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BACKGROUND: Abdominal aortic aneurysm (AAA) is a severe aortic disease without effective pharmacological approaches. The nuclear hormone receptor LXRα (liver X receptor α), encoded by the NR1H3 gene, serves as a critical transcriptional mediator linked to several vascular pathologies, but its role in AAA remains elusive. METHODS: Through integrated analyses of human and murine AAA gene expression microarray data sets, we identified NR1H3 as a candidate gene regulating AAA formation. To investigate the role of LXRα in AAA formation, we used global Nr1h3-knockout and vascular smooth muscle cell-specific Nr1h3-knockout mice in 2 AAA mouse models induced with angiotensin II (1000 ng·kg·min; 28 days) or calcium chloride (CaCl2; 0.5 mol/L; 42 days). RESULTS: Upregulated LXRα was observed in the aortas of patients with AAA and in angiotensin II- or CaCl2-treated mice. Global or vascular smooth muscle cell-specific Nr1h3 knockout inhibited AAA formation in 2 mouse models. Loss of LXRα function prevented extracellular matrix degeneration, inflammation, and vascular smooth muscle cell phenotypic switching. Uhrf1, an epigenetic master regulator, was identified as a direct target gene of LXRα by integrated analysis of transcriptome sequencing and chromatin immunoprecipitation sequencing. Susceptibility to AAA development was consistently enhanced by UHRF1 (ubiquitin-like containing PHD and RING finger domains 1) in both angiotensin II- and CaCl2-induced mouse models. We then determined the CpG methylation status and promoter accessibility of UHRF1-mediated genes using CUT&Tag (cleavage under targets and tagmentation), RRBS (reduced representation bisulfite sequencing), and ATAC-seq (assay for transposase-accessible chromatin with sequencing) in vascular smooth muscle cells, which revealed that the recruitment of UHRF1 to the promoter of miR-26b led to DNA hypermethylation accompanied by relatively closed chromatin states, and caused downregulation of miR-26b expression in AAA. Regarding clinical significance, we found that underexpression of miR-26b-3p correlated with high risk in patients with AAA. Maintaining miR-26b-3p expression prevented AAA progression and alleviated the overall pathological process. CONCLUSIONS: Our study reveals a pivotal role of the LXRα/UHRF1/miR-26b-3p axis in AAA and provides potential biomarkers and therapeutic targets for AAA.
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Aneurisma da Aorta Abdominal , Proteínas Estimuladoras de Ligação a CCAAT , Epigênese Genética , Receptores X do Fígado , Camundongos Knockout , MicroRNAs , Ubiquitina-Proteína Ligases , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Animais , Receptores X do Fígado/metabolismo , Receptores X do Fígado/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Camundongos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Masculino , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Metilação de DNA , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Angiotensina II/farmacologiaRESUMO
Coronaviruses (CoVs) pose a major threat to human and animal health worldwide, which complete viral replication by hijacking host factors. Identifying host factors essential for the viral life cycle can deepen our understanding of the mechanisms of virus-host interactions. Based on our previous genome-wide CRISPR screen of α-CoV transmissible gastroenteritis virus (TGEV), we identified the host factor dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), but not DYRK1B, as a critical factor in TGEV replication. Rescue assays and kinase inhibitor experiments revealed that the effect of DYRK1A on viral replication is independent of its kinase activity. Nuclear localization signal modification experiments showed that nuclear DYRK1A facilitated virus replication. Furthermore, DYRK1A knockout significantly downregulated the expression of the TGEV receptor aminopeptidase N (ANPEP) and inhibited viral entry. Notably, we also demonstrated that DYRK1A is essential for the early stage of TGEV replication. Transmission electron microscopy results indicated that DYRK1A contributes to the formation of double-membrane vesicles in a kinase-independent manner. Finally, we validated that DYRK1A is also a proviral factor for mouse hepatitis virus, porcine deltacoronavirus, and porcine sapelovirus. In conclusion, our work demonstrated that DYRK1A is an essential host factor for the replication of multiple viruses, providing new insights into the mechanism of virus-host interactions and facilitating the development of new broad-spectrum antiviral drugs.IMPORTANCECoronaviruses, like other positive-sense RNA viruses, can remodel the host membrane to form double-membrane vesicles (DMVs) as their replication organelles. Currently, host factors involved in DMV formation are not well defined. In this study, we used transmissible gastroenteritis virus (TGEV) as a virus model to investigate the regulatory mechanism of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) on coronavirus. Results showed that DYRK1A significantly inhibited TGEV replication in a kinase-independent manner. DYRK1A knockout (KO) can regulate the expression of receptor aminopeptidase N (ANPEP) and endocytic-related genes to inhibit virus entry. More importantly, our results revealed that DYRK1A KO notably inhibited the formation of DMV to regulate the virus replication. Further data proved that DYRK1A is also essential in the replication of mouse hepatitis virus, porcine deltacoronavirus, and porcine sapelovirus. Taken together, our findings demonstrated that DYRK1A is a conserved factor for positive-sense RNA viruses and provided new insights into its transcriptional regulation activity, revealing its potential as a candidate target for therapeutic design.
