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Chen Wei, Wenjun Fan, Ying Zhang, Yixiang Liu, Zhenjiang Ding, Yueqiao Si, Jingyi Liu, Lixian Sun Department of Cardiology, The Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of ChinaCorrespondence: Lixian Sun, Department of Cardiology, The Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China, Tel +86 0314 227 9016, Fax +86 0314 227 4895, Email lixiansun01@126.comPurpose: To develop and validate two nomograms incorporating the albumin/neutrophil-to-lymphocyte ratio score (ANS) for predicting the risk of coronary artery disease (CAD) or subclinical CAD.Patients and Methods: Four hundred fifty patients with suspected CAD who underwent coronary computed tomographic angiography were consecutively enrolled between September 2015 and June 2017. Nomograms were established based on independent predictors of CAD or subclinical CAD.Results: In total, 437 patients with suspected CAD who underwent coronary computed tomographic angiography were included. Male sex, age ≥ 65 years, smoking, hypertension, diabetes, dyslipidemia, ischemic stroke, and ANS were independent predictors of CAD and subclinical CAD. The areas under the curve of each nomogram were 0.799 (95% CI: 0.752– 0.846) and 0.809 (95% CI: 0.762– 0.856), respectively. The calibration curve and decision curve analysis showed good performance for the diagnostic nomograms. The prediction of CAD or subclinical CAD by the ANS was not modified by the independent predictors (all, p for interaction > 0.05).Conclusion: Our ANS-based nomograms can provide accurate and individualized risk predictions for patients with suspected CAD or subclinical CAD.Keywords: albumin/neutrophil-to-lymphocyte ratio score, ANS, coronary artery disease, diagnosis, nomogram

Neural machine translation (NMT), proven to be productively and qualitatively competitive, creates great challenges and opportunities for stakeholders in both the market and the education contexts. This paper explores how English-Chinese NMT post-editing (PE) is accepted in China from the perspectives of attitude, practice, and training, based on an integrative digital survey with role-specific popup questions for translators and clients in the market setting, and for translation teachers and students in the education setting. Descriptive statistics and correlation analyses of the survey data suggest Chinese stakeholders’ generally moderate view of PE, with outsiders like clients being more optimistic about PE than are insiders like translators. In the market setting, most translators use PE to different degrees in translating primarily informative texts; here, affiliated translators report a more frequent usage, and employ more sophisticated tools than do part-time or freelance translators. Whereas translators, on the whole, fail to notify clients of their own PE usage, or to charge clients for PE and human translation (HT) differently, most clients express their willingness to accept high-quality PE output for the sake of saving cost and time. In the education setting, despite students’ concealed usage of PE to do HT assignments to varying degrees, and their wish to learn PE out of concern for their future career, PE is generally not taught in translation classrooms of Chinese universities in the form of teaching PE as a course or integrating PE content into traditional translation course.

Metal(loid) selection contributes to selection pressure on antibiotic resistance, but to our knowledge, evidence of the dissemination of antibiotic resistance genes (ARGs) induced by metal(loid)s in mine soil ecosystems is rare. In the current study, using a high-throughput sequencing (HTS)-based metagenomic approach, 819 ARG subtypes were identified in a mine soil ecosystem, indicating that these environmental habitats are important reservoirs of ARGs. The results showed that metal(loid)-induced coselection has an important role in the distribution of soil ARGs. Furthermore, metal(loid) selection-induced ARGs were mainly associated with resistance-nodulation-division (RND) antibiotic efflux, which is distinct from what is observed in agricultural soil ecosystems. By using independent genome binning, metal(loid)s were shown impose coselection pressure on multiple ARGs residing on mobile genetic elements (MGEs), which promotes the dissemination of the antibiotic resistome. Interestingly, the current results showed that the density of several MGEs conferring ARGs was considerably higher in organisms most closely related to the priority pathogens Pseudomonas aeruginosa and Escherichia coli. Together, the results of this study indicate that mine soil ecosystems are important reservoirs of ARGs and that metal(loid)-induced coselection plays critical roles in the dissemination of ARGs in this type of soil habitat. KEY POINTS: • Mining soil ecosystem is a reservoir of antibiotic resistance genes (ARGs). • ARGs distribute via bacterial resistance-nodulation-division efflux systems. • Metal(loid)s coselected ARGs residing on mobile genetic elements in P. aeruginosa and E. coli.

The development of highly active and low-cost catalysts for use in oxygen reduction reaction (ORR) is crucial to many advanced and eco-friendly energy techniques. N-doped carbons are promising ORR catalysts. However, their performance is still limited. In this work, a zinc-mediated template synthesis strategy for the development of a highly active ORR catalyst with hierarchical porous structures was presented. The optimal catalyst exhibited high ORR performance in a 0.1 M KOH solution, with a half-wave potential of 0.89 V vs. RHE. Additionally, the catalyst exhibited excellent methanol tolerance and stability. After a 20,000 s continuous operation, no obvious performance decay was observed. When used as the air–electrode catalyst in a zinc–air battery (ZAB), it delivered an outstanding discharging performance, with peak power density and specific capacity as high as 196.3 mW cm−2 and 811.5 mAh gZn−1, respectively. Its high performance and stability endow it with potential in practical and commercial applications as a highly active ORR catalyst. Additionally, it is believed that the presented strategy can be applied to the rational design and fabrication of highly active and stable ORR catalysts for use in eco-friendly and future-oriented energy techniques.

