Risk factors for progression to severe infection and prolonged viral clearance time in hospitalized elderly patients infected with the Omicron variant of SARS-CoV-2: a retrospective study at Shanghai Fourth People's Hospital, School of Medicine, Tongji University.

Introduction: In elderly patients infected with the Omicron variant, disease progression to severe infection can result in poor outcomes. This study aimed to identify risk and protective factors associated with disease progression to severe infection and viral clearance time in elderly Omicron-infected patients. Methods: Shanghai Fourth People's Hospital, School of Medicine, Tongji University, was officially designated to provide treatment to patients with COVID-19. This study was conducted on confirmed Omicron cases admitted to the hospital between 10 April 2022 and 21 June 2022. In total, 1,568 patients aged 65 years or older were included. We conducted a retrospective, observational study using logistic regression to analyze risk and protective factors for the development of severe disease and Cox proportional hazards regression models to analyze factors influencing viral clearance time. Results: Aged over 80 years, having 2 or more comorbidities, combined cerebrovascular disease, chronic neurological disease, and mental disorders were associated with the development of severe disease, and full vaccination was a protective factor. Furthermore, aged over 80 years, combined chronic respiratory disease, chronic renal disease, cerebrovascular disease, mental disorders, and high viral load were associated with prolonged viral clearance time, and full vaccination was a protective factor. Discussion: This study analyzed risk factors for progression to severe infection and prolonged viral clearance time in hospitalized elderly Omicron-infected patients. Aged patients with comorbidities had a higher risk of developing severe infection and had longer viral clearance, while vaccination protected them against the Omicron infection.

Neutralization of SARS-CoV-2 BA.2.86 and JN.1 by CF501 adjuvant-enhanced immune responses targeting the conserved epitopes in ancestral RBD.

The emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants BA.2.86 and JN.1 raise concerns regarding their potential to evade immune surveillance and spread globally. Here, we test sera from rhesus macaques immunized with 3 doses of wild-type SARS-CoV-2 receptor-binding domain (RBD)-Fc adjuvanted with the STING agonist CF501. We find that the sera can potently neutralize pseudotyped XBB.1.5, XBB.1.16, CH.1.1, EG.5, BA.2.86, and JN.1, with 50% neutralization titers ranging from 3,494 to 7,424. We also demonstrate that CF501, but not Alum, can enhance immunogenicity of the RBD from wild-type SARS-CoV-2 to improve induction of broadly neutralizing antibodies (bnAbs) with binding specificity and activity similar to those of SA55, BN03, and S309, thus exhibiting extraordinary broad-spectrum neutralizing activity. Overall, the RBD from wild-type SARS-CoV-2 also contains conservative epitopes. The RBD-Fc adjuvanted by CF501 can elicit potent bnAbs against JN.1, BA.2.86, and other XBB subvariants. This strategy can be adopted to develop broad-spectrum vaccines to combat future emerging and reemerging viral infectious diseases.

Development and validation of a prognostic model based on clinical laboratory biomarkers to predict admission to ICU in Omicron variant-infected hospitalized patients complicated with myocardial injury.

Aims: The aim of this study was to develop and validate a prognostic model based on clinical laboratory biomarkers for the early identification of high-risk patients who require intensive care unit (ICU) admission among those hospitalized with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and complicated with myocardial injury (MI). Methods: This single-center study enrolled 263 hospitalized patients with confirmed Omicron variant infection and concurrent MI. The patients were randomly divided into training and validation cohorts. Relevant variables were collected upon admission, and the least absolute shrinkage and selection operator (LASSO) was used to select candidate variables for constructing a Cox regression prognostic model. The model's performance was evaluated in both training and validating cohorts based on discrimination, calibration, and net benefit. Results: Of the 263 eligible patients, 210 were non-ICU patients and 53 were ICU patients. The prognostic model was built using four selected predictors: white blood cell (WBC) count, procalcitonin (PCT) level, C-reactive protein (CRP) level, and blood urea nitrogen (BUN) level. The model showed good discriminative ability in both the training cohort (concordance index: 0.802, 95% CI: 0.716-0.888) and the validation cohort (concordance index: 0.799, 95% CI: 0.681-0.917). For calibration, the predicted probabilities and observed proportions were highly consistent, indicating the model's reliability in predicting outcomes. In the 21-day decision curve analysis, the model had a positive net benefit for threshold probability ranges of 0.2 to 0.8 in the training cohort and nearly 0.2 to 1 in the validation cohort. Conclusion: In this study, we developed a clinically practical model with high discrimination, calibration, and net benefit. It may help to early identify severe and critical cases among Omicron variant-infected hospitalized patients with MI.