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Infecções por Coronavirus , Coronavirus , Quinases Dyrk , Animais , Humanos , Camundongos , Antígenos CD13/genética , Coronavirus/classificação , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Deltacoronavirus , Vírus da Hepatite Murina/fisiologia , Suínos , Vírus da Gastroenterite Transmissível/genética , Tirosina , Replicação Viral/fisiologia , Quinases Dyrk/metabolismoRESUMO
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and characterized by dysregulated immune response. Studies have shown that the SARS-CoV-2 accessory protein ORF7b induces host cell apoptosis through the tumor necrosis factor alpha (TNF-α) pathway and blocks the production of interferon beta (IFN-ß). The underlying mechanism remains to be investigated. In this study, we found that ORF7b facilitated viral infection and production, and inhibited the RIG-I-like receptor (RLR) signaling pathway through selectively interacting with mitochondrial antiviral-signaling protein (MAVS). MAVS439-466 region and MAVS Lys461 were essential for the physical association between MAVS and ORF7b, and the inhibition of the RLR signaling pathway by ORF7b. MAVSK461/K63 ubiquitination was essential for the RLR signaling regulated by the MAVS-ORF7b complex. ORF7b interfered with the recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) and the activation of the RLR signaling pathway by MAVS. Furthermore, interfering peptides targeting the ORF7b complex reversed the ORF7b-suppressed MAVS-RLR signaling pathway. The most potent interfering peptide V disrupts the formation of ORF7b tetramers, reverses the levels of the ORF7b-inhibited physical association between MAVS and TRAF6, leading to the suppression of viral growth and infection. Overall, this study provides a mechanism for the suppression of innate immunity by SARS-CoV-2 infection and the mechanism-based approach via interfering peptides to potentially prevent SARS-CoV-2 infection.IMPORTANCEThe pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and continues to be a threat to public health. It is imperative to understand the biology of SARS-CoV-2 infection and find approaches to prevent SARS-CoV-2 infection and ameliorate COVID-19. Multiple SARS-CoV-2 proteins are known to function on the innate immune response, but the underlying mechanism remains unknown. This study shows that ORF7b inhibits the RIG-I-like receptor (RLR) signaling pathway through the physical association between ORF7b and mitochondrial antiviral-signaling protein (MAVS), impairing the K63-linked MAVS polyubiquitination and its recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) to MAVS. The most potent interfering peptide V targeting the ORF7b-MAVS complex may reverse the suppression of the MAVS-mediated RLR signaling pathway by ORF7b and prevent viral infection and production. This study may provide new insights into the pathogenic mechanism of SARS-CoV-2 and a strategy to develop new drugs to prevent SARS-CoV-2 infection.
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Proteínas Adaptadoras de Transdução de Sinal , COVID-19 , SARS-CoV-2 , Transdução de Sinais , Animais , Humanos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose , COVID-19/virologia , COVID-19/imunologia , COVID-19/metabolismo , Proteína DEAD-box 58/metabolismo , Células HEK293 , Imunidade Inata , Interferon beta/metabolismo , Receptores Imunológicos/metabolismo , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitinação , Proteínas Virais Reguladoras e Acessórias/metabolismo , Proteínas Virais Reguladoras e Acessórias/genéticaRESUMO
BACKGROUND: According to the 5th edition of the Japanese Guidelines for the Treatment of Gastric Cancer, proximal gastrectomy is recommended for patients with early upper gastric cancer who can retain the distal half of the residual stomach after R0 resection. However, a large number of recent clinical studies suggest that surgical indications for proximal gastrectomy in the guidelines may be too narrow. Therefore, this meta-analysis included patients with early and advanced gastric cancer and compared short- and long-term postoperative outcomes between the two groups. At the same time, we only had high-quality clinical studies such as propensity score-matched studies and randomized controlled trials, which made our research more authentic and credible. METHODS: Data were retrieved from PubMed, EMBASE, Medline, and Cochrane Library up to June 2023, and included treatment outcomes after proximal gastrectomy with double-tract reconstruction and total gastrectomy with Roux-en-Y reconstruction. The primary results were Early-phase complications(Anastomotic leakage, Anastomotic bleeding, Abdominal abscess, Abdominal infection, Pulmonary infection, Incision infection, Intestinal obstruction, Dumping syndrome, Pancreatic fistula), Late-phase complications(Intestinal obstruction, Anastomosis stricture, Dumping syndrome, Reoperation, Internal hernia, Incidence of endoscopic gastroesophageal reflux), Serious