Single-atom catalysts supported on solid substrates have inspired extensive interest, but the rational design of high-efficiency single-atom catalysts is still plagued by ambiguous structure determination of active sites and its local support effect. Here, we report hybrid single-atom catalysts by an axial coordination linkage of molecular cobalt phthalocyanine with carbon nanotubes for selective oxygen reduction reaction by screening from a series of metal phthalocyanines via preferential density-functional theory calculations. Different from conventional heterogeneous single-atom catalysts, the hybrid single-atom catalysts are proven to facilitate rational screening of target catalysts as well as understanding of its underlying oxygen reduction reaction mechanism due to its well-defined active site structure and clear coordination linkage in the hybrid single-atom catalysts. Consequently, the optimized Co hybrid single-atom catalysts exhibit improved 2e− oxygen reduction reaction performance compared to the corresponding homogeneous molecular catalyst in terms of activity and selectivity. When prepared as an air cathode in an air-breathing flow cell device, the optimized hybrid catalysts enable the oxygen reduction reaction at 300 mA cm−2 exhibiting a stable Faradaic efficiency exceeding 90% for 25 h.

This article explores English readers’ reception of Fortress Besieged as a translated literary work in the digital space, based on descriptive statistics, sentiment analysis, and content analysis of their comments at categorized dimensions. This study discovers that English readership online tends to devalue the translators’ craftsmanship, especially the interlingual transfer of cultural contents, and the sluggish pace of this novel’s storyline. However, the generally successful preservation of the humor and satire of the source text is appreciated. Through bringing cyberspace readers’ voices to the academic frontier, this study highlights the necessity of a fluent plot, cultural transfer challenges, and the adornment of figurative language when translating novels for English readers.

In this study, we explored the relationship between inflammatory adipokine levels and coronary artery disease (CAD). We collected subcutaneous adipose tissues(SAT), pericardial adipose tissues(PAT), and epicardial adipose tissues (EAT) and serum samples from 26 inpatients with CAD undergone coronary artery bypass grafting and 20 control inpatients without CAD. Serum inflammatory adipokines were measured by ELISA. Quantitative real-time PCR and western blot were used to measure gene and protein expression. Adipocyte morphology was assessed by H&E staining. Immunohistochemistry and immunofluorescence were used to measure endothelial and inflammatory markers. Serum pro- and anti-inflammatory adipokine levels were higher and lower, respectively, in the CAD group than those in the control group (P

Introduction: Preeclampsia (PE) is a gestational hypertensive disease with unclear pathogenesis. This study aimed to identify the genes that play an important role in determining the pathogenesis of PE using bioinformatics analysis and fundamental researches.Materials and methods: Datasets from the Gene Expression Omnibus (GEO) database were used to screen for differentially expressed genes (DEGs). The NCBI, SangerBox, and other databases were used to analyze the functions of the DEGs. Targetscan7, miRWalk, ENCORI, DIANA TOOLS, CircBank databases, and the Cytoscape tool were used to construct the lncRNA/circRNA-miRNA- LEP network. SRAMP, RPISeq, RBPsuite, and catRPAID were used to analyze the RNA modifications of LEP. Immune cell infiltration was analyzed using the dataset GSE75010. Placental tissues from normal pregnant women and PE patients were collected, screened for gene expression using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting. The results were further verified in HTR-8/SVneo cell line hypoxia model and PE mouse model.Results: Our analyses revealed that LEP was significantly upregulated in eight datasets. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses indicated that LEP was involved in the JAK/STAT signaling pathway, angiogenesis, and placental development. Immune cell infiltration analysis showed that M1 and M2 macrophages differed between normal pregnancies and those in PE patients. A competing endogenous RNA (ceRNA) network was constructed, and proteins interacting with LEP were identified. RNA modification sites of LEP were also identified. Finally, the overexpression of LEP in PE was confirmed in clinical samples, HTR-8/SVneo cell line and PE mouse model.Conclusion: Our results indicate that LEP overexpression is associated with PE and may be a potential diagnostic marker and therapeutic target.

