RESUMEN
Antibody-mediated immunity plays a key role in protection against SARS-CoV-2. We characterized B-cell-derived anti-SARS-CoV-2 RBD antibody repertoires from vaccinated and infected individuals and elucidate the mechanism of action of broadly neutralizing antibodies and dissect antibodies at the epitope level. The breadth and clonality of anti-RBD B cell response varies among individuals. The majority of neutralizing antibody clones lose or exhibit reduced activities against Beta, Delta, and Omicron variants. Nevertheless, a portion of anti-RBD antibody clones that develops after a primary series or booster dose of COVID-19 vaccination exhibit broad neutralization against emerging Omicron BA.2, BA.4, BA.5, BQ.1.1, XBB.1.5 and XBB.1.16 variants. These broadly neutralizing antibodies share genetic features including a conserved usage of the IGHV3-53 and 3-9 genes and recognize three clustered epitopes of the RBD, including epitopes that partially overlap the classically defined set identified early in the pandemic. The Fab-RBD crystal and Fab-Spike complex structures corroborate the epitope grouping of antibodies and reveal the detailed binding mode of broadly neutralizing antibodies. Structure-guided mutagenesis improves binding and neutralization potency of antibody with Omicron variants via a single amino-substitution. Together, these results provide an immunological basis for partial protection against severe COVID-19 by the ancestral strain-based vaccine and indicate guidance for next generation monoclonal antibody development and vaccine design.
Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , SARS-CoV-2/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Anticuerpos Neutralizantes/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Inmunización Secundaria , Epítopos/inmunología , Linfocitos B/inmunologíaRESUMEN
Echinatin is an active ingredient in licorice, a traditional Chinese medicine used in the treatment of inflammatory disorders. However, the protective effect and underlying mechanism of echinatin against acute lung injury (ALI) is still unclear. Herein, we aimed to explore echinatin-mediated anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated ALI and its molecular mechanisms in macrophages. In vitro, echinatin markedly decreased the levels of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-stimulated murine MH-S alveolar macrophages and RAW264.7 macrophages by suppressing inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) expression. Furthermore, echinatin reduced LPS-induced mRNA expression and release of interleukin-1ß (IL-1ß) and IL-6 in RAW264.7 cells. Western blotting and CETSA showed that echinatin repressed LPS-induced activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways through targeting transforming growth factor-beta-activated kinase 1 (TAK1). Furthermore, echinatin directly interacted with Kelch-like ECH-associated protein 1 (Keap1) and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to enhance heme oxygenase-1 (HO-1) expression. In vivo, echinatin ameliorated LPS-induced lung inflammatory injury, and reduced production of IL-1ß and IL-6. These findings demonstrated that echinatin exerted anti-inflammatory effects in vitro and in vivo, via blocking the TAK1-MAPK/NF-κB pathway and activating the Keap1-Nrf2-HO-1 pathway.
Asunto(s)
Lesión Pulmonar Aguda , Lipopolisacáridos , Quinasas Quinasa Quinasa PAM , Transducción de Señal , Animales , Masculino , Ratones , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/inducido químicamente , Antiinflamatorios/farmacología , Hemo-Oxigenasa 1/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Proteínas de la Membrana/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Células RAW 264.7 , Transducción de Señal/efectos de los fármacosRESUMEN
Proteins are fundamental to human physiology, with their targets being crucial in research and drug development. The identification and validation of crucial protein targets have become integral to drug development. Molecular docking is a computational tool widely utilized to investigate protein-ligand binding, especially in the context of drug and protein target interactions. For the experimental verification of the binding and to access the binding of the drug and its target directly, the cellular thermal shift assay (CETSA) method is used. This study aimed to integrate molecular docking with CETSA to predict and validate interactions between drugs and vital protein targets. Specifically, we predicted the interaction between xanthatin and Keap1 protein as well as its binding mode through molecular docking analysis, followed by verification of the interaction using the CETSA assay. Our results demonstrated that xanthatin could establish hydrogen bonds with specific amino acid residues of Keap1 protein and reduce the thermostability of Keap1 protein, indicating that xanthatin could directly interact with Keap1 protein.