A study of clinical and serological correlation of early myocardial injury in elderly patients infected with the Omicron variant.

Introduction: Myocardial injury in elderly Omicron variant patients is a leading cause of severe disease and death. This study focuses on elucidating the clinical characteristics and potential risk factors associated with myocardial injury in elderly patients infected with the Omicron variant. Methods: Myocardial injury was defined based on elevated cardiac troponin concentrations exceeding the 99th percentile upper reference limit. Among 772 elderly Omicron-infected patients, categorized into myocardial injury (n = 263) and non-myocardial injury (n = 509) groups. The stratified log-rank statistic was used to compare the probability of patients developing intensive care. Receiver operating characteristic curves were used to determine the best cut-off values of clinical and laboratory data for predicting myocardial injury. Univariate and multivariate logistic regression was adopted to analyze the risk factors for myocardial injury. Results: The occurrence of myocardial injury in Omicron variant-infected geriatric patients was up to 34.07% and these patients may have a higher rate of requiring intensive care (P < 0.05). By comparing myocardial injury patients with non-myocardial injury patients, notable differences were observed in age, pre-existing medical conditions (e.g., hypertension, coronary heart disease, cerebrovascular disease, arrhythmia, chronic kidney disease, and heart failure), and various laboratory biomarkers, including cycle threshold-ORF1ab gene (Ct-ORF1ab), cycle threshold-N gene (Ct-N), white blood cell count, neutrophil (NEUT) count, NEUT%, lymphocyte (LYM) count, LYM%, and D-dimer, interleukin-6, procalcitonin, C-reactive protein, serum amyloid A, total protein, lactate dehydrogenase, aspartate aminotransferase, glomerular filtration rate, blood urea nitrogen, and serum creatinine (sCr) levels (P < 0.05). Furthermore, in the multivariable logistic regression, we identified potential risk factors for myocardial injury in Omicron variant-infected elderly patients, including advanced age, pre-existing coronary artery disease, interleukin-6 > 22.69 pg/ml, procalcitonin > 0.0435 ng/ml, D-dimer > 0.615 mg/L, and sCr > 81.30 µmol/L. Conclusion: This study revealed the clinical characteristics and potential risk factors associated with myocardial injury that enable early diagnosis of myocardial injury in Omicron variant-infected elderly patients, providing important reference indicators for early diagnosis and timely clinical intervention.

Early-life perfluorooctanoic acid exposure disrupts the function of dopamine transporter protein with glycosylation changes implicating the links between decreased dopamine levels and disruptive behaviors in larval zebrafish.

Exposure to perfluorooctanoic acid (PFOA) during early embryonic development is associated with the increased risk of developmental neurotoxicity and neurobehavioral disorders in children. In our previous study, we demonstrated that exposure to PFOA affected locomotor activity and disrupted dopamine-related gene expression in zebrafish larvae. Consequently, we continue to study the dopaminergic system with a focus on dopamine levels and dopamine's effect on behaviors in relation to PFOA exposure. In the present study, we found a decrease in dopamine levels in larval zebrafish. We studied the dopamine transporter (DAT) protein, which is responsible for regulating dopamine levels through the reuptake of dopamine in neuronal cells. We demonstrated that exposure to PFOA disrupted the glycosylation process of DAT, inhibited its uptake function, and induced endoplasmic reticulum (ER) stress in dopaminergic cells. Besides, we conducted a light-dark preference test on larval zebrafish and observed anxiety/depressive-like behavioral changes following exposure to PFOA. Dopamine is one of the most prominent neurotransmitters that significantly influences human behavior, with low dopamine levels being associated with impairments such as anxiety and depression. The anxiety-like response in zebrafish larvae exposure to PFOA implies the link with the reduced dopamine levels. Taken together, we can deduce that glycosylation changes in DAT lead to dysfunction of DAT to regulate dopamine levels, which in turn alters behavior in larval zebrafish. Therefore, alternation in dopamine levels may play a pivotal role in the development of anxiety/depressive-like behavioral changes induced by PFOA.

