐plates algorithm is developed without an absorption layer, which induces another diffusion error in addition to the intrinsic Monte Carlo error. As there is not an analytic closed solution for the induced charge density on the parallel plates by a charge at the center between them, a series solution is used, combined with the acceptance–rejection sampling method. Using this algorithm, even though a series solution is used, it is shown that an exact sampling can be performed, which means that the random walk jump can be performed to the parallel planes without using the detailed WOS random walk jumps. It is verified that the proposed parallel plates algorithm is significantly more efficient than the current WOS algorithm. [ABSTRACT FROM AUTHOR]

Calcium (Ca2+) is an essential signaling molecule that controls a wide range of biological functions. In the immune system, calcium signals play a central role in a variety of cellular functions such as proliferation, differentiation, apoptosis, and numerous gene transcriptions. During an immune response, the engagement of T-cell and B-cell antigen receptors induces a decrease in the intracellular Ca2+ store and then activates store-operated Ca2+ entry (SOCE) to raise the intracellular Ca2+ concentration, which is mediated by the Ca2+ release-activated Ca2+ (CRAC) channels. Recently, identification of the two critical regulators of the CRAC channel, stromal interaction molecule (STIM) and Orai1, has broadened our understanding of the regulatory mechanisms of Ca2+ signaling in lymphocytes. Repetitive or prolonged increase in intracellular Ca2+ is required for the calcineurin-mediated dephosphorylation of the nuclear factor of an activated T cell (NFAT). Recent data indicate that Ca2+-calcineurin-NFAT1 to 4 pathways are dysregulated in autoimmune diseases. Therefore, calcineurin inhibitors, cyclosporine and tacrolimus, have been used for the treatment of such autoimmune diseases as systemic lupus erythematosus and rheumatoid arthritis. Here, we review the role of the Ca2+-calcineurin–NFAT signaling pathway in health and diseases, focusing on the STIM and Orai1, and discuss the deregulated calcium-mediated calcineurin-NFAT pathway in autoimmune diseases. [ABSTRACT FROM AUTHOR]

Objectives: To estimate the prevalence and associated factors of rotator cuff tear (RCT) in patients with hand osteoarthritis (HOA). Methods: Between June 2013 and December 2015, we recruited 1150 participants in rural area of South Korea. Of the 1150 participants, 307 participants with HOA were analyzed. Plain radiography of both hands, magnetic resonance imaging of both shoulders, and serum levels of high-sensitive C-reactive protein (hsCRP) and high-density lipoprotein (HDL) were obtained for all patients. HOA and RCT were diagnosed by clinical and radiologic findings. Results: The prevalence of RCT in patients with HOA (192/307, 62.5%) was higher than that in those without HOA (410/827, 49.5%, p<0.001). Among the 307 patients with HOA, the patients with RCT were older, and had higher hsCRP and lower HDL levels than the patients without RCT. Multiple logistic regression analysis confirmed significant associations of age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02–1.11), serum hsCRP levels ≥0.6mg/L (OR, 1.68; CI, 1.00–2.80), and low HDL levels (male, <50 mg/dL; female, <40 mg/dL) (OR, 1.93; CI, 1.05–3.56) with RCT in patients with HOA. For patients below 60 years old, the prevalence of RCT was 2.8-fold higher in the low HDL group than normal HDL group (p = 0.048). Finally, the prevalence of RCT was 2.6-fold higher in patients with HOA with both elevated hsCRP and low HDL levels compared with those with neither (p<0.05). Conclusions: Our findings suggest inflammation and metabolic factors were associated with the prevalence of RCT in HOA patients. [ABSTRACT FROM AUTHOR]

Samedov in [IEEE Trans. Nucl. Sci. 59(6), p. 3189 (2012)] obtained the exact analytical solution for the Green function, and the electric potential and the induced charge density for parallel-plate detector’s geometry using a conformal mapping. However, we can find a discrepancy here between the analytic induced charge solution and the one from series and diffusion simulations. Based on the total analytic sum of the induced charge on the plates being correct, we show that modification the Samedov’s analytic solution could be a good approximation, after a little rescaling. [ABSTRACT FROM AUTHOR]