Asunto(s)
Aminoácidos , Factor 2 Relacionado con NF-E2 , Humanos , Proteína 1 Asociada A ECH Tipo Kelch , Simulación del Acoplamiento Molecular , BioensayoRESUMEN
Recent investigations into heterochronic parabiosis have unveiled robust rejuvenating effects of young blood on aged tissues. However, the specific rejuvenating mechanisms remain incompletely elucidated. Here we demonstrate that small extracellular vesicles (sEVs) from the plasma of young mice counteract pre-existing aging at molecular, mitochondrial, cellular and physiological levels. Intravenous injection of young sEVs into aged mice extends their lifespan, mitigates senescent phenotypes and ameliorates age-associated functional declines in multiple tissues. Quantitative proteomic analyses identified substantial alterations in the proteomes of aged tissues after young sEV treatment, and these changes are closely associated with metabolic processes. Mechanistic investigations reveal that young sEVs stimulate PGC-1α expression in vitro and in vivo through their miRNA cargoes, thereby improving mitochondrial functions and mitigating mitochondrial deficits in aged tissues. Overall, this study demonstrates that young sEVs reverse degenerative changes and age-related dysfunction, at least in part, by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism.
Asunto(s)
Envejecimiento , Metabolismo Energético , Vesículas Extracelulares , Mitocondrias , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Animales , Vesículas Extracelulares/metabolismo , Metabolismo Energético/fisiología , Mitocondrias/metabolismo , Ratones , Envejecimiento/fisiología , Envejecimiento/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Proteómica/métodos , Ratones Endogámicos C57BL , MicroARNs/metabolismo , MicroARNs/genética , MasculinoRESUMEN
Objective: Malingering of neuropsychological damage is common among traumatic brain injury patients pursuing disability compensation in forensic contexts. There is an urgent need to explore differences in neuropsychological assessment outcomes with different levels of cooperation. Methods: A total of 420 participants with severe traumatic brain injury were classified into malingering group, partial cooperation group, and complete cooperation group according to the Binomial forced-choice digit memory test. The Wechsler Adult Intelligence Scale, event-related potential component, and Symptom Checklist 90 were applied subsequently to assess the psychological status of participants. Results: Participants in the malingering group presented lower scores in the binomial forced-choice digit memory test and the Wechsler Adult Intelligence Scale, lower P3 amplitude, and simultaneously higher scores in the Symptom Checklist 90 than the other two groups. The actual intelligence quotient of participants with malingering tendencies ranged mostly between normal and marginal damage, and they often reported elevated whole scale scores in the Symptom Checklist 90. The Cooperation Index (defined as the ratio of positive symptom distress index to global severity index, CI) was proposed and validated to function as an embedded validity indicator of the Symptom Checklist 90, and the area under the receiver operating characteristic (ROC) curve was 0.938. When valued at 1.28, CI has the highest classification ability in differentiating malingering from non-malingering. Combined with the CI and P3 amplitude, the area under the ROC curve for malingering diagnosis further reached 0.952. Conclusion: Any non-optimal effort in a forensic context will lead to unexpected deviation in psychology evaluation results. CI is a potential candidate to act as an embedded validity indicator of the Symptom Checklist 90. The combination of CI and P3 amplitude can help to identify malingering in participants after severe traumatic brain injury.
RESUMEN
Hydroxyl radicals (OH) determine the tropospheric self-cleansing capacity, thus regulating air quality and climate. However, the state-of-the-art mechanisms still underestimate OH at low nitrogen oxide and high volatile organic compound regimes even considering the latest isoprene chemistry. Here we propose that the reactive aldehyde chemistry, especially the autoxidation of carbonyl organic peroxy radicals (R(CO)O2) derived from higher aldehydes, is a noteworthy OH regeneration mechanism that overwhelms the contribution of the isoprene autoxidation, the latter has been proved to largely contribute to the missing OH source under high isoprene condition. As diagnosed by the quantum chemical calculations, the R(CO)O2 radicals undergo fast H-migration to produce unsaturated hydroperoxyl-carbonyls that generate OH through rapid photolysis. This chemistry could explain almost all unknown OH sources in areas rich in both natural and anthropogenic emissions in the warm seasons, and may increasingly impact the global self-cleansing capacity in a future low nitrogen oxide society under carbon neutrality scenarios.