The aggregate index of systemic inflammation (AISI), systemic inflammation response index (SIRI), and neutrophil-to-lymphocyte*platelet ratio (NLRP) are novel indices that simultaneously reflect the inflammatory and immune status. However, the role of these indices in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) remains unclear. We aimed to elucidate the predictive value of AISI, SIRI, and NLRP in patients with ACS undergoing PCI. A total of 1558 patients with ACS undergoing PCI were consecutively enrolled from January 2016 to December 2018. The AISI, SIRI, NLRP, systemic immune-inflammatory index, derived neutrophil-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio cutoff values for predicting major adverse cardiovascular events (MACE) were calculated using receiver-operating characteristic curves, and Spearman's test was used to analyze correlations between these indices. Kaplan–Meier curves and Cox regression models were used for survival analyses, and the endpoint was a MACE, which included all-cause mortality and rehospitalization for severe heart failure during the follow-up period. The Kaplan–Meier curves showed that higher AISI, SIRI, and NLRP values were associated with a higher risk of MACE (all P .05). Increasing tertiles of AISI, SIRI, and NLRP significantly increased the MACE risk ( P for trend < .05). AISI, SIRI, and NLRP may be suitable laboratory markers for identifying high-risk patients with ACS after PCI.

Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging. Nasopharyngeal carcinoma (NPC) is a distinctive cancer with poor differentiation and high prevalence of Epstein-Barr virus (EBV) infection. Here, we show that the expression of EBV latent protein LMP1 induces dedifferentiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA. Mechanistically, LMP1 upregulates STAT5A and recruits HDAC1/2 to the CEBPA locus to reduce its histone acetylation. HDAC inhibition restored CEBPA expression, reversing cellular dedifferentiation and stem-like status in mouse xenograft models. These findings provide a novel mechanistic epigenetic-based insight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.

Epicardial adipose tissue (EAT) and pericardial adipose tissue (PAT) are anatomically close to the myocardium and may influence cardiovascular pathology. Thus, in this study, we aim to assess whether EAT and PAT volumes were associated with coronary artery calcification score (CCS) in patients with suspected coronary artery disease (CAD), especially in overweight and obese individuals.We included consecutive patients with suspected CAD in whom EAT volume, PAT volume, and CCS were measured via computed tomography between September 2015 and June 2017 at the Affiliated Hospital of Chengde Medical University, China. Logistic regression models were applied to analyze the risk factors for CCS ≥ 100 Agatston units (AU) and in different body mass index (BMI) subgroups.EAT and PAT volumes were noted to be higher in people with BMI ≥ 24 kg/m

BackgroundThe C1q/TNF-related protein (CTRP) family affects inflammation regulation, energy metabolism, and insulin signaling. However, their role in acute coronary syndrome (ACS) development is unclear. In this cross-sectional study, we aimed to investigate the association between CTRP family and ACS.MethodsWe enrolled 289 consecutive inpatients with suspected ACS. Serum CTRP family, tumor necrosis factor-α (TNF-α), and adiponectin (ADP) levels were assessed using enzyme-linked immunosorbent assay (ELISA). Multivariate logistic regression and subgroup analyses were used to assess risk factors for ACS. Spearman's tests were used to analyze correlations between CTRP family and continuous variables.ResultsSerum CTRP family levels differed significantly between ACS and Control groups (p < 0.05). After adjusting for confounding factors, CTRP family were independently associated with ACS (p < 0.05). The association between serum CTRP family levels and ACS was stable in various subgroups according to sex, age, diabetes mellitus, and dyslipidemia status (p for interaction > 0.05). Increasing tertiles of serum CTRP1 levels, significantly increased ACS risks, which decreased gradually with increasing CTRP2, CTRP12, and CTRP13 tertiles (p for trend < 0.05). Additionally, serum CTRP1, CTRP2, CTRP13, and CTRP15 levels were weakly correlated with the severity of coronary artery stenosis.ConclusionCTRP1 and CTRP5 were identified as independent ACS risk factors, whereas CTRP2, CTRP3, CTRP9, CTRP12, CTRP13, and CTRP15 were independent protective factors for ACS. CTRP family, especially CTRP1 and CTRP3 could be novel potential clinical biomarkers of ACS.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is caused by prolonged inflammation of the paranasal sinus mucosa. The epithelial to mesenchymal transition (EMT) is involved in the occurrence and development of CRSwNP. The T-cell immunoglobulin domain and the mucin domain 4 (TIM-4) is closely related to chronic inflammation, but its mechanism in CRSwNP is poorly understood. In our study, we found that TIM-4 was increased in the sinonasal mucosa of CRSwNP patients and, especially, in macrophages. TIM-4 was positively correlated with α-SMA but negatively correlated with E-cadherin in CRS. Moreover, we confirmed that TIM-4 was positively correlated with the clinical parameters of the Lund-Mackay and Lund-Kennedy scores. In the NP mouse model, administration of TIM-4 neutralizing antibody significantly reduced the polypoid lesions and inhibited the EMT process. TIM-4 activation by stimulating with tissue extracts of CRSwNP led to a significant increase of TGF-β1 expression in macrophages in vitro. Furthermore, coculture of macrophages and human nasal epithelial cells (hNECs) results suggested that the overexpression of TIM-4 in macrophages made a contribution to the EMT process in hNECs. Mechanistically, TIM-4 upregulated TGF-β1 expression in macrophages via the ROS/p38 MAPK/Egr-1 pathway. In conclusion, TIM-4 contributes to the EMT process and aggravates the development of CRSwNP by facilitating the production of TGF-β1 in macrophages. Inhibition of TIM-4 expression suppresses nasal polyp formation, which might provide a new therapeutic approach for CRSwNP.