complications (≥ Grade III C-D score), Quality of life[Gastroesophageal reflux symptom evaluation (Visick score)(≥ III), Los Angeles classification(C or D)], Nutritional status(Hemoglobin, Receipt of vitamin B12 supplementation), Oncologic Outcomes(The 5-year overall survival rates). Secondary outcomes were surgical outcomes (Operative time, Estimated blood loss, Postoperative hospital stay, Number of harvested lymph nodes, Gas-passing, Postoperative mortality).The Cochrane risk-of-bias tool and NewcastleâOttawa scale were used to assess the quality of the included studies. RESULTS: After screening, 11 studies were finally included, including 1154 patients. Results from the combined literature showed that total gastrectomy had a significant advantage over proximal gastrectomy with double-tract reconstruction in mean operating time (MD = 4.92, 95% CI: 0.22â¼9.61 P = 0.04). However, meta-analysis results showed that Hemoglobin (MD = 7.12, 95% CI:2.40â¼11.84, P = 0.003) and Receipt of vitamin B12 supplementation (OR = 0.12, 95% CI:0.05â¼0.26, P < 0.00001) in the proximal gastrectomy with double-tract reconstruction group were better than those in the total gastrectomy with Roux-en-Y reconstruction group. There is no significant difference between the proximal gastrectomy with double-tract reconstruction and the total gastrectomy with Roux-en-Y reconstruction group in Early-phase complications(OR = 1.14,95% CI:0.79â¼1.64, P = 0.50), Late-phase complications(OR = 1.37,95% CI:0.78â¼2.39, P = 0.27), Gastroesophageal reflux symptom evaluation (Visick score)(≥ III)(OR = 0.94,95% CI:0.14â¼1.07 P = 0.07), Los Angeles classification(C or D)(OR = 0.33,95% CI:0.01â¼8.21, P = 0.50), the 5-year overall survival rates (HR = 1.01, 95% CI: 0.83 ~ 1.23, P = 0.89). CONCLUSION: Proximal gastrectomy with double-tract anastomosis is a safe and feasible treatment for upper gastric carcinoma. However, the operating time was slightly longer in the proximal gastrectomy with double-tract group compared to the total gastrectomy with Roux-en-Y group. The two groups were comparable to the total gastrectomy with Roux-en-Y group in terms of serious complications (≥ Grade III C-D score), early-phase complications, late-phase complications, and quality of life. Although the scope of proximal gastrectomy is smaller than that of total gastrectomy, it does not affect the 5-year survival rate, indicating good tumor outcomes for patients. Compared to total gastrectomy with Roux-en-Y group, proximal gastrectomy with double-tract reconstruction had higher hemoglobin levels, lower probability of vitamin B12 supplementation, and better long-term efficacy. In conclusion, proximal gastrectomy with double-tract reconstruction is considered one of the more rational surgical approaches for upper gastric cancer.
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Gastrectomia , Complicações Pós-Operatórias , Pontuação de Propensão , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Gástricas , Gastrectomia/métodos , Gastrectomia/efeitos adversos , Humanos , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/mortalidade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Anastomose em-Y de Roux/métodos , Anastomose em-Y de Roux/efeitos adversos , Resultado do Tratamento , Qualidade de Vida , Procedimentos de Cirurgia Plástica/métodosRESUMO
BACKGROUND: Invasive pneumococcal disease (IPD) is a significant health concern in children worldwide. In this study, we aimed to analyze the clinical features, antibiotic resistance, and risk variables for poor outcomes in patients with IPD in Hangzhou. METHODS: A retrospective single-centre study was performed using the pediatric intensive care (PIC) database from 2010 to 2018. The clinical characteristics, laboratory data, antimicrobial resistance, and risk factors for in-hospital mortality and sepsis in patients with IPD in intensive care units (ICUs) were analyzed systematically. RESULTS: A total of 178 IPD patients were included in the study. The majority of the IPD children were 2-10 years old. Antimicrobial resistance tests of S. pneumoniae isolates revealed high resistance to erythromycin, tetracycline and compound sulfamethoxazole (SMZ-Co). All the isolates were sensitive to vancomycin, linezolid, moxifloxacin, telithromycin, ofloxacin, and levofloxacin. IPD patients may experience poor outcomes, including death and sepsis. The in-hospital mortality was 3.93%, and 34.27% of patients suffered from sepsis. Temperature (OR 3.80, 95% CI 1.62-8.87; P = 0.0021), Partial Pressure of Oxygen in Arterial Blood (PaO2) (OR 0.99, 95% CI 0.98-1.00; P = 0.0266), and albumin (OR 0.89, 95% CI 0.80-0.99; P = 0.0329) were found to be independent risk factors for sepsis in children with IPD. CONCLUSION: Pediatric IPD deserves attention in China. Appropriate surveillance and antibiotic selection are crucial in managing resistant strains. Early identification of high-risk individuals with risk factors contributes to the development of appropriate treatment strategies.