RESUMEN
Solid-state nanopores have wide applications in DNA sequencing, energy conversion and storage, seawater desalination, sensors, and reactors due to their high stability, controllable geometry, and a variety of pore-forming materials. Solid-state nanopore sensors can be used for qualitative and quantitative analyses of ions, small molecules, proteins, and nucleic acids. The combination of nucleic acid amplification and solid-state nanopores to achieve trace detection of analytes is gradually attracting attention. This review outlines nucleic acid amplification strategies for enhancing the sensitivity of solid-state nanopore sensors by summarizing the articles published in the past 10 years. The future development prospects and challenges of nucleic acid amplification in solid-state nanopore sensors are discussed. This review helps readers better understand the field of solid-state nanopore sensors. We believe that solid-state nanopore sensors will break through the bottleneck of traditional detection and become a powerful single-molecule detection platform.
Asunto(s)
Nanoporos , Ácidos Nucleicos , Ácidos Nucleicos/análisis , Nanotecnología , Proteínas , Técnicas de Amplificación de Ácido NucleicoRESUMEN
BACKGROUND: Systemic inflammatory response syndrome (SIRS) greatly affects postoperative lives of afflicted aged patients. This study aimed to determine whether preoperative high hs-CRP/HDL ratio (CHR) was associated with an increased risk of postoperative SIRS in the elderly population. METHODS: This retrospective cohort study included data on patients aged ≥ 65 years who underwent general anesthesia surgery at two clinical centers between January 2015 and September 2020. The primary exposure was preoperative CHR which was divided into two groups (≤ 12.82 and > 12.82) based on its normal range in our hospital, and the primary outcome was the incidence of postoperative SIRS. Targeted maximum likelihood estimation analyses were used to model the exposure-outcome relationship. RESULTS: The analysis included 5595 elderly patients, of whom 1410 (25.20%) developed SIRS within three postoperative days. Targeted maximum likelihood estimation analysis revealed that elderly patients with CHR > 12.82 vs. CHR ≤ 12.82 was associated with increased risk of postoperative SIRS (aOR = 1.40, 95% CI [1.33, 1.48], P < 0.001). Those results were consistent both in subgroup analyses and sensitivity analyses. Compared with patients with CHR ≤ 12.82, patients with CHR > 12.82 had a higher prevalence of postoperative SIRS (49.06% vs. 22.70%), postoperative in-hospital mortality (3.40% vs. 0.65%), a longer hospital stay after surgery [10 (IQR, 6-16) vs. 8 (IQR, 5-11) days] and higher direct medical cost [10070 (IQR, 6878-15577) vs. 7117 (IQR, 4079-10314) euros, all P < 0.001]. CONCLUSIONS: In elderly patients, preoperative CHR > 12.82 was significantly associated with a higher risk of postoperative SIRS.