PurposeTo identify and compare the value of functional MRI (fMRI) in predicting the early response of metastatic cervical lymph nodes (LNs) to induction chemotherapy (IC) in nasopharyngeal carcinoma (NPC) patients.MethodsThis prospective study collected 94 metastatic LNs from 40 consecutive NPC patients treated with IC from January 2021 to May 2021. Conventional diffusion-weighted imaging, diffusion kurtosis imaging, intravoxel incoherent motion, and dynamic contrast-enhanced magnetic resonance imaging were performed before and after IC. The parameter maps apparent diffusion coefficient (ADC), mean diffusion coefficient (MD), mean kurtosis (MK), Dslow, Dfast, perfusion fraction (PF), Ktrans, Ve, and Kep) of the metastatic nodes were calculated by the Functool postprocessing software. All LNs were classified as the responding group (RG) and non-responding group (NRG) according to Response Evaluation Criteria in Solid Tumors 1.1. The fMRI parameters were compared before and after IC and between the RG and the NRG. The significant parameters are fitted by logistic regression analysis to produce new predictive factor (PRE)–predicted probabilities. Logistic regression analysis and receiver operating characteristic (ROC) curves were performed to further identify and compare the efficacy of the parameters.ResultsAfter IC, the mean values of ADC, MD, and Dslow significantly increased, while MK, Dfast, and Ktrans values decreased dramatically, while no significant difference was detected in Ve and Kep. Compared with NRG, PF-pre and Ktrans-pre values in the RG were higher statistically. The areas under the ROC for the pretreatment PF, Ktrans, and PRE were 0.736, 0.722, and 0.810, respectively, with the optimal cutoff value of 222 × 10-4, 934 × 10-3/min, and 0.6624, respectively.ConclusionsThe pretreatment fMRI parameters PF and Ktrans showed promising potential in predicting the response of the metastatic LNs to IC in NPC patients.Clinical Trial RegistrationThis study was approved by the ethics board of the Chinese PLA General Hospital, and registered on 30 January 2021, in the Chinese Clinical Trial Registry; http://www.chictr.org.cn/showproj.aspx?proj=121198, identifier (ChiCTR2100042863).

ObjectiveTo explore the population health impact of treating all US adults eligible for the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) with icosapent ethyl (IPE), we estimated (1) the number of ASCVD events and healthcare costs that could be prevented; and (2) medication costs.MethodsWe derived REDUCE-IT eligible cohorts in (1) the National Health and Nutrition Examination Surveys (NHANES) 2009-2014 and (2) the Optum Research Database (ORD). Population sizes were obtained from NHANES and observed first event rates (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina requiring hospitalization, or coronary revascularization) were estimated from the ORD. Hazard ratios from REDUCE-IT USA estimated events prevented with IPE therapy. The National Inpatient Sample estimated event costs (facility and professional) and daily IPE treatment cost was approximated at $4.59.ResultsWe estimate 3.6 million US adults to be REDUCE-IT eligible, and the observed five-year first event rate without IPE of 19.0% (95% confidence interval [CI] 16.6%-19.5%) could be lowered to 13.1% (95% CI 12.8%-13.5%) with five years of IPE treatment, preventing 212,000 (uncertainty range 163,000-262,000) events. We projected the annual IPE treatment cost for all eligible persons to be $6.0 billion (95% CI $4.7-$7.5 billion), but saving $1.8 billion annually due to first events prevented (net annual cost $4.3 billion). The total five-year event rate (first and recurrent) could be reduced from 42.5% (95% CI 39.6%-45.4%) to 28.9% (95% CI 26.9-30.9%) with five years of IPE therapy, preventing 490,000 (uncertainty range 370,000-609,000) events (net annual cost $2.6 billion).ConclusionsTreating all REDUCE-IT eligible US adults has substantial medication costs but could prevent a substantial number of ASCVD events and associated direct costs. Indirect cost savings by preventing events could outweigh much of the incurred direct costs.