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Antibacterianos , Mortalidade Hospitalar , Infecções Pneumocócicas , Streptococcus pneumoniae , Humanos , China/epidemiologia , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/tratamento farmacológico , Infecções Pneumocócicas/mortalidade , Infecções Pneumocócicas/epidemiologia , Criança , Masculino , Fatores de Risco , Estudos Retrospectivos , Feminino , Pré-Escolar , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/isolamento & purificação , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Lactente , Testes de Sensibilidade Microbiana , Sepse/microbiologia , Sepse/tratamento farmacológico , Sepse/mortalidade , Sepse/epidemiologia , Adolescente , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Farmacorresistência BacterianaRESUMO
BACKGROUND: Feline calicivirus (FCV) infection causes severe upper respiratory disease in cats, but there are no effective vaccines available for preventing FCV infection. Subunit vaccines have the advantages of safety, low cost and excellent immunogenicity, but no FCV subunit vaccine is currently available. The CDE protein is the dominant neutralizing epitope region of the main antigenic structural protein of FCV, VP1. Therefore, this study evaluated the effectiveness of the CDE region as a truncated FCV VP1 protein in preventing FCV infection to provide a strategy for developing potential FCV subunit vaccines. RESULTS: Through the prediction of FCV VP1 epitopes, we found that the E region is the dominant neutralizing epitope region. By analysing the spatial structure of VP1 protein, 13 amino acid sites in the CD and E regions were found to form hydrogen bonding interactions. The results show the presence of these interaction forces supports the E region, helping improve the stability and expression level of the soluble E protein. Therefore, we selected the CDE protein as the immunogen for the immunization of felines. After immunization with the CDE protein, we found significant stimulation of IgG, IgA and neutralizing antibody production in serum and swab samples, and the cytokine TNF-α levels and the numbers of CD4+ T lymphocytes were increased. Moreover, a viral challenge trial indicated that the protection generated by the CDE subunit vaccine significantly reduced the incidence of disease in animals. CONCLUSIONS: For the first time, we studied the efficacy of the CDE protein, which is the dominant neutralizing epitope region of the FCV VP1 protein, in preventing FCV infection. We revealed that the CDE protein can significantly activate humoral, mucosal and cellular immunity, and the resulting protective effect can significantly reduce the incidence of animal disease. The CDE region of the FCV capsid is easy to produce and has high stability and excellent immunogenicity, which makes it a candidate for low-cost vaccines.
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Calicivirus Felino , Animais , Gatos , Vacinas de Subunidades Antigênicas , Aminoácidos , Citocinas , EpitoposRESUMO
BACKGROUND: The cholinergic anti-inflammatory pathway (CAP) has been widely studied to modulate the immune response. Current stimulating strategies are invasive or imprecise. Noninvasive low-intensity pulsed ultrasound (LIPUS) has become increasingly appreciated for targeted neuronal modulation. However, its mechanisms and physiological role on myocarditis remain poorly defined. METHODS: The mouse model of experimental autoimmune myocarditis was established. Low-intensity pulsed ultrasound was targeted at the spleen to stimulate the spleen nerve. Under different ultrasound parameters, histological tests and molecular biology were performed to observe inflammatory lesions and changes in immune cell subsets in the spleen and heart. In addition, we evaluated the dependence of the spleen nerve and cholinergic anti-inflammatory pathway of low-intensity pulsed ultrasound in treating autoimmune myocarditis in mice through different control groups. RESULTS: The echocardiography and flow cytometry of splenic or heart infiltrating immune cells revealed that splenic ultrasound could alleviate the immune response, regulate the proportion and function of CD4+ Treg and macrophages by activating cholinergic anti-inflammatory pathway, and finally reduce heart inflammatory injury and improve cardiac remodeling, which is as effective as an acetylcholine receptor agonists GTS-21. Transcriptome sequencing showed significant differential expressed genes due to ultrasound modulation. CONCLUSIONS: It is worth noting that the ultrasound therapeutic efficacy depends greatly on acoustic pressure and exposure duration, and the effective targeting organ was the spleen but not the heart. This study provides novel insight into the therapeutic potentials of LIPUS, which are essential for its future application.
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Miocardite , Animais , Camundongos , Miocardite/terapia , Miocardite/patologia , Baço/patologia , Ultrassonografia , Modelos Animais de DoençasRESUMO
Rechargeable aqueous zinc-ion batteries (AZIBs) are among the most promising candidates for next-generation energy-storage devices. However, the large voltage polarisation and infamous dendrite growth hinder the practical application of AZIBs owing to their complex interfacial electrochemical environment. In this study, a hydrophobic zinc chelate-capped nano-silver (HZC-Ag) dual interphase is fabricated on the zinc anode surface using an emulsion-replacement strategy. The multifunctional HZC-Ag layer remodels the local electrochemical environment by facilitating the pre-enrichment and de-solvation of zinc ions and inducing homogeneous zinc nucleation, thus resulting in reversible dendrite-free zinc anodes. The zinc deposition mechanism on the HZC-Ag interphase is elucidated by density functional theory (DFT) calculations, dual-field simulations, and in situ synchrotron X-ray radiation imaging. The HZC-Ag@Zn anode exhibited superior dendrite-free zinc stripping/plating performance and an excellent lifespan of >2000 h with ultra-low polarisation of ≈17 mV at 0.5 mA cm-2 . Full cells coupled with a MnO2 cathode showed significant self-discharge inhibition, excellent rate performance, and improved cycling stability for >1000 cycles. Therefore, this multifunctional dual interphase may contribute to the design and development of dendrite-free anodes for high-performance aqueous metal-based batteries.
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Emerging coronaviruses (CoVs) pose a severe threat to human and animal health worldwide. To identify host factors required for CoV infection, we used α-CoV transmissible gastroenteritis virus (TGEV) as a model for genome-scale CRISPR knockout (KO) screening. Transmembrane protein 41B (TMEM41B) was found to be a bona fide host factor involved in infection by CoV and three additional virus families. We found that TMEM41B is critical for the internalization and early-stage replication of TGEV. Notably, our results also showed that cells lacking TMEM41B are unable to form the double-membrane vesicles necessary for TGEV replication, indicating that TMEM41B contributes to the formation of CoV replication organelles. Lastly, our data from a mouse infection model showed that the KO of this factor can strongly inhibit viral infection and delay the progression of a CoV disease. Our study revealed that targeting TMEM41B is a highly promising approach for the development of broad-spectrum anti-viral therapeutics.