Asunto(s)
Proteína C-Reactiva , Síndrome de Respuesta Inflamatoria Sistémica , Humanos , Anciano , Síndrome de Respuesta Inflamatoria Sistémica/epidemiología , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Proteína C-Reactiva/análisis , Estudios Retrospectivos , Complicaciones Posoperatorias/etiología , IncidenciaRESUMEN
BACKGROUND: Acute lung injury (ALI) is an acute inflammatory disease characterized by excess production of inflammatory factors in lung tissue and has a high mortality. This research was designed for the identification of novel diagnostic biomarkers for ALI and analyzing the possible association between critical genes and infiltrated immune cells. METHODS: The study used 2 datasets (GSE2411 and GSE18341) to identify differentially expressed genes (DEGs) between 2 groups. Then we performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses to identify the functions of these DEGs. The study also used SVM-recursive feature elimination analysis and least absolute shrinkage and selection operator regression model to screen possible markers. The study further analyzed immune cell infiltration via CIBERSORT. Gene Set Enrichment Analysis was used to explore the molecular mechanism of the critical genes. RESULTS: DEGs were identified between 2 groups. In total, 690 DEGs were obtained: 527 genes were upregulated and 163 genes were downregulated. We identified PDZK1IP1, CCKAR, and CXCL2 as critical genes. And we then found that these critical genes correlated with Mast Cells, Neutrophil Cells, M1 Macrophage, dendritic cell Actived, Eosinophil Cells, B Cells Naive, Mast Cells, and dendritic cell Immature. Furthermore, we investigated the specific signaling pathways involved in key genes and derived some potential molecular mechanisms by which key genes affect disease progression by use of Gene Set Enrichment Analysis. Moreover, we predict transcription factors. Also, we obtained critical gene-related microRNAs through the targetscan database, and visualized the microRNA network of the genes. CONCLUSION: Our findings might provide some novel clue for the exploration of novel markers for ALI diagnosis. The critical genes and their associations with immune infiltration may offer new insight into understanding ALI developments.
Asunto(s)
Lesión Pulmonar Aguda , MicroARNs , Humanos , Lesión Pulmonar Aguda/diagnóstico , Lesión Pulmonar Aguda/genética , Biomarcadores , Biología Computacional , Aprendizaje AutomáticoRESUMEN
The groundwater quality impacts associated with anthropogenic groundwater recharge (AGR) are of great concern for water management. However, the impacts of AGR on the molecular properties of dissolved organic matter (DOM) in aquifers are poorly understood. Herein, Fourier transform ion cyclotron resonance mass spectrometry was used to unravel the molecular characteristics of DOM in groundwaters from recharge areas by reclaimed water (RWRA) and natural water from South-to-North Water Diversion Project (SNWRA). Compared with RWRA groundwater, significantly fewer nitrogenous compounds, more sulfur-containing compounds, higher concentrations of NO3-N, and lower pH were observed in SNWRA groundwater, indicating the occurrence of deamination, sulfurization, and nitrification. The occurrence of these processes was further supported by transformations of more molecules related to nitrogen and sulfur in SNWRA groundwater relative to RWRA groundwater. The intensities of most common molecules in all samples were significantly correlated with the water quality indicators (e.g., Cl- and NO3-N) and fluorescent indicators (e.g., humic-like components (C1%)), indicating that those common molecules may have the potential to track the environmental impact of AGR on groundwater, especially these specific molecules having great mobility and being significantly correlated with other inert tracers like C1% and Cl-. This study is helpful to understand the environmental risks and regional applicability of AGR.
Asunto(s)
Materia Orgánica Disuelta , Agua Subterránea , Agua Subterránea/química , Calidad del Agua , Compuestos de AzufreRESUMEN
The oxidation of the emerging nanomaterial black phosphorus (BP) affected by pH and oxygen has been carefully documented. However, in natural waters, there is a large amount of chemically reactive organic matters like fulvic acid (FA), whose impacts on degradation and stability of few-layer BP or BP nanosheets (BPNS) are scarcely disclosed. Hence, we investigated the kinetics of BPNS degradation products (H2PO2-, HPO32-, and PO43-) in the presence of FA. The results showed that the apparent reaction rate constants of BPNS were 0.026, 0.050, and 0.060 d-1 under oxygen-and-light condition and 0.005, 0.016, and 0.023 d-1 under hypoxia-and-darkness condition at FA gradients of 0, 2.5, and 5 mgC/L, respectively. Microscopic observations, simple molecular simulation experiment, and density functional theory computation explained that FA significantly enhanced the degradation of P atoms on the BPNS surface through the indirect pathway of reducing the energy barrier of O2 dissociative adsorption and the direct pathway of chemical adsorption, which caused the P-P bond on the BPNS surface to break down and formed P-O bonds or C-P bonds. This study revealed for the first time the degradation mechanism of BPNS in the presence of FA, which is a chemical mechanism of the BPNS transformation behavior. It helps to make a more scientific risk assessment of BP in natural waters.