Phagosome maturation in macrophage is essential to the clearance of pathogenic materials in host defence but the dynamic features remain difficult to be measured in real time. Herein, we reported the multilayered Au@MnOx @SiO2 nanoparticle as a robust pH-sensitive plasmonic nanosensor for monitoring the dynamic acidification features over the phagosome maturation process in macrophage under darkfield microscopy. For this multilayered nanosensor, the gold nanoparticle core plays a role of signal reporter, the MnOx shell and the outmost SiO2 act as the sensing layer and the protecting layer, respectively. After subject to the acidic buffer solution, the MnOx layer in the multilayered nanoprobe could be decomposed rapidly, resulting in a remarkable spectral shift and color change under darkfield microscopy. We demonstrated this nanosensor for the investigation of single phagosome acidification dynamics by monitoring the color changes of nanoprobes after phagocytosis over time. The nanoprobes after phagocytosized in macrophage displayed a slight color change within the first hour and then cost several minutes to change from red to green in the next stage, indicating the phagosome undergoes a slow first and then fast acidification feature as well as a slow-to-fast acidification translation over the phagosome maturation process. Moreover, we validated that the slow-to-fast acidification translation was dependent on the activation of V-ATPase from the ATP depletion assay. We believed that this nanosensor is promising for studying the dynamic acidification features as well as disorders in phagosome maturation in phagocytic cells, which might provide valuable information for understanding the disease pathogenesis related to phagosome dysfunctions.

Earthen sites with historical, scientific, social, cultural, and artistic values can be destroyed by weathering. Chemical consolidation is an effective method to protect earthen sites, and organic–inorganic composites are often considered ideal. The primary aim of this study was to investigate the effect of polyvinyl alcohol (PVA) with a high degree of alcoholysis on the expansion and cracking behaviour of quicklime-treated soil. The expansion and surface cracking behaviour of the composite soil were investigated with a Crack Image Analysis System. Changes inside the soil samples were observed and analysed by X-ray computed tomography and ImageJ. The results indicated that the expansion of quicklime-treated soil decreased with increasing PVA content, and the cracking behaviour on the surface was different from the inside of the samples. Surface cracks were significantly weakened when PVA was added to soil with a quicklime content ≤ 5%. As the quicklime content increased to 10% or more, the PVA transformed long and wide surface cracks into short and narrow cracks. The development of internal cracks was not as evident as those developing at the surface. Soil samples with 1.0% PVA had no obvious internal cracks at 0–25% lime content. Samples with 0.5% PVA content had internal cracks only when the quicklime content was ≥ 20%. A mechanism for the cracking phenomenon was proposed considering the results obtained from X-ray diffractometry. Soil particles were cemented together through physicochemical reactions with PVA, and these soil particles shared the expansion resulting from the hydration reaction of quicklime instead of through local expansion.

RNA Polymerase I (Pol I) has recently been recognized as a cancer therapeutic target. The activity of this enzyme is essential for ribosome biogenesis and is universally activated in cancers. The enzymatic activity of this multi-subunit complex resides in its catalytic core composed of RPA194, RPA135, and RPA12, a subunit with functions in RNA cleavage, transcription initiation and elongation. Here we explore whether RPA12 influences the regulation of RPA194 in human cancer cells. We use a specific small-molecule Pol I inhibitor BMH-21 that inhibits transcription initiation, elongation and ultimately activates the degradation of Pol I catalytic subunit RPA194. We show that silencing RPA12 causes alterations in the expression and localization of Pol I subunits RPA194 and RPA135. Furthermore, we find that despite these alterations not only does the Pol I core complex between RPA194 and RPA135 remain intact upon RPA12 knockdown, but the transcription of Pol I and its engagement with chromatin remain unaffected. The BMH-21-mediated degradation of RPA194 was independent of RPA12 suggesting that RPA12 affects the basal expression, but not the drug-inducible turnover of RPA194. These studies add to knowledge defining regulatory factors for the expression of this Pol I catalytic subunit.

This article explores the differences of translation processes for expressive and informative texts by professional translators primarily by triangulating pausing and revision data retrieved by Keystroke logging experiment and rational report thereof via questionnaire survey and interview. The article discovers that in terms of temporal distribution, the drafting of informative text accounts for a larger proportion of time, while orientation and checking accounts for a smaller proportion compared with those of expressive texts. At orientation interval, translators come to fully understand the source expressive text at the very beginning, while generally conducting syntactic analysis of and re-sequencing the semantic component of source text in target language in translating informative text. At drafting interval, structural modification frequency word rate (MWR) in translating the expressive text is larger than that in translating the informative texts, while spelling and lexical MWRs of both texts are similar. At checking interval, both texts hardly see any structural modification, but lexical MWR for the former is much bigger than that for the latter. These data, along with pausing and revision rational report, suggest the priority of familiarity with standardized grammar and expertise in specialized field for translating informative text, and the importance of embedded reading and writing training for translating expressive text.