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Sistemas CRISPR-Cas , Gastroenterite Suína Transmissível/virologia , Interações Hospedeiro-Patógeno , Proteínas de Membrana/fisiologia , Organelas/virologia , Vírus da Gastroenterite Transmissível/fisiologia , Replicação Viral , Animais , Gastroenterite Suína Transmissível/genética , Gastroenterite Suína Transmissível/transmissão , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , SuínosRESUMO
Spin and orbital angular momenta are two of the most fundamental physical quantities that describe the complex dynamic behaviors of optical fields. A strong coupling between these two quantities leads to many intriguing spatial topological phenomena, where one remarkable example is the generation of a helicity-dependent optical vortex that converts spin to orbital degrees of freedom. The spin-to-orbit conversion occurs inherently in lots of optical processes and has attracted increasing attention due to its crucial applications in spin-orbit photonics. However, current researches in this area are mainly focused on the monochromatic optical fields whose temporal properties are naturally neglected. In this work, we demonstrate an intriguing temporal evolution of the spin-to-orbit conversion induced by tightly-focused femtosecond optical fields. The results indicate that the conversion in such a polychromatic focused field obviously depends on time. This temporal effect originates from the superposition of local fields at the focus with different frequencies and is sensitive to the settings of pulse width and central wavelength. This work can provide fundamental insights into the spin-orbit dynamics within ultrafast wave packets, and possesses the potential for applications in spin-controlled manipulations of light.
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BACKGROUND: Left atrial reservoir strain (LARS) is an early sensor of left ventricular (LV) diastolic dysfunction. Still, the clinical implications of LARS in patients with well-functioning bicuspid aortic valve (BAV) remain unknown. MATERIALS: The study recruited 103 patients with well-functioning BAV and 50 controls with tricuspid aortic valves. LARS, LV global longitudinal strain (LVGLS) and aortic elasticity indices (aortic strain, aortic distensibility and stiffness index) were acquired. This study aimed to analyze the changes of LARS and further explore the influential factors of LARS in patients with well-functioning BAV. RESULTS: Patients with BAV had lower LARS (34.17 ± 4.85 vs. 44.72 ± 6.06 %, P < .001) and LVGLS (20.53 ± 1.28 vs. 22.30 ± .62 %, P < .001), and abnormal aortic elasticity indices (aortic strain:7.14 ± 1.57 vs. 10.99 ± 1.03 %, aortic distensibility: 5.82 ± 1.50 vs. 8.98 ± 2.42 (10-6 cm2 dyne-1 ), and stiffness index: 6.30 ± 2.30 vs. 3.92 ± .98, all P < .05) compared with controls. LARS was associated with LVGLS (r = .799), interventricular septum index (r = -.232), lateral e' (r = .290), septal e' (r = .308), E/e' ratio (r = -.392), aortic strain (r = .829), aortic distensibility (r = .361), and stiffness index (r = -.724) (all P < .05). LVGLS, aortic strain and E/e' ratio were independent influencers of LARS in the multifactorial analysis model (all P < .05). CONCLUSION: In patients with well-functioning BAV, decreased LARS may provide evidence of subclinical LV diastolic function impairment. LARS may be helpful for clinical risk stratification in such a population.
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Fibrilação Atrial , Doença da Válvula Aórtica Bicúspide , Doenças das Valvas Cardíacas , Rigidez Vascular , Disfunção Ventricular Esquerda , Humanos , Valva Aórtica/diagnóstico por imagem , Disfunção Ventricular Esquerda/diagnóstico por imagemRESUMO
BACKGROUND: At present, there is no convincing evidence-based medical basis for the efficacy of single-port laparoscopic gastrectomy. To make a high-quality comparison of the short- and long-term outcomes of single-port laparoscopic gastrectomy versus multiport laparoscopic gastrectomy, we performed this meta-analysis, which only included propensity score-matched studies and randomized controlled trials comparing single-port laparoscopic gastrectomy with multiport laparoscopic gastrectomy for patients with gastric cancer. METHODS: Data were retrieved from the electronic databases PubMed, EMBASE, Medline, Cochrane Library, CNKI, Wanfang and VIP up to January 2023, and the data included the outcomes of treatment after single-port laparoscopic gastrectomy and multiport laparoscopic gastrectomy. The primary outcomes were early complications, survival rate after surgery at 1 year, and survival rate after surgery at 5 years. The secondary outcomes were number of pain medications, mean operation time, estimated blood loss, hospital mortality, time to first soft fluid diet, time to first flatus, hospital stay after surgery, and retrieved number of lymph nodes. The Jadad score and NewcastleâOttawa scale were used to assess the quality of the included studies. RESULTS: After screening, 9 studies were finally included, including 988 patients. The meta-analysis results showed that