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Atmospheric metal enrichment (that is, elements heavier than helium, also called 'metallicity') is a key diagnostic of the formation of giant planets1-3. The giant planets of the Solar System show an inverse relationship between mass and both their bulk metallicities and atmospheric metallicities. Extrasolar giant planets also display an inverse relationship between mass and bulk metallicity4. However, there is significant scatter in the relationship and it is not known how atmospheric metallicity correlates with either planet mass or bulk metallicity. Here we show that the Saturn-mass exoplanet HD 149026b (refs. 5-9) has an atmospheric metallicity 59-276 times solar (at 1σ), which is greater than Saturn's atmospheric metallicity of roughly 7.5 times solar10 at more than 4σ confidence. This result is based on modelling CO2 and H2O absorption features in the thermal emission spectrum of the planet measured by the James Webb Space Telescope. HD 149026b is the most metal-rich giant planet known, with an estimated bulk heavy element abundance of 66 ± 2% by mass11,12. We find that the atmospheric metallicities of both HD 149026b and the Solar System giant planets are more correlated with bulk metallicity than planet mass.
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There are no planets intermediate in size between Earth and Neptune in our Solar System, yet these objects are found around a substantial fraction of other stars1. Population statistics show that close-in planets in this size range bifurcate into two classes on the basis of their radii2,3. It is proposed that the group with larger radii (referred to as 'sub-Neptunes') is distinguished by having hydrogen-dominated atmospheres that are a few percent of the total mass of the planets4. GJ 1214b is an archetype sub-Neptune that has been observed extensively using transmission spectroscopy to test this hypothesis5-14. However, the measured spectra are featureless, and thus inconclusive, due to the presence of high-altitude aerosols in the planet's atmosphere. Here we report a spectroscopic thermal phase curve of GJ 1214b obtained with the James Webb Space Telescope (JWST) in the mid-infrared. The dayside and nightside spectra (average brightness temperatures of 553 ± 9 and 437 ± 19 K, respectively) each show more than 3σ evidence of absorption features, with H2O as the most likely cause in both. The measured global thermal emission implies that GJ 1214b's Bond albedo is 0.51 ± 0.06. Comparison between the spectroscopic phase curve data and three-dimensional models of GJ 1214b reveal a planet with a high metallicity atmosphere blanketed by a thick and highly reflective layer of clouds or haze.
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Foot-and-mouth disease, a class of animal diseases, is caused by foot-and-mouth disease virus (FMDV). The metabolic changes during FMDV infection remain unclear. Here, PK-15 cells, serum, and tonsils infected with FMDV were analyzed by metabolomics. A total of 284 metabolites in cells were significantly changed after FMDV infection, and most of them belong to amino acids and nucleotides. Further studies showed that FMDV infection significantly enhanced aspartate in vitro and in vivo. The amino acid transporter solute carrier family 38 member 8 (SLC38A8) was responsible for FMDV-upregulated aspartate. Enterovirus 71 (EV71) and Seneca Valley virus (SVV) infection also enhanced aspartate by SLC38A8. Aspartate aminotransferase activity was also elevated in FMDV-, EV71-, and SVV-infected cells, which may lead to reversible transition between the TCA cycle and amino acids synthesis. Aspartate and SLC38A8 were essential for FMDV, EV71, and SVV replication in cells. In addition, aspartate and SLC38A8 also promoted FMDV and EV71 replication in mice. Detailed analysis indicated that FMDV infection promoted the transfer of mTOR to lysosome to enhance interaction between mTOR and Rheb, and activated PI3K/AKT/TSC2/Rheb/mTOR/p70S6K1 pathway to promote viral replication. The mTORC1 signaling pathway was responsible for FMDV-induced SLC38A8 protein expression. For the first time, our data identified metabolic changes during FMDV infection. These data identified a novel mechanism used by FMDV to upregulate aspartate to promote viral replication and will provide new perspectives for developing new preventive strategies.