Allergic rhinitis (AR) is a heterogeneous disease and its pathogenesis is still unclear. Growing clinical evidence has thrown light on the key role of NOD-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation of allergic disease. However, the effect of NLRP3 activation in macrophages for AR has not been elucidated. This study aims to investigate the role of NLRP3 in ovalbumin (OVA)-stimulated bone marrow-derived macrophages (BMDMs) and to confirm the impact of macrophage pyroptosis in allergic rhinitis.Nasal inflammation levels were assessed by HE and dual immunofluorescence staining. BMDMs were cultured and were stimulated with OVA in the presence or absence of MCC950 to further investigate the effect of NLRP3 activation in macrophages. The cell lysates and supernatants were harvested to measure NLRP3 and downstream molecules, as well as cell rupture, and IL-1β production. Besides, an OVA-exposed AR mouse model was developed, and the histopathology in nasal mucosa, and the relationship between macrophage pyroptosis and local inflammation were detected. The inhibitory role of MCC950 was also evaluated.The present results uncovered that the number of macrophages and NLRP3 expression were increased in the nasal mucosa of AR subjects, and upregulation of macrophage pyroptosis contributed to local allergic inflammation. In addition, the OVA challenge induced NLRP3 inflammasome activation in BMDMs, as evidenced by enhanced expressions of NLRP3-ASC-caspase-1 inflammasome, gasdermin D, production of IL-1β, and increased macrophage lysis. Furthermore, inhibition of NLRP3 inflammasome attenuated nasal inflammation, accompanied by a reduced number of inflammatory cells and lower levels of IL-1β and OVA-specific IgE.Our results indicate that NLRP3 inflammasome played an important role in allergic airway inflammation by activating macrophage's pyroptotic cell death and releasing inflammatory mediators to local tissues. Inhibition of NLRP3 inflammasome-mediated pyroptosis could be a promising therapeutic strategy for ameliorating inflammatory responses in allergic rhinitis.

Although cardiovascular disease risk factors relate to COVID-19, the association of estimated atherosclerotic cardiovascular disease (ASCVD) risk with severe COVID-19 is not established. We examined the relation of the pooled-cohort ASCVD risk score to severe COVID-19 among 28,646 subjects from the National COVID Cohort Collaborative database who had positive SARS-CoV-2 test results from April 1, 2020 to April 1, 2021. In addition, 10-year ASCVD risk scores were calculated, and subjects were stratified into low-risk (=20%) groups. Severe COVID-19 outcomes (including death, remdesivir treatment, COVID-19 pneumonia, acute respiratory distress syndrome, and mechanical ventilation) occurring during follow-up were examined individually and as a composite in relation to ASCVD risk group across race and gender. Multiple logistic regression, adjusted for age, gender, and race, examined the relation of ASCVD risk group to the odds of severe COVID-19 outcomes. Our subjects had a mean age of 59.4 years; 14% were black and 57% were female. ASCVD risk group was directly related to severe COVID-19 prevalence. The adjusted odds ratio of the severe composite COVID-19 outcome by risk group (vs the low-risk group) was 1.8 (95% confidence interval 1.5 to 2.2) for the borderline-risk, 2.7 (2.3 to 3.2) for the intermediate-risk, and 4.6 (3.7 to 5.6) for the high-risk group. Black men and black women in the high-risk group showed higher severe COVID-19 prevalence compared with nonblack men and nonblack women. Prevalence of severe COVID-19 outcomes was similar in intermediate-risk black men and high-risk nonblack men (approximately 12%). In conclusion, although further research is needed, the 10-year ASCVD risk score in adults ages 40 to 79 years may be used to identify those who are at highest risk for COVID-19 complications and for whom more intensive treatment may be warranted.

Background: To estimate the population health impact of treating all US adults eligible for the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) with icosapent ethyl (IPE), we estimated (1) the number of ASCVD events and healthcare costs that could be prevented; and (2) medication costs. Methods: We derived REDUCE-IT eligible cohorts in (1) the National Health and Nutrition Examination Surveys (NHANES) 2009-2014 and (2) the Optum Research Database (ORD). Population sizes were obtained from NHANES and observed first event rates at five years (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina requiring hospitalization, or coronary revascularization) were estimated from ORD. Hazard ratios from REDUCE-IT USA estimated events prevented with IPE. Total (i.e., first and recurrent) event rates were estimated from the REDUCE-IT USA subgroup, applying the treatment effect on total events observed in the entire REDUCE-IT trial. The National Inpatient Sample estimated facility and professional event costs and daily IPE treatment cost was approximated at $4.16. Results: We estimate 3.6 million US adults to be REDUCE-IT eligible, and an observed first event rate of 19.0% could be lowered to 13.1% with five years of IPE treatment, preventing 212,000 events (Table). We projected the annual IPE treatment cost for all eligible persons to be $5.5 billion, but saving $1.7 billion annually due to first events prevented (net annual cost $3.8 billion). The total five-year event rate (first and recurrent) could be reduced from 42.5% to 28.9% with five years of IPE therapy, preventing 490,000 events (net annual cost $2.3 billion). Conclusions: Treating all REDUCE-IT eligible US adults has substantial medication costs but could prevent a substantial number of ASCVD events and associated direct costs. Indirect cost savings by preventing events could outweigh much of the incurred direct costs.