Socioeconomic status (SES), which takes into account household income and education level, is an important factor in the role of muscle strength as a discriminator of sarcopenia. Although the benefits of exercise on muscle strength are well recognized, its influence on people of different SES has not been fully elucidated, informing the aim of this study. A total of 6081 subjects, for which we had complete data on measurements of handgrip strength (HGS) and other relevant variables, were included from the Korea National Health and Nutrition Examination Surveys (KNHANES) VII-3. A multivariable analysis showed that people with a low household income (odds ratio (OR) 1.637, p = 0.005) and low education status (OR 2.351, p < 0.001) had a poor HGS compared to those with a high SES, and that the difference in HGS made by muscle exercise was greater for people with a low household income (OR 7.082 vs. 3.619, p < 0.001) and low education status (OR 14.711 vs. 6.383, p < 0.001). Three-step logistic regression analysis showed that muscle exercise mediated the relationship between muscle strength and low household income (OR from 1.772 to 1.736, z = 2.373, p = 0.017) and low education level (OR from 2.368 to 2.309, z = 2.489, p = 0.012). This study confirmed that exercise improves the negative effect of SES on muscle strength, suggesting the greater importance of muscle exercise for people with a low SES. [ABSTRACT FROM AUTHOR]

This study aimed to identify differences in clinical and dietary characteristics, serum adipokine levels, and metabolomic profiles between early- and late-onset gout. Eighty-three men with gout were divided into an early-onset group (n = 38, aged < 40 years) and a late-onset group (n = 45, aged ≥ 40 years). Dietary and clinical information was obtained at baseline. Serum adipokines, including adiponectin, resistin, leptin, and plasminogen activator inhibitor-1 (PAI-1), were quantified by a Luminex multiplex immunoassay. Metabolite expression levels in plasma were measured in 22 representative samples using metabolomics analysis based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Average body mass index, rate of consumption of sugar-sweetened beverages, and serum uric acid levels were significantly higher in the early-onset group (p < 0.05), as was the PAI-I concentration (105.01 ± 42.45 ng/mL vs. 83.76 ± 31.16 ng/mL, p = 0.013). Changes in levels of metabolites mostly involved those related to lipid metabolism. In the early-onset group, acylcarnitine analog and propylparaben levels were downregulated and negatively correlated with the PAI-1 concentration whereas LPC (22:6) and LPC (18:0) levels were upregulated and positively correlated with the PAI-1 concentration. Dietary and clinical features, serum adipokine concentrations, and metabolites differed according to whether the gout is early-onset or late-onset. The mechanisms of gout may differ between these groups and require different treatment approaches. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Despite several studies on SSc treatments, effective treatments for SSc are still lacking. Since evidence suggests an association between intestinal microbiota and SSc, we focused on butyrate, which has beneficial effects in autoimmune diseases as a bacterial metabolite. Here, we investigated the therapeutic potential of sodium butyrate (SB) using a bleomycin-induced fibrosis mouse model of SSc and human dermal fibroblasts (HDFs). SB attenuated bleomycin-induced dermal and lung fibrosis in mice. SB influenced fecal microbiota composition (phyla Actinobacteria and Bacteroidetes, genera Bifidobacterium and Ruminococcus_g2). SB controlled macrophage differentiation in mesenteric lymph nodes, spleen, and bronchoalveolar lavage cells of mice with bleomycin-induced skin fibrosis. Profibrotic and proinflammatory gene expression was suppressed by SB administration in skin. Furthermore, SB inhibited transforming growth factor β1-responsive proinflammatory expression with increased acetylation of histone 3 in HDFs. Subcutaneous SB application had antifibrogenic effects on the skin. Butyrate ameliorated skin and lung fibrosis by improving anti-inflammatory activity in a mouse model of SSc. Butyrate may exhibit indirect and direct anti-fibrogenic action on fibroblasts by regulating macrophage differentiation and inhibition of histone deacetylase 3. These findings suggest butyrate as an SSc treatment. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a highly inflammatory autoimmune disease. Although proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-6, play a key role in the pathogenesis of RA, the causes of chronic inflammation are not fully understood. Here, we report that protein phosphatase magnesium-dependent 1A (PPM1A) levels were increased in RA synovial fluid compared with osteoarthritis (OA) synovial fluid and positively correlated with TNF levels. In addition, PPM1A expression was increased in synovial tissue from RA patients and joint tissue from a mouse model of arthritis. Finally, extracellular PPM1A induced inflammation by stimulating macrophages to produce TNF through toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein 88 (MyD88) signaling pathway. Our findings suggest that extracellular PPM1A may contribute to the pathogenesis of RA by functioning as a damage-associated molecular pattern (DAMP) to induce inflammation. • PPM1A is increased in rheumatoid arthritis (RA) synovial fluid and tissue compared with those in osteoarthritis (OA). • PPM1A is increased in the joint tissue from murine model of arthritis. • Extracellular PPM1A induces TNF production in macrophages via TLR4 and MyD88 pathway. [ABSTRACT FROM AUTHOR]

