The coronavirus disease 2019 (COVID-19) pandemic poses a current world-wide public health threat. However, little is known about its hallmarks compared to other infectious diseases. Here, we report ...the single-cell transcriptional landscape of longitudinally collected peripheral blood mononuclear cells (PBMCs) in both COVID-19- and influenza A virus (IAV)-infected patients. We observed increase of plasma cells in both COVID-19 and IAV patients and XIAP associated factor 1 (XAF1)-, tumor necrosis factor (TNF)-, and FAS-induced T cell apoptosis in COVID-19 patients. Further analyses revealed distinct signaling pathways activated in COVID-19 (STAT1 and IRF3) versus IAV (STAT3 and NFκB) patients and substantial differences in the expression of key factors. These factors include relatively increase of interleukin (IL)6R and IL6ST expression in COVID-19 patients but similarly increased IL-6 concentrations compared to IAV patients, supporting the clinical observations of increased proinflammatory cytokines in COVID-19 patients. Thus, we provide the landscape of PBMCs and unveil distinct immune response pathways in COVID-19 and IAV patients.
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•We generated a single-cell atlas of PBMCs in both COVID-19 and influenza patients•Plasma cells increase significantly in both COVID-19 and influenza patients•COVID-19 is featured with XAF1-, TNF-, and FAS-induced T cell apoptosis•COVID-19 activates distinct pathway (STAT1/IRF3) versus influenza (STAT3/NFκB)
COVID-19 and influenza are both respiratory infections with cytokine release syndrome. Zhu et al. use single-cell RNA sequencing of longitudinally collected PBMCs in both patients to reveal distinct immune response landscapes of the two diseases and identify virus-specific cell composition and immune response pathways.
The air pollution has become an important environmental health problem due to its adverse health effect. The objective of this study was to investigate the effects of ambient temperature and ...pollutants on mortality of respiratory diseases (RD) in Hefei, China, a typical inland city.
Nonlinear exposure–response dependencies and delayed effects of urban daily mean temperature (DMT) and pollutants were evaluated by distributed lag non-linear models (DLNM). To further explore this effect, different genders and ages were also examined by stratified analysis.
A total of 12876 deaths from RD were collected from January 1, 2014 to December 31, 2018 in Hefei, China. There was a U-shaped correlation between DMT and RD mortality, and the RD mortality rised by 11.6% (95% CI: 2.2–22.0%) when the DMT was 35.8 °C (reference temperature is 20 °C). The results show that risk of death with short-term exposure to elevated concentrations of PM10 and SO2 was not significant. The maximum hysteresis and cumulative relative risk (RR) of RD mortality were 1.012 (95% CI: 1.003 ~ 1.021, lag 0 day) and 1.072 (95% CI: 1.014 ~1.133, lag 10 days) for each 10 μg/m3 augment in NO2; 1.005 (95% CI: 1.001–1.009, lag 0 day) and 1.027 (95% CI: 1.004–1.051, lag 10 days) for each 10 μg/m3 augment in O3; a negative association between CO exposure and the cumulative risk of death was observed (RR = 0.964, 95% CI: 0.935–0.993, lag 07 days). Subgroup analysis showed the effect of high temperatures, NO2, O3 and CO exposure was still statistically significant for the elderly and male.
The present study found that short-term exposure to high temperature, NO2, O3 and CO were significantly associated with the risk of RD mortality and male as well as elderly are more susceptible to these factors.
•High temperatures had a significant impact on the risk of respiratory disease mortality, but low temperatures were not found.•Exposure to NO2 and O3 were significantly linked with an increased risk of respiratory diseases mortality.•The negative association between CO exposure and the cumulative risk of death was observed.•The short-term effects of PM10 and SO2 on respiratory disease mortality were not significant.•Male as well as elderly are more susceptible to ambient temperature and pollutants.