Water-stable hydrophilic metal organic framework composite for the recognition of N-glycopeptides during diabetes progression by mass spectrometry.

A hydrophilic Al-MOFs composite was prepared using cheap and available reagents in water via a suitable large-scale production, an economical and environment-friendly method for capturing N-glycopeptides. The prepared Al-MOFs composite with high hydrolytically stable and hydrophilic 1D channels exhibits an ultralow detection limit (0.5 fmol/µL), and excellent reusability (at least 10 cycles) in the capture of N-glycopeptides from standard bio-samples. Interestingly, the Al-MOFs composite also shows remarkable performance in practical applications, where 300 N-glycopeptides ascribed to 124 glycoproteins were identified in 1 µL human serum and were successfully applied in profiling the differences of N-glycopeptides during diabetes progression. Moreover, 12 specific glycoproteins used as biomarkers to accurately distinguish the progression of diabetes are identified. The present work provides a potential commercial method for large-scale glycoproteomics research in complex clinical samples while offering new guidance for the precise diagnosis of diabetes progression.

Hypoxia-induced circ-CDYL-EEF1A2 transcriptional complex drives lung metastasis of cancer stem cells from hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is often associated with poor outcomes due to lung metastasis. ICAM-1+ circulating tumor cells, termed circulating cancer stem cells (CCSCs), possess stem cell-like characteristics. However, it is still unexplored how their presence indicates lung metastasis tendency, and particularly, what mechanism drives their lung metastasis. Here, we demonstrated that a preoperative CCSC count in 5 mL of blood (CCSC5) of >3 was a risk factor for lung metastasis in clinical HCC patients. The CSCs overexpressed with circ-CDYL entered the bloodstream and developed lung metastases in mice. Mechanistically, circ-CDYL promoted COL14A1 expression and thus ERK signaling to facilitate epithelial-mesenchymal transition. Furthermore, we uncovered that an RNA-binding protein, EEF1A2, acted as a novel transcriptional (co-) factor to cooperate with circ-CDYL and initiate COL14A1 transcription. A high circ-CDYL level is caused by HIF-1⍺-mediated transcriptional upregulation of its parental gene CDYL and splicing factor EIF4A3 under a hypoxia microenvironment. Hence, the hypoxia microenvironment enables the high-tendency lung metastasis of ICAM-1+ CCSCs through the HIF-1⍺/circ-CDYL-EEF1A2/COL14A1 axis, potentially allowing clinicians to preoperatively detect ICAM-1+ CCSCs as a real-time biomarker for precisely deciding HCC treatment strategies.

Perfluorooctanoic acid disrupts thyroid-specific genes expression and regulation via the TSH-TSHR signaling pathway in thyroid cells.

Perfluorooctanoic acid (PFOA) is a highly persistent and widespread chemical in the environment with endocrine disruption effects. Although it has been reported that PFOA can affect multiple aspects of thyroid function, the exact mechanism by which it reduces thyroxine levels has not yet been elucidated. In this study, FRTL-5 rat thyroid follicular cells were used as a model to study the toxicity of PFOA to the genes related to thyroid hormone synthesis and their regulatory network. Our results reveal that PFOA interfered with the phosphorylation of the cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) induced by thyroid-stimulating hormone (TSH), as well as the transcription levels of paired box 8 (PAX8), thyroid transcription factor 1 (TTF1), sodium/iodide cotransporter (NIS), thyroglobulin (TG), and thyroid peroxidase (TPO). However, the above outcomes can be alleviated by enhancing cAMP production with forskolin treatment. Further investigations showed that PFOA reduced the mRNA level of TSH receptor (TSHR) and impaired its N-glycosylation, suggesting that PFOA has disrupting effects on both transcriptional regulation and post-translational regulation. In addition, PFOA increased endoplasmic reticulum (ER) stress and decreased ER mass in FRTL-5 cells. Based on these findings, it can be inferred that PFOA disrupts the TSH-activated cAMP signaling pathway by inhibiting TSHR expression and its N-glycosylation. We propose that this mechanism may contribute to the decrease in thyroid hormone levels caused by PFOA. Our study sheds light on the molecular mechanism by which PFOA can disrupt thyroid function and provides new insights and potential targets for interventions to counteract the disruptive effects of PFOA.

