Nucleocapsid mutations R203K/G204R increase the infectivity, fitness, and virulence of SARS-CoV-2

Previous work found that the co-occurring mutations R203K/G204R on the SARS-CoV-2 nucleocapsid (N) protein are increasing in frequency among emerging variants of concern or interest. Through a combination of in silico analyses, this study demonstrates that R203K/G204R are adaptive, while large-scale phylogenetic analyses indicate that R203K/G204R associate with the emergence of the high-transmissibility SARS-CoV-2 lineage B.1.1.7. Competition experiments suggest that the 203K/204R variants possess a replication advantage over the preceding R203/G204 variants, possibly related to ribonucleocapsid (RNP) assembly. Moreover, the 203K/204R virus shows increased infectivity in human lung cells and hamsters. Accordingly, we observe a positive association between increased COVID-19 severity and sample frequency of 203K/204R. Our work suggests that the 203K/204R mutations contribute to the increased transmission and virulence of select SARS-CoV-2 variants. In addition to mutations in the spike protein, mutations in the nucleocapsid protein are important for viral spreading during the pandemic

SEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway

Interferon-gamma (IFN-γ) signaling is necessary for the proinflammatory activation of macrophages but IFN-γ-independent pathways, for which the initiating stimuli and downstream mechanisms are lesser known, also contribute. Here we identify, by high-content screening, SEPTIN2 (SEPT2) as a negative regulation of IFN-γ-independent macrophage autoactivation. Mechanistically, endoplasmic reticulum (ER) stress induces the expression of SEPT2, which balances the competition between acetylation and ubiquitination of heat shock protein 5 at position Lysine 327, thereby alleviating ER stress and constraining M1-like polarization and proinflammatory cytokine release. Disruption of this negative feedback regulation leads to the accumulation of unfolded proteins, resulting in accelerated M1-like polarization, excessive inflammation and tissue damage. Our study thus uncovers an IFN-γ-independent macrophage proinflammatory autoactivation pathway and suggests that SEPT2 may play a role in the prevention or resolution of inflammation during infection

Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection

Coronavirus disease 2019 is a respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence on the pathogenesis of SARS-CoV-2 is accumulating rapidly. In addition to structural proteins such as Spike and Envelope, the functional roles of non-structural and accessory proteins in regulating viral life cycle and host immune responses remain to be understood. Here, we show that open reading frame 8 (ORF8) acts as messenger for inter-cellular communication between alveolar epithelial cells and macrophages during SARS-CoV-2 infection. Mechanistically, ORF8 is a secretory protein that can be secreted by infected epithelial cells via both conventional and unconventional secretory pathways. Conventionally secreted ORF8 is glycosylated and loses the ability to recognize interleukin 17 receptor A of macrophages, possibly due to the steric hindrance imposed by N-glycosylation at Asn78. However, unconventionally secreted ORF8 does not undergo glycosylation without experiencing the ER-Golgi trafficking, thereby activating the downstream NF-κB signaling pathway and facilitating a burst of cytokine release. Furthermore, we show that ORF8 deletion in SARS-CoV-2 attenuates inflammation and yields less lung lesions in hamsters. Our data collectively highlights a role of ORF8 protein in the development of cytokine storms during SARS-CoV-2 infection

A systematic review and meta-analysis of the effectiveness of social support on turnover intention in clinical nurses

BackgroundNurse turnover has become a salient issue in healthcare system worldwide and seriously compromises patient outcomes. Social support is considered an effective contributor to alleviate nurse turnover intention (TI). However, the degree of correlation between social support and nurse TI remains elusive.AimsThis study aims to evaluate the strength of the effectiveness of social support on TI among nurses as well as its potential moderators.DesignThis systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.MethodsTo obtained qualified studies, two researchers searched Embase, PubMed, Web of science, CINAHL, CNKI, WanFang, and Chinese Medical Journal Full Text Database from inception to January 6, 2024. Meta-analysis, publication bias, and sensitivity analysis were carried out on the included studies using CMA 3.0 software, and the moderating effect was verified through meta-analysis of variance (ANOVA).ResultsA total of 38 studies were obtained, involving 63,989 clinical nurses. The comprehensive effect size of the random effect model showed a significant medium negative correlation between social support and TI among nurses (p < 0.001). The sample size and TI measurement tools significantly moderated the correlation between social support and TI (p < 0.050). However, nurse department, gender, data collection time, and social support measurement tools did not moderate the correlation between the two variables.ConclusionSocial support is negatively associated with TI in nurses. Nursing administrators and the medical community should fully recognize the importance of social support for nurses and take corresponding measures to enhance it, thereby reducing TI and ensuring the stability of the nursing team

Artificial intelligence-based non-invasive tumor segmentation, grade stratification and prognosis prediction for clear-cell renal-cell carcinoma

