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Interleukin-6 (IL-6) plays a crucial role in host defense against infection and tissue injuries and is a bioindicator of multiple distinct types of cytokine storms. In this review, we present the current understanding of the diverse roles of IL-6, its receptors, and its signaling during acute severe systemic inflammation. IL-6 directly affects vascular endothelial cells, which produce several types of cytokines and chemokines and activate the coagulation cascade. Endothelial cell dysregulation, characterized by abnormal coagulation and vascular leakage, is a common complication in cytokine storms. Emerging evidence indicates that a humanized anti-IL-6 receptor antibody, tocilizumab, can effectively block IL-6 signaling and has beneficial effects in rheumatoid arthritis, juvenile systemic idiopathic arthritis, and Castleman’s disease. Recent work has also demonstrated the beneficial effect of tocilizumab in chimeric antigen receptor T-cell therapy-induced cytokine storms as well as coronavirus disease 2019 (COVID-19). Here, we highlight the distinct contributions of IL-6 signaling to the pathogenesis of several types of cytokine storms and discuss potential therapeutic strategies for the management of cytokine storms, including those associated with sepsis and COVID-19. Inflammation: Stopping the storm Blocking interleukin-6, a signaling molecule known as a cytokine, may help in treatment of both chronic and acute inflammation. IL-6 is part of a healthy immune response, but is also implicated in chronic inflammatory diseases such as rheumatoid arthritis and in ‘cytokine storms’, when the inflammatory response spirals out of control. Sujin Kang and Tadamitsu Kishimoto at Osaka University in Japan have reviewed the roles IL-6 plays in chronic and acute inflammation, and how an antibody to the IL-6 receptor, tocilizumab, shows therapeutic potential. They report that tocilizumab successfully blocks IL-6 signaling and has beneficial effects against rheumatoid and juvenile systemic idiopathic arthritis, and other chronic inflammatory conditions. Tocilizumab has also been shown to suppress cytokine storms brought on by CAR-T cell therapy and COVID-19. These results pave the way for better treatments for inflammatory conditions.

Background The degree to which a validated instrument is able to detect clinically significant change over time is an important issue for the better management of hip or knee replacement surgery. This study examines the internal responsiveness of the EQ-5D-3L, the Oxford Hip Score (OHS), and the Oxford Knee Score (OKS) by various methods. Data from NHS patient-reported outcome measures (PROMs) linked to the Hospital Episodes Statistics (HES) dataset (2009–2015) was analysed for patients who underwent primary hip surgery ( N = 181,424) and primary knee surgery ( N = 191,379). Methods Paired data-specific univariate responsiveness was investigated using the standardized response mean (SRM), the standardized effect size (SES), and the responsiveness index (RI). Multivariate responsiveness was furthermore examined using the defined capacity of benefit score (i.e. paired data-specific MCID), adjusting baseline covariates such as age, gender, and comorbidities in the Box-Cox regression models. The observed and predicted percentages of patient improvement were examined both as a whole and by the patients' self-assessed transition level. Results The results showed that both the OHS and the OKS demonstrated great univariate and multivariate responsiveness. The percentages of the observed (predicted) total improvement were high: 51 (54)% in the OHS and 73 (58)% in OKS. The OHS and the OKS showed distinctive differences in improvement by the 3-level transition, i.e. a little better vs. about the same vs. a little worse . The univariate responsiveness of the EQ-5D-3L showed moderate effects in total by Cohen’s thresholds. The percentages of improvement in the EQ-5D-3L were moderate: 44 (48)% in the hip and 42 (44)% for the knee replacement population. Conclusions Distinctive percentage differences in patients’ perception of improvement were observed when the paired data-specific capacity of benefit score was applied to examine responsiveness. This is useful in clinical practice as rationale for access to surgery at the individual-patient level. This study shows the importance of analytic methods and instruments for investigation of the health status in hip and/or knee replacement surgery. The study finding also supports the idea of using a generic measure along with the disease-specific instruments in terms of cross-validation.

To achieve good rate capability of lithium metal anodes for high-energy-density batteries, one fundamental challenge is the slow lithium diffusion at the interface. Here we report an interpenetrated, three-dimensional lithium metal/lithium tin alloy nanocomposite foil realized by a simple calendering and folding process of lithium and tin foils, and spontaneous alloying reactions. The strong affinity between the metallic lithium and lithium tin alloy as mixed electronic and ionic conducting networks, and their abundant interfaces enable ultrafast charger diffusion across the entire electrode. We demonstrate that a lithium/lithium tin alloy foil electrode sustains stable lithium stripping/plating under 30 mA cm −2 and 5 mAh cm −2 with a very low overpotential of 20 mV for 200 cycles in a commercial carbonate electrolyte. Cycled under 6  C (6.6 mA cm −2 ), a 1.0 mAh cm −2 LiNi 0.6 Co 0.2 Mn 0.2 O 2 electrode maintains a substantial 74% of its capacity by pairing with such anode. Sluggish lithium diffusion on the surface of Li metal anodes poses a fundamental challenge. Here the authors report a Li/Li 22 Sn 5 alloy design to address this issue. The composite anode sustains stable Li stripping/plating cycling with a low overpotential of 20 mV under 30 mA cm −2  in a commercial carbonate electrolyte.

An amendment to this paper has been published and can be accessed via the original article.

Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.