estimated blood loss (MD=-29.35, 95% CI: -42.95-15.75, P < 0.0001), hospital stay (MD=-0.99, 95% CI:-1.82~-0.17, P = 0.02), and number of pain medications(MD=-0.65, 95% CI:-1.07~-0.23, P = 0.002) in the single-port laparoscopic gastrectomy group were better than those in the multiport laparoscopic gastrectomy group. There is no significant difference between the single-port laparoscopic gastrectomy group and the multiport laparoscopic gastrectomy group in mean operation time(MD = 5.23,95% CI:-16.58~27.04,P = 0.64), time to first soft fluid diet(MD=-0.06,95% CI: -0.30~0.18,P = 0.63), time to first flatus(MD=-0.18,95% CI:-0.43~0.07,P = 0.16), early complication(OR = 0.73,95% CI:0.50~1.09,P = 0.12), hospital mortality(OR = 1.00,95% CI:0.09~11.16,P = 1.00), retrieved number of lymph nodes(MD=-1.15, 95% CI:-2.71~0.40, P = 0.15), survival rate after surgery 1 year(OR = 2.14,95% CI:0.50~9.07,P = 0.30), and survival rate after surgery 5 year(93.7 vs. 87.6%; p = 0.689). CONCLUSION: This meta-analysis showed that single-port laparoscopic gastrectomy is both safe and feasible for laparoscopic radical gastrectomy for gastric cancer, with similar operation times and better short-term outcomes than multiport laparoscopic gastrectomy in terms of hospital stay, postoperative pain, and estimated blood loss. There was no significant difference in long-term outcomes between single-port laparoscopic gastrectomy and multiport laparoscopic gastrectomy.
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Laparoscopia , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Flatulência/cirurgia , Pontuação de Propensão , Ensaios Clínicos Controlados Aleatórios como Assunto , Laparoscopia/métodos , Dor Pós-Operatória/cirurgia , Gastrectomia/métodos , Resultado do Tratamento , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/cirurgiaRESUMO
Nanocarriers have been widely studied and applied in the field of cancer treatment. However, conventional nanocarriers still suffer from complicated preparation processes, low drug loading, and potential toxicity of carriers themselves. To tackle the hindrance, carrier-free nanodrugs with biological activity have received increasing attention in cancer therapy. Extensive efforts have been made to exploit new self-assembly methods and mechanisms to expand the scope of carrier-free nanodrugs with enhanced therapeutic performance. In this review, we summarize the advanced progress and applications of carrier-free nanodrugs based on different types of assembly mechanisms and strategies, which involved noncovalent interactions, a combination of covalent bonds and noncovalent interactions, and metal ions-coordinated self-assembly. These carrier-free nanodrugs are introduced in detail according to their assembly and antitumor applications. Finally, the prospects and existing challenges of carrier-free nanodrugs in future development and clinical application are discussed. We hope that this comprehensive review will provide new insights into the rational design of more effective carrier-free nanodrug systems and advancing clinical cancer and other diseases (e.g., bacterial infections) infection treatment.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Portadores de Fármacos/química , Fotoquimioterapia/métodos , Nanopartículas/uso terapêutico , Nanopartículas/químicaRESUMO
BACKGROUND: Selenium rich bread is a good carrier of selenium, but the inorganic selenium used in the actual production process is toxic. It is necessary to develop a new green bread production technology. The extraction and utilization of humic acid chelated selenium from selenium-rich soil is beneficial for reducing resource waste and pollution without destroying the soil ecosystem in selenium-deficient areas. Sodium selenite and nanoselenium were selected as controls because they are commonly used as selenium agronomic enhancers in production. RESULTS: Humic acid chelated selenium can be absorbed and accumulated by wheat leaves, and humic acid chelated selenium had no significant effect on wheat yield, which was also shown in the treatments with nanoselenium and sodium selenite. Excessive accumulation of selenium in wheat grains can lead to a deterioration of processing quality. Among them, the use of excessive nanoselenium at the filling stage inhibited the accumulation of wheat grain protein, whereas humic acid chelated selenium is beneficial to grain protein accumulation and has the least negative effect on the processing quality. The accumulation of excessive selenium in wheat seeds had a negative effect on seed germination and growth; specifically, the seed vigor of wheat treated with humic acid chelated selenium was higher than that of untreated wheat. CONCLUSION: Humic acid chelated selenium is particularly suitable for the whole process of Se-enriched bread wheat production. The seed vigour of wheat treated with humic acid chelated selenium, which supplied a moderate amount of selenium, was higher than that of untreated wheat. Conversely, the accumulation of excessive selenium in wheat seeds reduced germination and seedling growth. © 2023 Society of Chemical Industry.