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Enterovirus , Virus de la Fiebre Aftosa , Fiebre Aftosa , Animales , Ratones , Sistemas de Transporte de Aminoácidos Neutros , Ácido Aspártico/metabolismo , Virus de la Fiebre Aftosa/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Replicación Viral/fisiologíaRESUMEN
The innate immune system is the first line of the host's defense, and studying the mechanisms of the negative regulation of interferon (IFN) signaling is important for maintaining the balance of innate immune responses. Here, we found that the host GTP-binding protein 4 (NOG1) is a negative regulator of innate immune responses. Overexpression of NOG1 inhibited viral RNA- and DNA-mediated signaling pathways, and NOG1 deficiency promoted the antiviral innate immune response, resulting in the ability of NOG1 to promote viral replication. Vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1) infection induced a higher level of IFN-ß protein in NOG1 deficient mice. Meanwhile, NOG1-deficient mice were more resistant to VSV and HSV-1 infection. NOG1 inhibited type I IFN production by targeting IRF3. NOG1 was also found to interact with phosphorylated IFN regulatory factor 3 (IRF3) to impair its DNA binding activity, thereby downregulating the transcription of IFN-ß and downstream IFN-stimulated genes (ISGs). The GTP binding domain of NOG1 is responsible for this process. In conclusion, our study reveals an underlying mechanism of how NOG1 negatively regulates IFN-ß by targeting IRF3, which uncovers a novel role of NOG1 in host innate immunity.
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Herpes Simple , Infecciones por Herpesviridae , Interferón Tipo I , Animales , Ratones , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/metabolismo , Interferón beta/metabolismo , Expresión Génica , Inmunidad Innata , ADN , Interferón Tipo I/metabolismoRESUMEN
Cyclic GMP-AMP synthase (cGAS) plays a key role in the innate immune responses to both DNA and RNA virus infection. Here, we found that enterovirus 71 (EV-A71), Seneca Valley virus (SVV), and foot-and-mouth disease virus (FMDV) infection triggered mitochondria damage and mitochondrial DNA (mtDNA) release in vitro and vivo. These responses were mediated by picornavirus 2B proteins which induced mtDNA release during viral replication. SVV infection caused the opening of mitochondrial permeability transition pore (mPTP) and led to voltage-dependent anion channel 1 (VDAC1)- and BCL2 antagonist/killer 1 (Bak) and Bak/BCL2-associated X (Bax)-dependent mtDNA leakage into the cytoplasm, while EV-A71 and FMDV infection induced mPTP opening and resulted in VDAC1-dependent mtDNA release. The released mtDNA bound to cGAS and activated cGAS-mediated antiviral immune response. cGAS was essential for inhibiting EV-A71, SVV, and FMDV replication by regulation of IFN-ß production. cGAS deficiency contributed to higher mortality of EV-A71- or FMDV-infected mice. In addition, we found that SVV 2C protein was responsible for decreasing cGAS expression through the autophagy pathway. The 9th and 153rd amino acid sites in 2C were critical for induction of cGAS degradation. Furthermore, we also show that EV-A71, CA16, and EMCV 2C antagonize the cGAS-stimulator of interferon genes (STING) pathway through interaction with STING, and highly conserved amino acids Y155 and S156 were critical for this inhibitory effect. In conclusion, these data reveal novel mechanisms of picornaviruses to block the antiviral effect mediated by the cGAS-STING signaling pathway, which will provide insights for developing antiviral strategies against picornaviruses.