This study aimed to investigate whether Forkhead box O3a (FOXO3a) modulates inflammation and oxidative stress in ankylosing spondylitis (AS). We applied bioinformatics analysis, quantitative ...real-time polymerase chain reaction, immunoblotting, enzyme linked immunosorbent assay, chromatin immunoprecipitation, and dual-luciferase reporter assay. Gene overexpression and knockdown of FOXO3a were conducted
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lentivirus and small interfering RNA, respectively. Downregulated FOXO3a expression was first confirmed in AS patients. Interleukin-8 (IL-8) and IL-17A were highly expressed and negatively related with FOXO3a in AS. Total antioxidant capacity (T-AOC) were markedly decreased and positively associated with FOXO3a in AS. Overexpression of FOXO3a inhibited the secretion of inflammatory cytokines and promoted the production of antioxidant enzymes in Jurkat cells. Transforming growth factor-β (TGF-β) and heme oxygenase 1 (HO-1), which had binding sites to FOXO3a based on bioinformatics analysis, were abnormally expressed and positively related with FOXO3a. Accordingly, FOXO3a obviously elevated the protein and transcription levels of TGF-β and HO-1 in Jurkat cells. The above results were verified by silencing FOXO3a. Moreover, FOXO3a directly interacted with and promoted the transcription of TGF-β and HO-1. In summary, the modulation of cellular inflammation and oxidative stress
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FOXO3a-mediated TGF-β and HO-1 activation is partly involved in the pathogenesis of AS.
Background
Rice is not only an essential food but also a source of high quality protein. Polyploidy is an evolutionary trajectory in plants, and enhancing glutelin by polyploidization is an ...attractive strategy for improving the nutritional value of rice seeds and presents a great potential for enhancing the commercial value of rice. Elucidating the mechanisms underlying glutelin synthesis and accumulation in tetraploid rice is of great significance.
Results
To enhance the nutritional value of rice, we developed tetraploid rice and evaluated the contents of various nutrient elements in mature seeds. The results revealed a significant increase in protein contents, including the total seed storage proteins, glutelins, and amino acids in tetraploid rice when compared with those in diploid rice. Tandem mass tag-based quantitative proteomic analyses of seeds revealed that glutelins regulated by several glutelin genes in 9311-4x were significantly up-regulated (≥1.5-fold), which was further verified by immunoblot analyses. In addition, temporal expression patterns of various glutelin subunits in different rice lines were investigated. The results revealed significant differences in the expression patterns between diploid and tetraploid rice seeds. Cytohistological analyses results revealed that the thickness of aleurone cell layers increased significantly by 32% in tetraploid rice, the structures of protein storage vacuoles (PSVs) in sub-aleurone cells were more diverse and abundant than those of diploid rice. Temporal expression and proteomic analyses results revealed that protein disulfide isomerase-like 1–1 expression levels were higher in tetraploid rice than in diploid rice, and that the gene responded to oxidative folding with increased levels of proglutelin and appropriate distribution of seed glutelins in tetraploid rice.
Conclusion
The results of the present study revealed that polyploidization increased glutelin content by influencing glutelin biosynthesis, transport, and deposition, while variations in glutelin accumulation between tetraploid and diploid rice were largely manifested in the initial time, duration, and relative levels of various glutelin gene expressions during seed filling stages. These findings provide novel insights into improving the protein quality and nutritional value of rice seeds by polyploid breeding.
Despite the optimization of diagnostic and therapeutic strategy for HCC treatment, the prognosis has not been markedly improved 3. ...elucidating tumor-specific mechanisms for HCC onset and ...progression is essential for identifying novel therapeutic targets and developing therapeutic strategies. In 2011, Salmena et al. put forward a ceRNA hypothesis, that is, mRNAs, lncRNAs and other ncRNAs share common miRNA response elements (MREs), thus restraining miRNA biological function by competitively binding with MREs on the target mRNA 5. ...lncRNAs and mRNAs may act as potential diagnostic and prognostic biomarkers for HCC due to their good specificity and accessibility. ...lncRNA TUG1 binding the same 3′-UTR site of hsa-miR-328-3p with SRSF9 mRNA was screened by miRanda, and its expression trend in HCC tissues and the adjacent non-cancerous liver tissues was also similar to that of SRSF9 mRNA. ...the dual-luciferase reporter gene assay validated that both SRSF9 mRNA and lncRNA TUG1 were the targets of hsa-miR-328-3p with the same binding site (Additional file 1: ...the occurrence of SRSF9 mRNA and lncRNA TUG1 overexpression in male HCC patients was both more frequent than that in female.