Serum Ferritin in Geriatric Individuals in the Shanghai Region: Distribution, Correlations, and Reference Intervals.

BACKGROUND: Serum ferritin levels have a clinical application in diagnosing diseases. However, the clinical standard levels and distribution characteristics of serum ferritin based on reference intervals (RIs) in the geriatric Han Chinese population in the East China region have not previously been well reported. This work aimed to investigate the correlation between serum ferritin levels and 14 metabolic markers, analyse the distribution of serum ferritin, and establish serum ferritin RIs for geriatric (> 60 years) individuals in Shanghai. METHODS: Four hundred and sixty-nine healthy Chinese Han subjects (age, 61 - 95 years; median, 71 years) were recruited from the Health Examination Center of Shanghai Fourth People's Hospital in 2021. Serum ferritin was measured on a Roche Cobas 8000 e602, and 14 biochemical parameters were measured on a Siemens Atellica CH-930 to analyse distributions and correlations and to establish serum ferritin RIs for the elderly population in Shanghai. RESULTS: Serum ferritin levels were significantly different between genders (p = 0.06). The established RIs for serum ferritin were 24.44 - 627.09 ng/mL and 48.18 - 554.88 ng/mL in males and females, respectively. Correlation analyses revealed that ferritin levels were correlated with 7 parameters, including body mass index (BMI, p = 0.02), gamma-glutamyl transferase (GGT, p < 0.01), alanine aminotransferase (ALT, p < 0.01), triglycerides (TGs, p < 0.01), high-density lipoprotein (HDL, p < 0.01), total protein (TP, p < 0.01) and prealbumin (PAB, p < 0.01). When the participants were further divided by BMI, aspartate aminotransferase (AST) was an additional variable that was positively correlated only in the overweight/obese group (p = 0.04), while globulin (GLO) was an additional variable that was positively correlated only in the other group (p < 0.01). CONCLUSIONS: Nutrition and metabolism may play a great role in the regulation of serum ferritin levels in geriatric individuals in vivo. The RIs established for serum ferritin may provide precise references for further studies on ferritin-related disease in geriatric individuals.

Biological effect abundance analysis of hemolytic pathogens based on engineered biomimetic sensor.

Conventional pathogen detection strategies based on the molecular structure or chemical characteristics of biomarkers can only provide the "physical abundance" of microorganisms, but cannot reflect the "biological effect abundance" in the true sense. To address this issue, we report an erythrocyte membrane-encapsulated biomimetic sensor cascaded with CRISPR-Cas12a (EMSCC). Taking hemolytic pathogens as the target model, we first constructed an erythrocyte membrane-encapsulated biomimetic sensor (EMS). Only hemolytic pathogens with biological effects can disrupt the erythrocyte membrane (EM), resulting in signal generation. Then the signal was amplified by cascading CRISPR-Cas12a, and more than 6.67 × 104-fold improvement in detection sensitivity compared to traditional erythrocyte hemolysis assay was achieved. Notably, compared with polymerase chain reaction (PCR) or enzyme linked immunosorbent assay (ELISA)-based quantification methods, EMSCC can sensitively respond to the pathogenicity change of pathogens. For the detection of simulated clinical samples based on EMSCC, we obtained an accuracy of 95% in 40 samples, demonstrating its potential clinical value.

Novel Three-Dimensional Hierarchical Porous Carbon Probe for the Discovery of N-Glycan Biomarkers and Early Hepatocellular Carcinoma Detection.