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Virus de la Fiebre Aftosa , Infecciones por Picornaviridae , Animales , Ratones , Antivirales/metabolismo , ADN Mitocondrial/genética , Virus de la Fiebre Aftosa/genética , Inmunidad Innata , Interferón beta/metabolismo , Mitocondrias/metabolismo , Nucleotidiltransferasas/metabolismo , Infecciones por Picornaviridae/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
BACKGROUND AND AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by severely elevated LDL cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. In the pivotal Phase 3 HoFH trial (NCT03399786), evinacumab significantly decreased LDL-C in patients with HoFH. This study assesses the long-term safety and efficacy of evinacumab in adult and adolescent patients with HoFH. METHODS: In this open-label, single-arm, Phase 3 trial (NCT03409744), patients aged ≥12 years with HoFH who were evinacumab-naïve or had previously received evinacumab in other trials (evinacumab-continue) received intravenous evinacumab 15â mg/kg every 4 weeks with stable lipid-lowering therapy. RESULTS: A total of 116 patients (adults: n = 102; adolescents: n = 14) were enrolled, of whom 57 (49.1%) were female. Patients were treated for a median (range) duration of 104.3 (28.3-196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 93 (80.2%) and 27 (23.3%) patients, respectively. Two (1.7%) deaths were reported (neither was considered related to evinacumab). Three (2.6%) patients discontinued due to TEAEs (none were considered related to evinacumab). From baseline to Week 24, evinacumab decreased mean LDL-C by 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] in the overall population; mean LDL-C reduction in adults and adolescents was 41.7% [mean (SD), 3.2 (3.3) mmol/L] and 55.4% [mean (SD), 4.7 (2.5) mmol/L], respectively. CONCLUSIONS: In this large cohort of patients with HoFH, evinacumab was generally well tolerated and markedly decreased LDL-C irrespective of age and sex. Moreover, the efficacy and safety of evinacumab was sustained over the long term.
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LDL-Colesterol , Hiperlipoproteinemia Tipo II , Humanos , Femenino , Masculino , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Adolescente , Adulto , LDL-Colesterol/sangre , Persona de Mediana Edad , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Resultado del Tratamiento , Adulto Joven , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/administración & dosificación , Niño , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , HomocigotoRESUMEN
The E-twenty-six variant 1 (ETV1)-dependent transcriptome plays an important role in atrial electrical and structural remodelling and the occurrence of atrial fibrillation (AF), but the underlying mechanism of ETV1 in AF is unclear. In this study, cardiomyocyte-specific ETV1 knockout (ETV1f/fMyHCCre/+, ETV1-CKO) mice were constructed to observe the susceptibility to AF and the underlying mechanism in AF associated with ETV1-CKO mice. AF susceptibility was examined by intraesophageal burst pacing, induction of AF was increased obviously in ETV1-CKO mice than WT mice. Electrophysiology experiments indicated shortened APD50 and APD90, increased incidence of DADs, decreased density of ICa,L in ETV1-CKO mice. There was no difference in VINACT,1/2 and VACT,1/2, but a significantly longer duration of the recovery time after inactivation in the ETV1-CKO mice. The recording of intracellular Ca2+ showed that there was significantly increased in the frequency of calcium spark, Ca2+ transient amplitude, and proportion of SCaEs in ETV1-CKO mice. Reduction of Cav1.2 rather than NCX1 and SERCA2a, increase RyR2, p-RyR2 and CaMKII was reflected in ETV1-CKO group. This study demonstrates that the increase in calcium spark and SCaEs corresponding to Ca2+ transient amplitude may trigger DAD in membrane potential in ETV1-CKO mice, thereby increasing the risk of AF.
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Fibrilación Atrial , Calcio , Atrios Cardíacos , Ratones Noqueados , Miocitos Cardíacos , Factores de Transcripción , Animales , Miocitos Cardíacos/metabolismo , Ratones , Fibrilación Atrial/metabolismo , Fibrilación Atrial/genética , Calcio/metabolismo , Atrios Cardíacos/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Señalización del Calcio , Potenciales de Acción , Potenciales de la Membrana , MasculinoRESUMEN
Plants delicately regulate endogenous auxin levels through the coordination of transport, biosynthesis, and inactivation, which is crucial for growth and development. While it is well-established that the actin cytoskeleton can regulate auxin levels by affecting polar transport, its potential role in auxin biosynthesis has remained largely unexplored. Using LC-MS/MS-based methods combined with fluorescent auxin marker detection, we observed a significant increase in root auxin levels upon deletion of the actin bundling proteins AtFIM4 and AtFIM5. Fluorescent observation, immunoblotting analysis, and biochemical approaches revealed that AtFIM4 and AtFIM5 affect the protein abundance of the key auxin synthesis enzyme YUC8 in roots. AtFIM4 and AtFIM5 regulate the auxin synthesis enzyme YUC8 at the protein level, with its degradation mediated by the 26S proteasome. This regulation modulates auxin synthesis and endogenous auxin levels in roots, consequently impacting root development. Based on these findings, we propose a molecular pathway centered on the 'actin cytoskeleton-26S proteasome-YUC8-auxin' axis that controls auxin levels. Our findings shed light on a new pathway through which plants regulate auxin synthesis. Moreover, this study illuminates a newfound role of the actin cytoskeleton in regulating plant growth and development, particularly through its involvement in maintaining protein homeostasis via the 26S proteasome.