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Proteínas de Grãos , Selênio , Selênio/metabolismo , Selenito de Sódio/metabolismo , Substâncias Húmicas , Triticum/metabolismo , Biofortificação , Ecossistema , SoloRESUMO
Porcine epidemic diarrhea virus (PEDV) is an enteric pathogen in the swine industry, causing high mortality in neonatal piglets. Efficient PEDV infection usually relies on the presence of trypsin, yet the mechanism of trypsin dependency is ambiguous. Here, we identified two PEDV strains, trypsin-enhanced YN200 and trypsin-independent DR13, in which the spike (S) protein of YN200 exhibits a stronger ability to induce syncytium formation and cleaved by trypsin than that of DR13. Using a full-length infectious YN200 cDNA clone, we confirmed that the S protein is a trypsin dependency determinant by comparison of rYN200 and rYN200-SDR13 To explore the trypsin-associated sites of the YN200 S protein, we then constructed a series of mutations adjacent to the fusion peptide. The results show that the putative S2' cleavage site (R892G) is not the determinant for virus trypsin dependency. Hence, we generated viruses carrying chimeric S proteins: the S1 subunit, S2 subunit, and S2720â¼892 aa domain (NS2') were individually replaced by the corresponding DR13 sequences. Intriguingly, only the S2 substitution, not the S1 or NS2' substitutions, provides trypsin-independent growth of YN200. Additionally, the NS2' recombinant virus significantly abrogated effective infection, indicating a vital role for NS2' in viral entry. These findings suggest that the trypsin dependency of PEDV is mainly controlled by mutations in the S2 subunit rather than directly trypsin cleavage site.ImportanceWith the emergence of new variants, PEDV remains a major problem in the global swine industry. Efficient PEDV infection usually requires trypsin, while the mechanism of trypsin dependency is complex. Here, we used two PEDV strains, trypsin-enhanced YN200 and trypsin-independent DR13, and results showed that the S protein determined PEDV trypsin dependency by using a reverse genetic system of YN200. The S2 subunit was verified as the main portion of PEDV trypsin dependency, though the putative S2' site mutation cannot render trypsin-independent growth of YN200. Finally, these results provide some different insight to the PEDV trypsin dependency and might inspire vaccine development.
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Coronaviruses that infect humans belong to the Alpha-coronavirus (including HCoV-229E) and Beta-coronavirus (including SARS-CoV and SARS-CoV-2) genera. In particular, SARS-CoV-2 is currently a major threat to public health worldwide. The spike (S) homotrimers bind to their receptors via the receptor-binding domain (RBD), which is a major target to block viral entry. In this study, we selected Alpha-coronavirus (HCoV-229E) and Beta-coronavirus (SARS-CoV and SARS-CoV-2) as models. Their RBDs exist two different conformational states (lying or standing) in the prefusion S-trimer structure. Then, the differences in the immune responses to RBDs from these coronaviruses were analyzed structurally and immunologically. Our results showed that more RBD-specific antibodies (antibody titers: 1.28×105; 2.75×105) were induced by the S-trimer with the RBD in the "standing" state (SARS-CoV and SARS-CoV-2) than the S-trimer with the RBD in the "lying" state (HCoV-229E, antibody titers: <500), and more S-trimer-specific antibodies were induced by the RBD in the SARS-CoV and SARS-CoV-2 (antibody titers: 6.72×105; 5×105) than HCoV-229E (antibody titers:1.125×103). Besides, we found that the ability of the HCoV-229E RBD to induce neutralizing antibodies was lower than S-trimer, and the intact and stable S1 subunit was essential for producing efficient neutralizing antibodies against HCoV-229E. Importantly, our results reveal different vaccine strategies for coronaviruses, and S-trimer is better than RBD as a target for vaccine development in Alpha-coronavirus Our findings will provide important implications for future development of coronavirus vaccines.Importance Outbreak of coronaviruses, especially SARS-CoV-2, poses a serious threat to global public health. Development of vaccines to prevent the coronaviruses that can infect humans has always been a top priority. Coronavirus spike (S) protein is considered as a major target for vaccine development. Currently, structural studies have shown that Alpha-coronavirus (HCoV-229E) and Beta-coronavirus (SARS-CoV and SARS-CoV-2) RBDs are in "lying" and "standing" states in the prefusion S-trimer structure. Here, we evaluated the ability of S-trimer and RBD to induce neutralizing antibodies among these coronaviruses. Our results showed that the S-trimer and RBD are both candidates for subunit vaccines in Beta-coronavirus (SARS-CoV and SARS-CoV-2) with a RBD "standing" state. However, for Alpha-coronavirus (HCoV-229E) with a RBD "lying" state, the S-trimer may be more suitable for subunit vaccines than the RBD. Our results will provide novel ideas for the development of vaccines targeting S protein in the future.
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In recent years, singular optical beams, including optical vortex (OV) beams with phase singularities and cylindrical vector beams (CVBs) with polarization singularities, have brought new degrees of freedom for many applications. Although there have been various microscale devices for OV detection, the detection of CVBs with a microscale device is still a challenge. Here, we propose a new method for detection of CVBs with a designed on-chip plasmonic spin-Hall metalens structure. The focal position of the metalens and the splitting effect of at focus are studied in both an analytical model and numerical simulation. The results demonstrate that the metalens can not only detect different polarization orders of incident CVBs but also have an ability to distinguish radial, azimuthal and other vectorial polarization states under the same order of CVBs. This method has potential applications in compact integrated optical communication and processing systems.