Cadmium (Cd) contamination of agricultural soils poses a potential public health issue for humans. Phytoremediation-based accumulating plants are an effective and sustainable technology for Cadmium remediation of contaminated agricultural soil. The rhizosphere microbiome can promote the growth and Cadmium accumulation in hyperaccumulators, but its taxonomic and functional traits remain elusive. The present study used two ecotypes of Sedum alfredii, an accumulating ecotype (AE) and a non-accumulating ecotype (NAE), as model plants to investigate the rhizosphere microbiome assemblages and influence on plant growth under high cadmium conditions. Our results showed that distinct root microbiomes assembled in association with both ecotypes of S. alfredii and that the assemblages were based largely on the lifestyles of the two ecotypes. In addition, we demonstrated that the functions of the microbes inhabiting the rhizosphere soils were closely associated with root-microbe interactions in both ecotypes of S. alfredii. Importantly, our results also demonstrated that the rhizosphere microbiome assembled in the AE rhizosphere soils contributed to plant growth and cadmium uptake under high cadmium conditions through functions such as nitrogen fixation, phosphorus solubilization, indole acetic acid (IAA) synthesis, and siderophore metabolism. However, this phenomenon was not clearly observed in the NAE. Our results suggest that the rhizosphere microbiome plays important roles in biogeochemical nutrient and metal cycling that can contribute to host plant fitness.

Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression, yet how this process is regulated by oncogenic signal remains largely unknown. Here, we unveil that non-canonical activation of nuclear AURKA promotes an oncogenic RNA splicing of tumor suppressor RBM4 directed by m6A reader YTHDC1 in lung cancer. Nuclear translocation of AURKA is a prerequisite for RNA aberrant splicing, specifically triggering RBM4 splicing from the full isoform (RBM4-FL) to the short isoform (RBM4-S) in a kinase-independent manner. RBM4-S functions as a tumor promoter by abolishing RBM4-FL-mediated inhibition of the activity of the SRSF1-mTORC1 signaling pathway. Mechanistically, AURKA disrupts the binding of SRSF3 to YTHDC1, resulting in the inhibition of RBM4-FL production induced by the m6A-YTHDC1-SRSF3 complex. In turn, AURKA recruits hnRNP K to YTHDC1, leading to an m6A-YTHDC1-hnRNP K-dependent exon skipping to produce RBM4-S. Importantly, the small molecules that block AURKA nuclear translocation, reverse the oncogenic splicing of RBM4 and significantly suppress lung tumor progression. Together, our study unveils a previously unappreciated role of nuclear AURKA in m6A reader YTHDC1-dependent oncogenic RNA splicing switch, providing a novel therapeutic route to target nuclear oncogenic events.

Polymorphism drives survival under stress and provides adaptability. Genetic polymorphism of ribosomal RNA (rRNA) genes derives from internal repeat variation of this multicopy gene, and from interindividual variation. A considerable amount of rRNA sequence heterogeneity has been proposed but has been challenging to estimate given the scarcity of accurate reference sequences. We identified four rDNA copies on chromosome 21 (GRCh38) with 99% similarity to recently introduced reference sequence KY962518.1. We customized a GATK bioinformatics pipeline using the four rDNA loci, spanning a total 145 kb, for variant calling and used high-coverage whole-genome sequencing (WGS) data from the 1000 Genomes Project to analyze variants in 2504 individuals from 26 populations. We identified a total of 3791 variant positions. The variants positioned nonrandomly on the rRNA gene. Invariant regions included the promoter, early 5′ ETS, most of 18S, 5.8S, ITS1, and large areas of the intragenic spacer. A total of 470 variant positions were observed on 28S rRNA. The majority of the 28S rRNA variants were located on highly flexible human-expanded rRNA helical folds ES7L and ES27L, suggesting that these represent positions of diversity and are potentially under continuous evolution. Several variants were validated based on RNA-seq analyses. Population analyses showed remarkable ancestry-linked genetic variance and the presence of both high penetrance and frequent variants in the 5′ ETS, ITS2, and 28S regions segregating according to the continental populations. These findings provide a genetic view of rRNA gene array heterogeneity and raise the need to functionally assess how the 28S rRNA variants affect ribosome functions.

The controllable anchoring of multiple isolated metal atoms into a single support exhibits scientific and technological opportunities, while the synthesis of catalysts with multiple single metal atoms remains a challenge and has been rarely reported. Herein, we present a general route for anchoring up to eleven metals as highly dispersed single-atom centers on porous nitride-doped carbon supports with the developed movable type printing method, and label them as high-entropy single-atom catalysts. Various high-entropy single-atom catalysts with tunable multicomponent are successfully synthesized with the same method by adjusting only the printing templates and carbonization parameters. To prove utility, quinary high-entropy single-atom catalysts (FeCoNiCuMn) is investigated as oxygen reduction reaction catalyst with much more positive activity and durability than commercial Pt/C catalyst. This work broadens the family of single-atom catalysts and opens a way to investigate highly efficient single-atom catalysts with multiple compositions.