Due to the highly heterogeneous nature of hepatocellular carcinoma (HCC), the accurate diagnosis of HCC during the early phase of development is still a challenging task. Therefore, the further development of novel diagnostic methods by discovering new biomarkers is required to improve the rate of HCC diagnosis in the early phase. In this work, an oxygen-modified three-dimensional interconnected porous carbon probe is designed and fabricated to profile the differences of N-glycans in human serum from health controls (H) and patients with hepatic dysfunction (HD) and HCC for the discovery of new biomarkers with HCC development. Excitingly, we discovered that the expression levels of 12 serum N-glycans were gradually increased from H to patients with HD and eventually to patients with HCC. Moreover, two machine learning models established based on these 12 serum N-glycans reached a satisfactory accuracy for predicting HCC development where the receiver operating characteristic curve arrived above 0.95 for distinguishing healthy controls and patients with liver diseases (HD or HCC) and the ROC curve arrived at 0.85 for distinguishing HD and HCC. Our work not only developed a new method for the large-scale characterization of serum N-glycans but also provided valuable guidance for accurate and highly sensitive diagnosis of early liver cancer development in a non-invasive manner.

Naked-Eye Readout Distance Quantitative Lateral Flow Assay Based on the Permeability Changes of Enzyme-Catalyzed Hydrogelation.

Traditional lateral flow assay (LFA) is restricted to providing qualitative or semi-quantitative results and often requires special equipment for obtaining quantitative results. Herein, we proposed a naked-eye readout distance quantitative lateral flow assay based on the permeability changes in enzyme-catalyzed hydrogelation, which not only has the advantages of being simple, immediate, of high efficiency and low cost, and accurate in quantification but also avoids the use of special equipment. The developed LFA method includes three principal components of a nitrocellulose (NC) membrane containing a control line (C line) loading goat anti-rabbit (GAR) antibodies and a test line (T line) loading specific antibodies, alginate-tyramine conjugates forming a hydrogel in the presence of hydrogen peroxide (H2O2) and horseradish peroxidase (HRP), and the HRP-AuNPs-Ab probe only labeling targets captured on the T line. Hemoglobin A1c (HbA1c) was chosen as a representative example to demonstrate the feasibility of our method. Under the optimal conditions, the developed LFA method shows excellent performance in standard samples and real human blood samples where the results of real human blood samples show a high linear correlation with the clinical data obtained by ion exchange chromatography (R2 = 0.9929) and the margin of recovery is only 3.8%. All results demonstrated that our developed LFA method not only has enormous potential in the quantitative detection of HbA1c in clinical complex samples but also can serve as a versatile method for highly efficient detection of other target biomolecules due to the fungibility of antibodies.

Global Burden, Risk Factor Analysis, and Prediction Study of Ischemic Stroke, 1990-2030.

BACKGROUND AND OBJECTIVES: Ischemic stroke (IS), 1 of the 2 main subtypes of stroke, occurs because of brain ischemia caused by thrombosis of a cerebral blood vessel. IS is one of the most important neurovascular causes of death and disability. It is affected by many risk factors, such as smoking and a high body mass index (BMI), which are also critical in the preventive control of other cardiovascular and cerebrovascular diseases. However, there are still few systematic analyses of the current and predicted disease burden and the attributable risk factors of IS. METHODS: Based on the Global Burden of Disease 2019 database, we used age-standardized mortality rate and disability-adjusted life year to systematically present the geographical distribution and trends of IS disease burden worldwide from 1990 to 2019 by calculating the estimated annual percentage change and to analyze and predict the death number of IS accounted by 7 major risk factors for 2020-2030. RESULTS: Between 1990 and 2019, the global number of IS deaths increased from 2.04 million to 3.29 million and is expected to increase further to 4.90 million by 2030. The downward trend was more pronounced in women, young people, and high sociodemographic index (SDI) regions. At the same time, a study of attributable risk factors of IS found that 2 behavioral factors, smoking and diet in high sodium, and 5 metabolic factors, including high systolic blood pressure, high low-density lipoprotein cholesterol, kidney dysfunction, high fasting plasma glucose, and a high BMI, are major contributors to the increased disease burden of IS now and in the future. DISCUSSION: Our study provides the first comprehensive summary for the past 30 years and the prediction of the global burden of IS and its attributable risk factors until 2030, providing detailed statistics for decision-making on the prevention and control of IS globally. An inadequate control of the 7 risk factors would lead to an increased disease burden of IS in young people, especially in low SDI regions. Our study identifies high-risk populations and helps public health professionals develop targeted preventive strategies to reduce the global disease burden of IS.

SARS-CoV-2 Omicron XBB subvariants exhibit enhanced fusogenicity and substantial immune evasion in elderly population, but high sensitivity to pan-coronavirus fusion inhibitors.