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SARS-CoV-2 infection, which is the cause of the COVID-19 pandemic, has expanded across various animal hosts, and the virus can be transmitted particularly efficiently in minks. It is still not clear how SARS-CoV-2 is selected and evolves in its hosts, or how mutations affect viral fitness. In this report, sequences of SARS-CoV-2 isolated from human and animal hosts were analyzed, and the binding energy and capacity of the spike protein to bind human ACE2 and the mink receptor were compared. Codon adaptation index (CAI) analysis indicated the optimization of viral codons in some animals such as bats and minks, and a neutrality plot demonstrated that natural selection had a greater influence on some SARS-CoV-2 sequences than mutational pressure. Molecular dynamics simulation results showed that the mutations Y453F and N501T in mink SARS-CoV-2 could enhance the binding of the viral spike to the mink receptor, indicating the involvement of these mutations in natural selection and viral fitness. Receptor binding analysis revealed that the mink SARS-CoV-2 spike interacted more strongly with the mink receptor than the human receptor. Tracking the variations and codon bias of SARS-CoV-2 is helpful for understanding the fitness of the virus in virus transmission, pathogenesis, and immune evasion.
Assuntos
Uso do Códon , Adaptação ao Hospedeiro , SARS-CoV-2 , Animais , Humanos , Quirópteros/genética , COVID-19/virologia , Adaptação ao Hospedeiro/genética , Vison/genética , Pandemias , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Seleção Genética/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Uso do Códon/genéticaRESUMO
Stimulants have become the most popular psychopharmacologic drugs used in therapy for attention-deficit/hyperactivity disorder (ADHD). Childhood and adolescence are crucial periods for optimizing bone health to prevent osteoporosis-related fractures in old age. However, controversy remains regarding the relationship between stimulant use and bone health. The present study was designed to examine the bone mineral content (BMC) and bone mineral density (BMD) of 5472 individuals aged 8-16 years with or without stimulant use based on National Health and Nutrition Examination Survey (NHANES) 2011-2018 data and to further assess the association between stimulant use and bone health. Among these, 284 (5.2%) participants were using stimulants. In analyses stratified by sex, the BMC and BMD at the level of the lumbar spine, pelvis, and total body were generally lower among stimulant users than among nonusers in males (all P < 0.001), while the differences were not statistically significant in females. In multivariable linear regression models, the increasing range of BMCs and BMDs with age was lower in participants using stimulants than in those not using stimulants after fully adjusting for potential confounding factors. Compared to participants not using stimulants, stimulant use ≥ 3 months was associated with significantly lower BMCs [lumbar spine: ß = - 1.35, (95% CI: - 2.56, - 0.14); pelvis: ß = - 9.06, (95% CI: - 15.21, - 2.91); and total: ß = - 52.96, (95% CI: - 85.87, - 20.04)] and BMDs [pelvis: ß = - 0.03, (95% CI: - 0.04, - 0.01), total: ß = - 0.01, (95% CI: - 0.02, - 0.00)]. CONCLUSIONS: Children and adolescents using stimulants exhibited reductions in BMC and BMD at the lumbar spine, pelvis, and total body compared to those who were not using stimulants, especially among males. WHAT IS KNOWN: ⢠Childhood and adolescence are crucial periods for optimizing bone health to prevent osteoporosis-related fractures in old age. ⢠Controversy remains regarding the relationship between stimulant use and bone health. WHAT IS NEW: ⢠The bone mineral content and bone mineral density at the level of the lumbar spine, pelvis, and total body were generally lower among stimulant users than among nonusers in males, while the differences were not statistically significant in females. ⢠Body mass index and serum alkaline phosphatase may be predictors for loss of bone mineral content and bone mineral density in stimulant users.
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Densidade Óssea , Osso e Ossos , Absorciometria de Fóton , Adolescente , Criança , Feminino , Humanos , Vértebras Lombares , Masculino , Inquéritos NutricionaisRESUMO
OBJECTIVE: Managing critically ill patients with high mortality can be difficult for clinicians in pediatric intensive care units (PICU), which need to identify appropriate predictive biomarkers. The lactate/albumin (L/A) ratio can precisely stratify critically ill adults. However, the role of the L/A ratio in predicting the outcomes of critically ill children remains unclear. Therefore, this study aimed to evaluate the prognostic performance of the L/A ratio in predicting in-hospital mortality in unselected critically ill patients in the PICU. METHODS: This was a single-center retrospective study. Clinical data of 8,832 critical patients aged between 28 days and 18 years were collected from the pediatric intensive care (PIC) database from 2010 to 2018. The primary outcome was the in-hospital mortality rate. RESULTS: There was a higher level of L/A ratio in non-survivors than survivors (P < 0.001). Logistic regression indicated that the association between the L/A ratio and in-hospital mortality was statistically significant (OR 1.44, 95% CI 1.31-1.59, P < 0.001). The AUROC of the L/A ratio for predicting in-hospital mortality was higher than lactate level alone (0.74 vs 0.70, P < 0.001). Stratification analysis showed a significant association between the L/A ratio and in-hospital mortality in the age and primary disease groups (P < 0.05). CONCLUSIONS: Our study suggested that the L/A ratio was a clinical tool to predict in-hospital mortality in critically ill children better than lactate level alone. However, given that the study was retrospective, more prospective studies should be conducted to test the predictive value of the L/A ratio in critical illness.