Asunto(s)
Nanoestructuras , Fósforo , Fósforo/química , Benzopiranos/química , OxígenoAsunto(s)
COVID-19 , Epidemias , Humanos , Condiciones Sociales , COVID-19/epidemiología , Medios de Comunicación de MasasRESUMEN
The synthesis of the cell-wall peptidoglycan during bacterial cell division is mediated by a multiprotein machine, called the divisome. The essential membrane protein complex of FtsB, FtsL and FtsQ (FtsBLQ) is at the heart of the divisome assembly cascade in Escherichia coli. This complex regulates the transglycosylation and transpeptidation activities of the FtsW-FtsI complex and PBP1b via coordination with FtsN, the trigger for the onset of constriction. Yet the underlying mechanism of FtsBLQ-mediated regulation is largely unknown. Here, we report the full-length structure of the heterotrimeric FtsBLQ complex, which reveals a V-shaped architecture in a tilted orientation. Such a conformation could be strengthened by the transmembrane and the coiled-coil domains of the FtsBL heterodimer, as well as an extended ß-sheet of the C-terminal interaction site involving all three proteins. This trimeric structure may also facilitate interactions with other divisome proteins in an allosteric manner. These results lead us to propose a structure-based model that delineates the mechanism of the regulation of peptidoglycan synthases by the FtsBLQ complex.
Asunto(s)
Proteínas de Escherichia coli , Proteínas de Escherichia coli/metabolismo , Proteínas de Ciclo Celular/metabolismo , Peptidoglicano/metabolismo , Proteínas de la Membrana/metabolismo , División Celular , Escherichia coli/metabolismo , Proteínas Bacterianas/metabolismoRESUMEN
Significant progress is made in drug delivery systems, but they still face problems such as poor stability in vivo, off-target drugs, and difficulty in crossing biological barriers. It is urgent to realize efficient targeted delivery and precisely controlled sustained release of drugs by using the integrated nanoplatform. Theranostic nanoplatform is a new biomedical technology that combines diagnosis or monitoring of diseases with treatment. Here, an integrated strategy of diagnosis and treatment is reported for delivering NIR-II imaged and therapeutic AgAuSe quantum dots (QDs) carried by peptidoglycan multilayer networks of bacteria to hitchhike circulating neutrophils for targeting the tumor. The assembled nanomaterials have good stability, which can not only initiate endogenous cells for drug delivery and achieve efficient targeting, but also guide drug imaging with excellent fluorescence property. Meanwhile, the elimination of established solid tumor is achieved with the administration of sonodynamic therapy without recurrence. This drug system expands the application of endogenous cell to participate in drug delivery system. Thus, the assembly strategy demonstrates the potential of endogenous neutrophils in functioning as natural drug vehicles and the application of NIR-II fluorescent QDs in biomedical engineering.
Asunto(s)
Nanopartículas , Neoplasias , Puntos Cuánticos , Humanos , Peptidoglicano , Neutrófilos/patología , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológicoRESUMEN
Objective: Little is known about the effect of age at first childbirth on lung function. We aimed to investigate the association between age at first childbirth and lung function in Chinese women and further test whether this association is mediated by body mass index (BMI). Methods: This cross-sectional study is a partial survey of the China Kadoorie Biobank (CKB) which was conducted in Xinxiang City, Henan Province between 2004 and 2008. A total of 16,584 postmenopausal women aged 30-79 years were enrolled. Multiple linear and logistic regression were used to investigate the association between age at first childbirth and lung function and overweight/obesity. The mediation analysis was performed using the PROCESS procedure for SPSS. Results: The mean (SD) age at first childbirth was 23.1 (2.7) years. Women with first childbirth aged ≤19 years and 20-22 years had lower lung function than women who gave first childbirth aged 23-25 years. Per 1-year increase in the age at first childbirth was associated with a 3.31 mL increase in FEV1 (95% CI = 1.27-5.35), 3.91 mL increase in FVC (95% CI = 1.63-6.18), 0.15% increase in FEV1, % predicted (95% CI = 0.05-0.24) and 0.14% increase in FVC, % predicted (95% CI = 0.05-0.22). There was no clear association between age at first childbirth and FEV1/FVC ratio. BMI played a contribution to the association between age at first childbirth and FEV1 and the proportion was 16.4% (indirect effect: ß = 0.65, 95% CI = 0.46-0.89; total effect: ß = 3.96, 95% CI = 1.92-5.99). Similarly, the proportion to FVC, FEV1, % predicted, and FVC, % predicted was 25.0%, 16.6%, and 25.0%, respectively. Conclusion: Early age at first childbirth was associated with lower lung function and BMI mediated the association. It is important to test lung function and popularize the knowledge of weight control in women who gave first childbirth at an early age.