Low-dose radiotherapy (LDRT) has been explored as a treatment option for various inflammatory diseases; however, its application in the context of rheumatoid arthritis (RA) is lacking. This study aimed to elucidate the mechanism underlying LDRT-based treatment for RA and standardize it. LDRT reduced the total numbers of immune cells, but increased the apoptotic CD4 + T and B220 + B cells, in the draining lymph nodes of collagen induced arthritis and K/BxN models. In addition, it significantly reduced the severity of various pathological manifestations, including bone destruction, cartilage erosion, and swelling of hind limb ankle. Post-LDRT, the proportion of apoptotic CD4 + T and CD19 + B cells increased significantly in the PBMCs derived from human patients with RA. LDRT showed a similar effect in fibroblast-like synoviocytes as well. In conclusion, we report that LDRT induces apoptosis in immune cells and fibro-blast-like synoviocytes, contributing to attenuation of arthritis., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2024. The Korean Association of Immunologists.)

Severe fever with thrombocytopenia syndrome (SFTS) has a high mortality rate compared to other infectious diseases. SFTS is particularly associated with a high risk of mortality in immunocompromised individuals, while most patients who die of SFTS exhibit symptoms of severe encephalitis before death. However, the region of brain damage and mechanisms by which the SFTS virus (SFTSV) causes encephalitis remains unknown. Here, we revealed that SFTSV infects the brainstem and spinal cord, which are regions of the brain associated with respiratory function, and motor nerves in IFNAR1 -/- mice. Further, we show that A1-reactive astrocytes are activated, causing nerve cell death, in infected mice. Primary astrocytes of SFTSV-infected IFNAR1 -/- mice also induced neuronal cell death through the activation of A1-reactive astrocytes. Herein, we showed that SFTSV induces fatal neuroinflammation in the brain regions important for respiratory function and motor nerve, which may underlie mortality in SFTS patients. This study provides new insights for the treatment of SFTS, for which there is currently no therapeutic approach., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Introduction: The intricate connection between gut microbiota and rheumatoid arthritis (RA) pathogenesis has gained prominence, although the specific microbial species contributing to RA development remain largely unknown. Recent studies have sought to comprehensively explore alterations in the human microbiome, focusing on identifying disease-related microbial species through blood analysis. Consequently, this study aimed to identify RA-associated microbial species using a serum microbial array system and to investigate the efficacy and underlying mechanisms of potential microbial species for RA treatment., Methods: Serum immunoglobulin M levels against 384 intestinal microbial species were assessed using a microbial microarray in patients with RA and healthy individuals. We investigated the therapeutic potential of the identified microbial candidate regarding arthritis development, immune responses, gut barrier function, and gut microbiome using a collagen-induced arthritis (CIA) mouse model., Results: Our findings revealed significant alterations in antibody levels against 36 microbial species in patients with RA compared to healthy individuals. Notably, the antibody levels against Peptoniphilus gorbachii ( PG ) were decreased in patients with RA and exhibited an inverse correlation with RA disease activity. In vitro experiments demonstrated that PG produced acetate and butyrate, while exhibiting anti-inflammatory properties. In CIA mice, PG administration suppressed arthritis symptoms, reduced the accumulation of inflammatory monocytes in the mesenteric lymph nodes, and downregulated gene expression of pro-inflammatory cytokines in the ileum. Additionally, PG supplementation restored intestinal barrier integrity and partially resolved gut microbial dysbiosis in CIA mice. The fecal microbiota in PG -treated mice corresponded to improved intestinal barrier integrity and reduced inflammatory responses., Conclusion: This study highlights the potential of serum-based detection of anti-microbial antibodies to identify microbial targets at the species level for RA treatment. Moreover, our findings suggest that PG , identified through the microbial microarray analysis, holds therapeutic potential for RA by restoring intestinal barrier integrity and suppressing the immunologic response associated with RA., Competing Interests: Authors S-JP and MP are employed by Bifido Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kim, Chun, Cheon, Kim, Kim, Lee, Hong, Park, Park, Suh and Lee.)