To explore the association between methylation level and transcript level of Forkhead box O3a (FOXO3a) gene with ankylosing spondylitis (AS) susceptibility. Methylation levels of the FOXO3a promoter ...were measured in 84 AS patients and 83 healthy controls. A total of 77 patients and 66 healthy subjects were included in subsequent mRNA level testing. DNA methylation levels of 107 CpG sites on 6 CpG islands in the FOXO3a gene were investigated. This study indicated that CpG-4 and CpG-5 islands were markedly hypomethylated in AS patients. The methylation level of CpG-4 island in AS patients was negatively correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and Ankylosing Spondylitis Disease Activity Score (ASDAS). Moreover, FOXO3a mRNA levels were significantly decreased in AS patients and were obviously negatively correlated with the methylation levels of CpG-2 and CpG-5 islands in AS patients without treatment. The sensitivity and specificity of differential methylated CpG sites of FOXO3a were 74.7 and 85.4%, respectively. Besides, FOXO3a mRNA had a sensitivity of 80.0% and a specificity of 68.8%. DNA methylation and transcription of FOXO3a might be related to AS susceptibility and play a crucial role in the diagnosis of AS, but many open questions remain.
To screen novel markers for hepatocellular carcinoma (HCC) by a combination of expression profile, interaction network analysis and clinical validation.
HCC significant molecules which are ...differentially expressed or had genetic variations in HCC tissues were obtained from five existing HCC related databases (OncoDB.HCC, HCC.net, dbHCCvar, EHCO and Liverome). Then, the protein-protein interaction (PPI) network of these molecules was constructed. Three topological features of the network ('Degree', 'Betweenness', and 'Closeness') and the k-core algorithm were used to screen candidate HCC markers which play crucial roles in tumorigenesis of HCC. Furthermore, the clinical significance of two candidate HCC markers growth factor receptor-bound 2 (GRB2) and GRB2-associated-binding protein 1 (GAB1) was validated.
In total, 6179 HCC significant genes and 977 HCC significant proteins were collected from existing HCC related databases. After network analysis, 331 candidate HCC markers were identified. Especially, GAB1 has the highest k-coreness suggesting its central localization in HCC related network, and the interaction between GRB2 and GAB1 has the largest edge-betweenness implying it may be biologically important to the function of HCC related network. As the results of clinical validation, the expression levels of both GRB2 and GAB1 proteins were significantly higher in HCC tissues than those in their adjacent nonneoplastic tissues. More importantly, the combined GRB2 and GAB1 protein expression was significantly associated with aggressive tumor progression and poor prognosis in patients with HCC.
This study provided an integrative analysis by combining expression profile and interaction network analysis to identify a list of biologically significant HCC related markers and pathways. Further experimental validation indicated that the aberrant expression of GRB2 and GAB1 proteins may be strongly related to tumor progression and prognosis in patients with HCC. The overexpression of GRB2 in combination with upregulation of GAB1 may be an unfavorable prognostic factor for HCC.
Artesunate (ART) has been indicated as a candidate drug for hepatocellular carcinoma (HCC). Glucosylceramidase (GBA) is required for autophagic degradation. Whether ART regulates autophagic flux by ...targeting GBA in HCC remains to be defined. Herein, our data demonstrated that the dramatic overexpression of GBA was significantly associated with aggressive progression and short overall survival times in HCC. Subsequent experiments revealed an association between autophagic activity and GBA expression in clinical HCC samples, tumor tissues from a rat model of inflammation-induced HCC and an orthotopic mouse model, and human HCC cell lines. Interestingly, probe labeling identified GBA as an ART target, which was further verified by both a glutathione-S-transferase pulldown assay and surface plasmon resonance analysis. The elevated protein expression of LC3B, the increased numbers of GFP-LC3B puncta and double-membrane vacuoles, and the enhanced expression of SQSTM1/p62 indicated that the degradation of autophagosomes in HCC cells was inhibited by ART treatment. Both the in vitro and in vivo data revealed that autophagosome accumulation through targeting of GBA was responsible for the anti-HCC effects of ART. In summary, this preclinical study identified GBA as one of the direct targets of ART, which may have promising potential to inhibit lysosomal autophagy for HCC therapy.