Due to the complicated histopathological characteristics of clear-cell renal-cell carcinoma (ccRCC), non-invasive prognosis before operative treatment is crucial in selecting the appropriate treatment. A total of 126 345 computerized tomography (CT) images from four independent patient cohorts were included for analysis in this study. We propose a V Bottleneck multi-resolution and focus-organ network (VB-MrFo-Net) using a cascade framework for deep learning analysis. The VB-MrFo-Net achieved better performance than VB-Net in tumor segmentation, with a Dice score of 0.87. The nuclear-grade prediction model performed best in the logistic regression classifier, with area under curve values from 0.782 to 0.746. Survival analysis revealed that our prediction model could significantly distinguish patients with high survival risk, with a hazard ratio (HR) of 2.49 [95% confidence interval (CI): 1.13-5.45, P = 0.023] in the General cohort. Excellent performance had also been verified in the Cancer Genome Atlas cohort, the Clinical Proteomic Tumor Analysis Consortium cohort, and the Kidney Tumor Segmentation Challenge cohort, with HRs of 2.77 (95%CI: 1.58-4.84, P = 0.0019), 3.83 (95%CI: 1.22-11.96, P = 0.029), and 2.80 (95%CI: 1.05-7.47, P = 0.025), respectively. In conclusion, we propose a novel VB-MrFo-Net for the renal tumor segmentation and automatic diagnosis of ccRCC. The risk stratification model could accurately distinguish patients with high tumor grade and high survival risk based on non-invasive CT images before surgical treatments, which could provide practical advice for deciding treatment options.</p

The Correlation between Thyrotropin and Dyslipidemia in a Population-based Study

This study investigated the relationship between serum thyrotrophin levels and dyslipidemia in subclinical hypothyroid and euthyroid subjects. A total of 110 subjects with subclinical hypothyroidism and 1,240 euthyroid subjects enrolled in this study. Patients with subclinical hypothyroidism had significantly lower high density lipoprotein cholesterol (HDL-C) levels than those who were euthyroid. The lipid profiles were each categorized and mean thyrotrophin levels were higher in subjects in the dyslipidemia subclasses than subjects in the normal subclasses. Thyrotrophin was positively associated with serum triglyceride and negatively associated with serum HDL-C in women. Thyrotrophin was also positively associated with total cholesterol (TC) in the overweight population along with TC and LDL-C in overweight women. In the euthyroid population, thyrotrophin was positively associated with TC in the overweight population. In conclusion, serum thyrotrophin was correlated with dyslipidemia in subclinical hypothyroid and euthyroid subjects; the correlation was independent of insulin sensitivity

Vitamin E stabilizes iron and mitochondrial metabolism in pulmonary fibrosis

Introduction: Pulmonary fibrosis (PF) is a fatal chronic lung disease that causes structural damage and decreased lung function and has a poor prognosis. Currently, there is no medicine that can truly cure PF. Vitamin E (VE) is a group of natural antioxidants with anticancer and antimutagenic properties. There have been a few reports about the attenuation of PF by VE in experimental animals, but the molecular mechanisms are not fully understood.Methods: Bleomycin-induced PF (BLM-PF) mouse model, and cultured mouse primary lung fibroblasts and MLE 12 cells were utilized. Pathological examination of lung sections, immunoblotting, immunofluorescent staining, and real-time PCR were conducted in this study.Results: We confirmed that VE significantly delayed the progression of BLM-PF and increased the survival rates of experimental mice with PF. VE suppressed the pathological activation and fibrotic differentiation of lung fibroblasts and epithelial-mesenchymal transition and alleviated the inflammatory response in BLM-induced fibrotic lungs and pulmonary epithelial cells in vitro. Importantly, VE reduced BLM-induced ferritin expression in fibrotic lungs, whereas VE did not exhibit iron chelation properties in fibroblasts or epithelial cells in vitro. Furthermore, VE protected against mitochondrial dysmorphology and normalized mitochondrial protein expression in BLM-PF lungs. Consistently, VE suppressed apoptosis in BLM-PF lungs and pulmonary epithelial cells in vitro.Discussion: Collectively, VE markedly inhibited BLM-induced PF through a complex mechanism, including improving iron metabolism and mitochondrial structure and function, mitigating inflammation, and decreasing the fibrotic functions of fibroblasts and epithelial cells. Therefore, VE presents a highly potential therapeutic against PF due to its multiple protective effects with few side effects

Dynamical Evolution of Planetary Systems

Planetary systems can evolve dynamically even after the full growth of the planets themselves. There is actually circumstantial evidence that most planetary systems become unstable after the disappearance of gas from the protoplanetary disk. These instabilities can be due to the original system being too crowded and too closely packed or to external perturbations such as tides, planetesimal scattering, or torques from distant stellar companions. The Solar System was not exceptional in this sense. In its inner part, a crowded system of planetary embryos became unstable, leading to a series of mutual impacts that built the terrestrial planets on a timescale of ~100 My. In its outer part, the giant planets became temporarily unstable and their orbital configuration expanded under the effect of mutual encounters. A planet might have been ejected in this phase. Thus, the orbital distributions of planetary systems that we observe today, both solar and extrasolar ones, can be different from the those emerging from the formation process and it is important to consider possible long-term evolutionary effects to connect the two.Comment: Review to appear as a chapter in the "Handbook of Exoplanets", ed. H. Deeg & J.A. Belmont