Interstitial lung disease (ILD) involves persistent inflammation and fibrosis, leading to respiratory failure and even death. Adult tissue-derived mesenchymal stem cells (MSCs) show potential in ILD therapeutics but obtaining an adequate quantity of cells for drug application is difficult. Daewoong Pharmaceutical's MSCs (DW-MSCs) derived from embryonic stem cells sustain a high proliferative capacity following long-term culture and expansion. The aim of this study was to investigate the therapeutic potential of DW-MSCs in experimental mouse models of ILD. DW-MSCs were expanded up to 12 passages for in vivo application in bleomycin-induced pulmonary fibrosis and collagen-induced connective tissue disease-ILD mouse models. We assessed lung inflammation and fibrosis, lung tissue immune cells, fibrosis-related gene/protein expression, apoptosis and mitochondrial function of alveolar epithelial cells, and mitochondrial transfer ability. Intravenous administration of DW-MSCs consistently improved lung fibrosis and reduced inflammatory and fibrotic markers expression in both models across various disease stages. The therapeutic effect of DW-MSCs was comparable to that following daily oral administration of nintedanib or pirfenidone. Mechanistically, DW-MSCs exhibited immunomodulatory effects by reducing the number of B cells during the early phase and increasing the ratio of Tregs to Th17 cells during the late phase of bleomycin-induced pulmonary fibrosis. Furthermore, DW-MSCs exhibited anti-apoptotic effects, increased cell viability, and improved mitochondrial respiration in alveolar epithelial cells by transferring their mitochondria to alveolar epithelial cells. Our findings indicate the strong potential of DW-MSCs in the treatment of ILD owing to their high efficacy and immunomodulatory and anti-apoptotic effects., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2023. The Korean Association of Immunologists.)

Lymph node fibroblastic reticular cells (LN-FRCs) provide functional structure to LNs and play important roles in interactions between T cells and antigen-presenting cells. However, the direct impact of LN-FRCs on naive CD4+ T cell differentiation has not been explored. Here, we show that T cell zone FRCs of LNs (LN-TRCs) express CD25, the α chain of the IL-2 receptor heterotrimer. Moreover, LN-TRCs trans-present IL-2 to naive CD4+ T cells through CD25, thereby facilitating early IL-2-mediated signaling. CD25-deficient LN-TRCs exhibit attenuated STAT5 phosphorylation in naive CD4+ T cells during T cell differentiation, promoting T helper 17 (Th17) cell differentiation and Th17 response-related gene expression. In experimental autoimmune disease models, disease severity was elevated in mice lacking CD25 in LN-TRCs. Therefore, our results suggest that CD25 expression on LN-TRCs regulates CD4+ T cell differentiation by modulating early IL-2 signaling of neighboring, naive CD4+ T cells, influencing the overall properties of immune responses., (© 2022 Kim et al.)