Breast cancer stem cells are responsible for cancer initiation, progression, and drug resistance. However, effective targeting strategies against the cell subpopulation are still limited. Here, we unveil two splice variants of very-low-density lipoprotein receptor, VLDLR-I and -II, which are highly expressed in breast cancer stem cells. In breast cancer cells, VLDLR silencing suppresses sphere formation abilities in vitro and tumor growth in vivo. We find that VLDLR knockdown induces transition from self-renewal to quiescence. Surprisingly, ligand-binding activity is not involved in the cancer-promoting functions of VLDLR-I and -II. Proteomic analysis reveals that citrate cycle and ribosome biogenesis-related proteins are upregulated in VLDLR-I and -II overexpressed cells, suggesting that VLDLR dysregulation is associated with metabolic and anabolic regulation. Moreover, high expression of VLDLR in breast cancer tissues correlates with poor prognosis of patients. Collectively, these findings indicate that VLDLR may be an important therapeutic target for breast cancer treatment.

Objective The long-noncoding RNAs (lncRNAs) have been identified as key players in diverse cellular processes in non-small cell lung cancer (NSCLC). However, the understanding of biological functions and detailed mechanisms of lncRNAs is still limited. Herein, the lncRNA cancer susceptibility candidate 9 (CASC9) on NSCLC progression is investigated. Materials and methods Expressions of CASC9, HuR and cell division cycle 6 (CDC6) in NSCLC tissues were detected with quantitative real-time polymerase chain reaction (qRT-PCR). The cell counting kit-8, transwell assays, and flow cytometry were used to examine cell proliferation, migration, and the cell cycle. Tumor growth in vivo was evaluated by xenograft tumor experiments and immunohistochemistry. RNA-binding protein immunoprecipitation (RIP) was used to identify the interaction between HuR and CDC6, and CASC9 and HuR. Results CASC9, CDC6 and HuR expression were found significantly upregulated in NSCLC tissues, which predicted poorer 5-year overall survival in NSCLC patients. Inhibition of CASC9 significantly reduced the malignancy of NSCLC cells, such as proliferation, migration and cell cycle. In vivo experiments further demonstrated that CASC9 knockdown reduced the tumor growth and the Ki-67 expression. Moreover, CASC9 knockdown inhibited the expression of CDC6 which was detected overexpressed in NSCLC tumor tissues. Then, up-regulation of CDC6 could partly reverse the negative effects of CASC9 on cell proliferation, migration and cell cycle. RIP assay and rescue experiment showed that CASC9 regulated CDC via binding to HuR. Conclusion Our results indicate that CASC9 conferred an aggressive phenotype in NSCLC and might be a pivotal target for this disease.

Introduction Hypertriglyceridemia is associated with increased atherosclerotic cardiovascular disease (ASCVD) event risk, which persists even in statin-treated patients. The objective of this analysis was to estimate the prevalence of triglyceride (TG) levels ≥ 150 mg/dl in statin-treated adults with diabetes or ASCVD in the United States. Methods Laboratory data, medical history, and prescription data from 40,617 subjects who participated in the US National Health and Nutrition Examination Survey (NHANES) spanning 8 years (four 2-year surveys; 2007–2014) were analyzed. Patients included were ≥ 20 years old and had morning fasting (at least 8.5 h) TG values available. The proportion and weighted number of individuals in the US population with TG ≥ 150 mg/dl was calculated according to statin use, as well as in key subgroups of statin-treated patients including those with low-density lipoprotein cholesterol (LDL-C) levels

The role of NT-proBNP and hs-cTnT levels in predicting heart failure (HF) and cardiovascular disease (CVD) events in persons with prediabetes (pre-DM) and diabetes mellitus (DM) is not well-established. We examined the individual and combined relations of N-terminal natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) levels among asymptomatic adults with pre-DM and DM with the development of incident HF and CVD events. 5,584 participants with biomarker measures aged 45 to 84 years were included from the Multi-Ethnic Study of Atherosclerosis, of which 4,090 were normoglycemic, 799 had pre-DM, and 695 had DM at baseline and were followed for 12.4 ± 3.8 years. In those with DM, HF incidence rates per 1,000 person-years ranged from 3.2 to 39.4 across quartiles of NT-proBNP and 0.6 to 18.2 for hs-cTnT, respectively. Corresponding values for CVD incidence per 1,000 person-years ranged from 13.7 to 39.4 for NT-proBNP and 13.2 to 35.4 for hs-cTnT. Multivariate adjusted HRs were highest when both NT-proBNP and hs-cTnT were above versus below the median in those with pre-DM/DM (16.7 for incident HF and 2.1 for CVD events, both p

Developing efficient non-precious-metal catalysts to accelerate the sluggish oxygen reduction reaction (ORR) is highly desired but remains a great challenge. Herein, using 2D bimetallic Zn/Fe-MOF as the precursor and g-C