RESUMEN
BACKGROUND: Acute respiratory distress syndrome (ARDS) is a respiratory condition caused by severe endothelial barrier dysfunction within the lung. In ARDS, excessive inflammation, tissue edema, and immune cell influx prevents endothelial cell regeneration that is crucial in repairing the endothelial barrier. However, little is known about the molecular mechanism that underpin endothelial cell regeneration in ARDS. METHODS: R-based bioinformatics tools were used to analyze microarray-derived transcription profiles in human lung microvascular endothelial cells (HLMVECs) subjected to non-treatment or lipopolysaccharide (LPS) exposure. We generated endothelial cell-specific interferon regulatory factor 1 (Irf1) knockout (Irf1EC-/-) and Irf1fl/fl control mice for use in an endotoxemic murine model of acute lung injury (ALI). In vitro studies (qPCR, immunoblotting, and ChIP-qPCR) were conducted in mouse lung endothelial cells (MLECs) and HLMVECs. Dual-luciferase promoter reporter assays were performed in HLMVECs. RESULTS: Bioinformatics analyses identified IRF1 as a key up-regulated gene in HLMVECs post-LPS exposure. Endothelial-specific knockout of Irf1 in ALI mice resulted in enhanced regeneration of lung endothelium, while liposomal delivery of endothelial-specific Irf1 to wild-type ALI mice inhibited lung endothelial regeneration in a leukemia inhibitory factor (Lif)-dependent manner. Mechanistically, we demonstrated that LPS-induced Stat1Ser727 phosphorylation promotes Irf1 transactivation, resulting in downstream up-regulation of Lif that inhibits endothelial cell proliferation. CONCLUSIONS: These results demonstrate the existence of a p-Stat1Ser727-Irf1-Lif axis that inhibits lung endothelial cell regeneration post-LPS injury. Thus, direct inhibition of IRF1 or LIF may be a promising strategy for enhancing endothelial cell regeneration and improving clinical outcomes in ARDS patients.
Asunto(s)
Lesión Pulmonar Aguda , Factor 1 Regulador del Interferón , Síndrome de Dificultad Respiratoria , Animales , Humanos , Ratones , Lesión Pulmonar Aguda/inducido químicamente , Células Endoteliales , Endotelio , Inflamación/tratamiento farmacológico , Factor 1 Regulador del Interferón/genética , Lipopolisacáridos/farmacología , Pulmón , Ratones Endogámicos C57BL , Regeneración , Ratones NoqueadosRESUMEN
CONTEXT: Evidence about the effect of age at menarche (AAM) on blood pressure (BP) has largely been drawn from studies in developed countries. Studies in developing countries are expanding recently but have not been summarised. OBJECTIVE: To systematically explore the association between AAM and BP and the potential modifiers in developing countries. METHODS: We searched PubMed, Embase, and Web of Science for publications until March 2022. A random-effects model was used to calculate the pooled relative risk (RR) with 95% confidence interval (CI). RESULTS: Twenty studies were eligible. In studies with participants' mean age at BP assessment <55 years, women in the oldest group as compared with the middle or the youngest group of AAM had a higher risk of hypertension in those studies without adjustment for confounders (RR 1.79, 95% CI 1.41-2.28, I2=97.0%), those with adjustment for confounders excluding adiposity (1.25,1.04-1.51, I2=84.8%), and those with adjustment for confounders including adiposity (1.38,1.03-1.86, I2=91.8%). In studies with participants' mean age at BP assessment ≥55 years, no significant differences were found for studies without adjustment for confounders (RR 1.07, 95% CI 0.78-1.47, I2=90.3%), studies with adjustment for confounders excluding adiposity (0.85, 0.78-0.92, I2=12.3%), or studies with adjustment for confounders including adiposity (0.95, 0.80-1.11, I2=45.5%). A similar association was observed between AAM and baseline systolic BP and diabolic BP. CONCLUSION: Late menarche was associated with a higher risk of BP and this association was modified by age and adiposity in developing countries.