With the increasing severity of the malignant tumors situation worldwide, the impacts of climate on them are receiving increasing attention. In this study, for the first time, all-malignant tumors ...were used as the dependent variable and absolute humidity (AH) was innovatively introduced into the independent variable to investigate the relationship between all-malignant tumors and meteorological factors. A total of 42,188 cases of malignant tumor deaths and meteorological factors in Wuhu City were collected over a 7-year (2014-2020) period. The analysis method combines distributed lagged nonlinear modeling (DLNM) as well as generalized additive modeling (GAM), with prior pre-analysis using structural equation modeling (SEM). The results showed that AH, temperature mean (T mean) and diurnal temperature range (DTR) all increased the malignant tumors mortality risk. Exposure to low and exceedingly low AH increases the malignant tumors mortality risk with maximum RR values of 1.008 (95% CI: 1.001, 1.015, lag 3) and 1.016 (95% CI: 1.001, 1.032, lag 1), respectively. In addition, low and exceedingly low T mean exposures also increased the risk of malignant tumors mortality, the maximum RR was 1.020 (95% CI: 1.006, 1.034) for low T mean and 1.035 (95% CI: 1.014, 1.058) for exceedingly low T mean. As for DTR, all four levels (exceedingly low, low, high, exceedingly high, from low to high) of exposure increased the risk of death from malignant tumors, from exceedingly low to exceedingly high maximum RR values of 1.018 (95% CI: 1.004, 1.032), 1.011 (95% CI: 1.005, 1.017), 1.006 (95% CI: 1.001, 1.012) and 1.019 (95% CI: 1.007, 1.031), respectively. The results of the stratified analysis suggested that female appear to be more sensitive to humidity, while male require additional attention to reduce exposure to high level of DTR.
Mutant p53 protein over-expression has been reported to induce serum antibodies against p53. We assessed the diagnostic precision of serum p53 (s-p53) antibodies for diagnosis of cancer patients and ...compared the positive rates of the s-p53 antibody in different types of cancers.
We systematically searched PubMed and Embase, through May 31, 2012. Studies were assessed for quality using QUADAS (quality assessment of studies of diagnostic accuracy). The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were pooled separately and compared with overall accuracy measures using diagnostic odds ratios (DORs) and Area under the curve(AUC). Meta regression and subgroup analyses were done, and heterogeneity and publication bias were assessed.
Of 1089 studies initially identified, 100 eligible studies with 23 different types of tumor met the inclusion criteria for the meta-analysis (cases = 15953, controls = 8694). However, we could conduct independent meta analysis on only 13 of 36 types of tumors. Approximately 56% (56/100) of the included studies were of high quality (QUADAS score≥8). The summary estimates for quantitative analysis of serum p53 antibody in the diagnosis of cancers were: PLR 5.75 (95% CI: 4.60-7.19), NLR 0.81 (95%CI: 0.79-0.83) and DOR 7.56 (95% CI: 6.02-9.50). However, for the 13 types of cancers on which meta-analysis was conducted, the ranges for PLR (2.33-11.05), NLR (0.74-0.97), DOR (2.86-13.80), AUC(0.29-0.81), and positive rate (4.47%-28.36%) indicated significant heterogeneity. We found that breast, colorectal, esophageal, gastric, hepatic, lymphoma, lung and ovarian cancer had relatively reasonable diagnostic accuracy. The remaining results of the five types of cancers suggested that s-p53 antibody had limited value.
The current evidence suggests that s-p53 antibody has potential diagnostic value for cancer, especially for breast, colorectal, esophageal, gastric, hepatic, lymphoma, lung and ovarian cancer. The results showed that s-p53 antibody had high correlation with cancers.
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