Numerous emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants have shown significant immune evasion capacity and caused a large number of infections, as well as vaccine-breakthrough infections, especially in elderly populations. Recently emerged Omicron XBB was derived from the BA.2 lineage, but bears a distinct mutant profile in its spike (S) protein. In this study, we found that Omicron XBB S protein drove more efficient membrane-fusion kinetics on human lung-derived cells (Calu-3). Considering the high susceptibility of the elderly to the current Omicron pandemic, we performed a comprehensive neutralization assessment of elderly convalescent or vaccine sera against XBB infection. We found that the sera from elderly convalescent patients who experienced with BA.2 infection or breakthrough infection potently inhibited BA.2 infection, but showed significantly reduced efficacy against XBB. Moreover, recently emerged XBB.1.5 subvariant also showed more significant resistance to the convalescent sera of BA.2- or BA.5-infected elderly. On the other hand, we found that the pan-CoV fusion inhibitors EK1 and EK1C4 can potently block either XBB-S- or XBB.1.5-S-mediated fusion process and viral entry. Moreover, EK1 fusion inhibitor showed potent synergism when combined with convalescent sera of BA.2- or BA.5-infected patients against XBB and XBB.1.5 infection, further indicating that EK1-based pan-CoV fusion inhibitors are promising candidates for development as clinical antiviral agents to combat the Omicron XBB subvariants.

Development and validation of a prognostic model based on immune variables to early predict severe cases of SARS-CoV-2 Omicron variant infection.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has prevailed globally since November 2021. The extremely high transmissibility and occult manifestations were notable, but the severity and mortality associated with the Omicron variant and subvariants cannot be ignored, especially for immunocompromised populations. However, no prognostic model for specially predicting the severity of the Omicron variant infection is available yet. In this study, we aim to develop and validate a prognostic model based on immune variables to early recognize potentially severe cases of Omicron variant-infected patients. Methods: This was a single-center prognostic study involving patients with SARS-CoV-2 Omicron variant infection. Eligible patients were randomly divided into the training and validation cohorts. Variables were collected immediately after admission. Candidate variables were selected by three variable-selecting methods and were used to construct Cox regression as the prognostic model. Discrimination, calibration, and net benefit of the model were evaluated in both training and validation cohorts. Results: Six hundred eighty-nine of the involved 2,645 patients were eligible, consisting of 630 non-ICU cases and 59 ICU cases. Six predictors were finally selected to establish the prognostic model: age, neutrophils, lymphocytes, procalcitonin, IL-2, and IL-10. For discrimination, concordance indexes in the training and validation cohorts were 0.822 (95% CI: 0.748-0.896) and 0.853 (95% CI: 0.769-0.942). For calibration, predicted probabilities and observed proportions displayed high agreements. In the 21-day decision curve analysis, the threshold probability ranges with positive net benefit were 0~1 and nearly 0~0.75 in the training and validation cohorts, correspondingly. Conclusions: This model had satisfactory high discrimination, calibration, and net benefit. It can be used to early recognize potentially severe cases of Omicron variant-infected patients so that they can be treated timely and rationally to reduce the severity and mortality of Omicron variant infection.

SARS-CoV-2 Omicron subvariants exhibit distinct fusogenicity, but similar sensitivity, to pan-CoV fusion inhibitors.

Continuous emergence of the Omicron variant, along with its subvariants, has caused an increasing number of infections, reinfections, and vaccine-breakthrough infections, seriously threatening human health. Recently, several new Omicron subvariants, such as BA.5, BA.2.75, BA.4.6, and BF.7, bearing distinct mutation profiles in their spike (S) proteins, have significantly increased their capacity to evade vaccine-induced immunity and have shown enhanced infectivity and transmissibility, quickly becoming dominant sublineages. In this study, we found the S proteins of these Omicron subvariants to have 2- to 4-fold more efficient membrane fusion kinetics than that of the original Omicron variant (BA.1), indicating that these novel Omicron subvariants might possess increased pathogenicity. We also identified that peptide-based pan-CoV fusion inhibitors, EK1 and EK1C4, showed equal efficacy against membrane fusion mediated by S proteins of the noted Omicron subvariants and infection by their pseudoviruses. Additionally, either immune sera induced by wild-type (WT) SARS-CoV-2 RBD-based vaccine or BA.2 convalescent sera showed potent synergism with EK1 against both WT SARS-CoV-2 and various Omicron subvariants, further suggesting that EK1-based fusion inhibitors are promising candidates for development as clinical antiviral agents against the currently circulating Omicron subvariants.