Rheumatoid arthritis (RA) is a representative autoimmune disease that is primarily characterized by persistent inflammation and progressive destruction of synovial joints. RA has a complex and heterogeneous pathophysiology, involving interactions among various immune and joint stromal cells and a diverse network of cytokines and intracellular signaling pathways. With improved understanding of RA, over the past decades, therapeutic strategies have become considerably advanced and now included targeted molecular therapies, such as tumor necrosis factor inhibitors, IL-6 blockers, B-cell depletion agents, as well as inhibitors of T-cell co-stimulation and Janus kinases. However, a considerable proportion of RA patients experience refractory disease and interrupted treatment owing to the associated risk of developing serious infections and cancers. In contrast, although IL-1β, IL-17A, and p38α play significant roles in RA pathogenesis, several drugs targeting these factors have not been approved because of their low efficacy and severe adverse effects. In this review, we provide an overview of the working mechanism, advantages, and limitations of the currently available targeted drugs for RA. Additionally, we suggest potential mechanistic causes for clinically approved and failed drugs. Thus, this review provides perspectives on approaches for basic and translational studies that hold promise for identifying future next-generation therapeutics for RA., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2022. The Korean Association of Immunologists.)

Immunoreactive dynamics of tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment in breast cancer are not well understood. This study aimed to investigate the spatiotemporal cellular dynamics of TILs in breast cancer models. Breast cancer cells were implanted into the dorsal skinfold chamber of BALB/c nude mice, and T lymphocytes were adoptively transferred. Longitudinal intravital imaging was performed, and the spatiotemporal dynamics of TILs were assessed. In the 4T1 model, TILs progressively exhibited increased motility, and their motility inside the tumor was significantly higher than that outside the tumor. In the MDA-MB-231 model, the motility of TILs progressively decreased after an initial increase. TIL motility in the MDA-MB-231 and MCF-7 models differed significantly, suggesting an association between programmed death-ligand 1 expression levels and TIL motility, which warrants further investigation. Furthermore, intravital imaging of TILs can be a useful method for addressing dynamic interactions between TILs and breast cancer cells., Competing Interests: The authors declare that they have no competing interests., (© 2021 Korean Breast Cancer Society.)

The lung is highly vulnerable during sepsis, yet its functional deterioration accompanied by disturbances in the pulmonary microcirculation is poorly understood. This study aimed to investigate how the pulmonary microcirculation is distorted in sepsis-induced acute lung injury (ALI) and reveal the underlying cellular pathophysiologic mechanism.Using a custom-made intravital lung microscopic imaging system in a murine model of sepsis-induced ALI, we achieved direct real-time visualisation of the pulmonary microcirculation and circulating cells in vivo We derived the functional capillary ratio (FCR) as a quantitative parameter for assessing the fraction of functional microvasculature in the pulmonary microcirculation and dead space.We identified that the FCR rapidly decreases in the early stage of sepsis-induced ALI. The intravital imaging revealed that this decrease resulted from the generation of dead space, which was induced by prolonged neutrophil entrapment within the capillaries. We further showed that the neutrophils had an extended sequestration time and an arrest-like dynamic behaviour, both of which triggered neutrophil aggregates inside the capillaries and arterioles. Finally, we found that Mac-1 (CD11b/CD18) was upregulated in the sequestered neutrophils and that a Mac-1 inhibitor restored the FCR and improved hypoxaemia.Using the intravital lung imaging system, we observed that Mac-1-upregulated neutrophil aggregates led to the generation of dead space in the pulmonary microcirculation that was recovered by a Mac-1 inhibitor in sepsis-induced ALI., Competing Interests: Conflict of interest: I. Park has nothing to disclose. Conflict of interest: M. Kim has nothing to disclose. Conflict of interest: K. Choe has nothing to disclose. Conflict of interest: E. Song has nothing to disclose. Conflict of interest: H. Seo has nothing to disclose. Conflict of interest: Y. Hwang has nothing to disclose. Conflict of interest: J. Ahn has nothing to disclose. Conflict of interest: S-H. Lee has nothing to disclose. Conflict of interest: J.H. Lee has nothing to disclose. Conflict of interest: Y.H. Jo has nothing to disclose. Conflict of interest: K. Kim has nothing to disclose. Conflict of interest: G.Y. Koh has nothing to disclose. Conflict of interest: P. Kim has nothing to disclose., (Copyright ©ERS 2019.)