Asunto(s)
Hipertensión , Menarquia , Adulto , Humanos , Femenino , Persona de Mediana Edad , Menarquia/fisiología , Presión Sanguínea , Factores de Riesgo , Países en Desarrollo , Hipertensión/epidemiología , Hipertensión/etiología , ObesidadRESUMEN
BACKGROUND AND AIM: Small ubiquitin-like modifier (SUMO)-specific protease (SENP)3 is a protease molecule that responds to reactive oxygen species (ROS) with high sensitivity. However, the role of ROS and SENP3 in the formation of nasal polyps (NPs) remains unclear. This study aimed to explore how SENP3 influenced the outcome of chronic rhinosinusitis (CRS) by altering macrophage function, that is, the formation of NPs. METHODS: The alternative activation of macrophage (M2) was detected with CD68+ CD206+ in humans and CD206+ in mice. The nasal mucosa of patients with CRS was tested using flow cytometry (CD68, CD80, and CD206) and triple-color immunofluorescence staining (CD68, CD206, and SENP3). The bone marrow-derived macrophages from SENP3 knockout and control mice were stimulated with interleukin (IL)-4 and IL-13 to analyze alternative macrophage polarization in vitro. An animal model of allergic rhinitis was constructed using SENP3 knockout mice. CD206 was detected by immunofluorescence staining. The thickening of eosinophil-infiltrated mucosa was detected by Luna staining. RESULTS: The number of CD68+ CD206+ M2 increased in the nasal mucosa of patients with CRS with NP (CRSwNP) compared with patients with CRS without NP (CRSsNP), but with no significant difference between the groups. SENP3 knockout increased the polarization of F4/80+ CD206+ M2. Meanwhile, the number of CD206+ M2 significantly increased in the allergic rhinitis model constructed using SENP3 knockout mice and controls, with a more obvious proliferation of the nasal mucosa. CONCLUSION: Downregulation of SENP3 promotes the formation of nasal polyps mediated by increasing alternative activated macrophage in nasal mucosal inflammation.
Asunto(s)
Pólipos Nasales , Rinitis Alérgica , Rinitis , Humanos , Animales , Ratones , Especies Reactivas de Oxígeno , Mucosa Nasal , Macrófagos , Péptido Hidrolasas , Inflamación , Cisteína EndopeptidasasRESUMEN
Antibody-mediated immunity plays a crucial role in protection against SARS-CoV-2 infection. We isolated a panel of neutralizing anti-receptor-binding domain (RBD) antibodies elicited upon natural infection and vaccination and showed that they recognize an immunogenic patch on the internal surface of the core RBD, which faces inwards and is hidden in the "down" state. These antibodies broadly neutralize wild type (Wuhan-Hu-1) SARS-CoV-2, Beta and Delta variants and some are effective against other sarbecoviruses. We observed a continuum of partially overlapping antibody epitopes from lower to upper part of the inner face of the RBD and some antibodies extend towards the receptor-binding motif. The majority of antibodies are substantially compromised by three mutational hotspots (S371L/F, S373P and S375F) in the lower part of the Omicron BA.1, BA.2 and BA.4/5 RBD. By contrast, antibody IY-2A induces a partial unfolding of this variable region and interacts with a conserved conformational epitope to tolerate all antigenic variations and neutralize diverse sarbecoviruses as well. This finding establishes that antibody recognition is not limited to the normal surface structures on the RBD. In conclusion, the delineation of functionally and structurally conserved RBD epitopes highlights potential vaccine and therapeutic candidates for COVID-19.