The N6-methyladenosine modification enhances ferroptosis resistance through inhibiting SLC7A11 mRNA deadenylation in hepatoblastoma.

BACKGROUND: Solute carrier family 7 member 11 (SLC7A11) is overexpressed in multiple human tumours and functions as a transporter importing cystine for glutathione biosynthesis. It promotes tumour development in part by suppressing ferroptosis, a newly identified form of cell death that plays a pivotal role in the suppression of tumorigenesis. However, the role and underlying mechanisms of SLC7A11-mediated ferroptosis in hepatoblastoma (HB) remain largely unknown. METHODS: Reverse transcription quantitative real-time PCR (RT-qPCR) and western blotting were used to measure SLC7A11 levels. Cell proliferation, colony formation, lipid reactive oxygen species (ROS), MDA concentration, 4-HNE, GSH/GSSG ratio and cell death assays as well as subcutaneous xenograft experiments were used to elucidate the effects of SLC7A11 in HB cell proliferation and ferroptosis. Furthermore, MeRIP-qPCR, dual luciferase reporter, RNA pulldown, RNA immunoprecipitation (RIP) and RACE-PAT assays were performed to elucidate the underlying mechanism through which SLC7A11 was regulated by the m6A modification in HB. RESULTS: SLC7A11 expression was highly upregulated in HB. SLC7A11 upregulation promoted HB cell proliferation in vitro and in vivo, inhibiting HB cell ferroptosis. Mechanistically, SLC7A11 mRNA exhibited abnormal METTL3-mediated m6A modification, which enhanced its stability and expression. IGF2 mRNA-binding protein 1 (IGF2BP1) was identified as the m6A reader of SLC7A11, enhancing SLC7A11 mRNA stability and expression by inhibiting SLC7A11 mRNA deadenylation in an m6A-dependent manner. Moreover, IGF2BP1 was found to block BTG2/CCR4-NOT complex recruitment via competitively binding to PABPC1, thereby suppressing SLC7A11 mRNA deadenylation. CONCLUSIONS: Our findings demonstrated that the METTL3-mediated SLC7A11 m6A modification enhances HB ferroptosis resistance. The METTL3/IGF2BP1/m6A modification promotes SLC7A11 mRNA stability and upregulates its expression by inhibiting the deadenylation process. Our study highlights a critical role of the m6A modification in SLC7A11-mediated ferroptosis, providing a potential strategy for HB therapy through blockade of the m6A-SLC7A11 axis.

Perfluorooctanoic acid exposure increases both proliferation and apoptosis of human placental trophoblast cells mediated by ER stress-induced ROS or UPR pathways.

Perfluorooctanoate acid (PFOA) is a highly persistent and widespread chemical in the environment. PFOA serum levels in pregnant women are positively associated with an increased risk of placenta-related disorders. However, the mechanism of PFOA cytotoxicity involved in placental cells and cellular responses such as ER stress remains poorly understood. In this study, we studied the cellular toxicity of PFOA with a focus on proliferation and apoptosis in a human placental trophoblast cell line. Cell viability, number, apoptosis, stress response, activation of the involved signaling pathways were assessed. Our results showed PFOA affected cell viability, proliferation and also resulted in apoptosis. Besides, both pro-proliferation and pro-apoptosis effects were attenuated by endoplasmic reticulum (ER) stress inhibitors. Further experiments demonstrated that two different signaling pathways were activated by PFOA-induced ER stress and involved in PFOA toxicity: the reactive oxygen species (ROS)-dependent ERK signaling triggered trophoblast proliferation, while the ATF4-dependent C/EBP homologous protein (CHOP) signaling was the trigger of apoptosis. We conclude that PFOA-induced ER stress is the trigger of proliferation and apoptosis of trophoblast via ROS or UPR signaling pathway, which leads to the altered balance critical to the normal development and function of the placenta.