Adjusting to college life is important for nursing students to achieve academic and work performance successfully. Growth mindset has been proposed as a mediating concept that can induce positive psychological outcomes in stressful life contexts, and may be a potential facilitating factor for adjustment to college life among nursing students experiencing stressful college life. This study aimed to examine the mediating effect of growth mindset in the relationship between college life stress and adjustment to college life in nursing students. This was a cross-sectional descriptive study. The study participants were 250 undergraduate nursing students recruited from three nursing colleges in Korea. Self-reported data on college life stress, growth mindset and adjustment to college life were collected using the online survey questionnaire. The data were analyzed using an independent t-test, one-way ANOVA, Kruskal-Wallis H test, Pearson’s correlation, and multiple regression analysis. The mediating effects were verified through the bootstrapping method using the PROCESS macro for SPSS. Higher levels of adjustment to college life were reported in nursing students who were in good health status and were satisfied with the nursing major. Nursing students’ adjustment to college life was negatively affected by college life stress and positively affected by growth mindset. Growth mindset mediated the link between college life stress and adjustment to college life of nursing students. Educators may be aware that growth mindset can transform stress into challenging opportunities for nursing students. As both types of growth mindset—intelligence and personality—mediated the relationship between college life stress and adjustment to college life, pedagogical strategies cultivating growth mindset in both domains should be developed and implemented to support nursing students’ adjustment.

Sepsis remains a major cause of death. Cytokines interact closely with each other and play a crucial role in the progression of sepsis. We focussed on the associations of a cytokine network with prognosis and disease severities in sepsis. This retrospective study included 31 patients with sepsis and 13 healthy controls. Blood samples were collected from patients on days 1, 2, 4, 6, 8, 11 and 15 and from healthy controls. Levels of PAI-1, IFN-α, IFN-γ, IL-1β, IL-6, IL-8, IL-12/IL-23p40, IL-17A, TNF-α, MCP-1, IL-4 and IL-10 were measured. SOFA, JAAM DIC and ISTH DIC scores were evaluated at the same times blood samples were taken. Network analysis revealed a network formed by PAI-1, IL-6, IL-8, MCP-1 and IL-10 on days 1, 2 and 4 throughout the acute phase of sepsis. There were positive correlations of each cytokine and the combined score (IL-6 + IL-8 + IL-10 + MCP-1) with the SOFA, JAAM DIC and ISTH DIC scores throughout the acute phase. A Cox proportional hazards model focussed on the acute phase showed that the above combined score was significantly related with patient prognosis, suggesting that the cytokine network of IL-6, IL-8, MCP-1 and IL-10 could play a pivotal role in the acute phase of sepsis.

The global prevalence of metabolic diseases, such as obesity, diabetes, and atherosclerosis, is rapidly increasing and has now reached epidemic proportions. Chronic tissue inflammation is a characteristic of these metabolic diseases, indicating that immune responses are closely involved in the pathogenesis of metabolic disorders. However, the regulatory mechanisms underlying immunometabolic crosstalk in these diseases are not completely understood. Recent studies have revealed the multifaceted functions of semaphorins, originally identified as axon guidance molecules, in regulating tissue inflammation and metabolic disorders, thereby highlighting the functional coupling between semaphorin signaling and immunometabolism. In this review, we explore how semaphorin signaling transcends beyond merely guiding axons to controlling immune responses and metabolic diseases.

Human cytomegalovirus (HCMV) has evolved sophisticated immune evasion mechanisms that target both the innate and adaptive immune responses. However, how HCMV encoded proteins are involved in this immune escape is not clear. Here, we show that HCMV glycoprotein US9 inhibits the IFN-β response by targeting the mitochondrial antiviral-signaling protein (MAVS) and stimulator of interferon genes (STING)-mediated signaling pathways. US9 accumulation in mitochondria attenuates the mitochondrial membrane potential, leading to promotion of MAVS leakage from the mitochondria. Furthermore, US9 disrupts STING oligomerization and STING–TBK1 association through competitive interaction. Intriguingly, US9 blocks interferon regulatory factor 3 (IRF3) nuclear translocation and its cytoplasmic domain is essential for inhibiting IRF3 activation. Mutant HCMV lacking US7-16 is impaired in antagonism of MAVS/STING-mediated IFN-β expression, an effect that is reversible by the introduction of US9. Our findings indicate that HCMV US9 is an antagonist of IFN signaling to persistently evade host innate antiviral responses. MAVS and STING signaling are central to interferon-inducing antiviral immunity. Here, the authors show how the human cytomegalovirus protein US9 can evade this immunity by antagonizing these pathways.

Polarization of macrophages into pro-inflammatory or anti-inflammatory states has distinct metabolic requirements, with mechanistic target of rapamycin (mTOR) kinase signaling playing a critical role. However, it remains unclear how mTOR regulates metabolic status to promote polarization of these cells. Here we show that an mTOR–Semaphorin 6D (Sema6D)–Peroxisome proliferator receptor γ (PPARγ) axis plays critical roles in macrophage polarization. Inhibition of mTOR or loss of Sema6D blocked anti-inflammatory macrophage polarization, concomitant with severe impairments in PPARγ expression, uptake of fatty acids, and lipid metabolic reprogramming. Macrophage expression of the receptor Plexin-A4 is responsible for Sema6D-mediated anti-inflammatory polarization. We found that a tyrosine kinase, c-Abl, which associates with the cytoplasmic region of Sema6D, is required for PPARγ expression. Furthermore, Sema6D is important for generation of intestinal resident CX3CR1 hi macrophages and prevents development of colitis. Collectively, these findings highlight crucial roles for Sema6D reverse signaling in macrophage polarization, coupling immunity, and metabolism via PPARγ. Semaphorins play well-known roles in axon guidance. Kumanogoh and colleagues demonstrate that Semaphorin 6D cell-intrinsically activates anti-inflammatory macrophage polarization.