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OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. RESEARCH AND DESIGN METHODS: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping. RESULTS: Between the baseline and 12-month time point, plasma IL-1B was reduced (- 1.8 pg/mL, P = 0.003) while ketones were increased (0.26 mM, P = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (- 158.9 pmole/min/106 cells, P = 0.0497 vs. - 5.2 pmole/min/106 cells, P = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups. GOV REGISTRATION: NCT03782259.
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Compuestos de Bencidrilo , Biomarcadores , Diabetes Mellitus Tipo 2 , Glucósidos , Mediadores de Inflamación , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Glucósidos/uso terapéutico , Glucósidos/efectos adversos , Femenino , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Masculino , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Persona de Mediana Edad , Anciano , Resultado del Tratamiento , Mediadores de Inflamación/sangre , Biomarcadores/sangre , Factores de Tiempo , Antiinflamatorios/uso terapéutico , Fibrosis , Inflamación/tratamiento farmacológico , Inflamación/sangre , Inflamación/diagnóstico , Método Doble Ciego , Miocardio/patología , Miocardio/metabolismo , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/diagnóstico por imagen , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/sangreRESUMEN
Investigating soil organic matter's (SOM) microscale assembly and functionality is challenging due to its complexity. This study constructs comparatively realistic SOM models, including diverse components such as Leonardite humic acid (LHA), lipids, peptides, carbohydrates, and lignin, to unveil their spontaneous self-assembly behavior at the mesoscopic scale through microsecond coarse-grained molecular dynamics simulations. We discovered an ordered SOM aggregation creating a layered phase from its hydrophobic core to the aqueous phase, resulting in an increasing O/C ratio and declining structural amphiphilicity. Notably, the amphiphilic lipids formed a bilayer membrane, partnering with lignin to constitute SOM's hydrophobic core. LHA, despite forming a layer, was embedded within this structure. The formation of such complex architectures was driven by nonbonded interactions between components. Our analysis revealed component-dependent diffusion effects within the SOM system. Lipids, peptides, and lignin showed inhibitory effects on self-diffusion, while carbohydrates facilitated diffusion. This study offers novel insights into the dynamic behavior and assembly of SOM components, introducing an effective approach for studying dynamic SOM mechanisms in aquatic environments.
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Simulación de Dinámica Molecular , Suelo , Suelo/química , Agua/química , Lignina , Sustancias Húmicas , Péptidos/química , Lípidos , CarbohidratosRESUMEN
Fluorene-9-bisphenol (BHPF) is an emerging contaminant. Presently, there is no report on its interaction with G protein-coupled estrogen receptor 1 (GPER). By using an integrated toxicity research scenario that combined theoretical study with experimental methods, BHPF was found to inhibit the GPER-mediated effect via direct receptor binding. Molecular dynamics simulations found that Trp2726.48 and Glu2756.51 be the key amino acids of BHPF binding with GPER. Moreover, the calculation indicated that BHPF was a suspected GPER inhibitor, which neither can activate GPER nor is able to form water channels of GPER. The role of two residues was successfully verified by following gene knockout and site-directed mutagenesis assays. Further in vitro assays showed that BHPF could attenuate the increase in intracellular concentration of free Ca2+ induced by G1-activated GPER. Besides, BHPF showed an enhanced cytotoxicity compared with G15, indicating that BHPF might be a more potent GPER inhibitor than G15. In addition, a statistically significant effect on the mRNA level of GPER was observed for BHPF. In brief, the present study proposes that BHPF be a GPER inhibitor, and its GPER molecular recognition mechanism has been revealed, which is of great significance for the health risk and assessment of BHPF.
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Apoptosis , Humanos , Apoptosis/efectos de los fármacos , Neuroblastoma/metabolismo , Neuroblastoma/patología , Línea Celular Tumoral , Fluorenos , Fenoles/farmacología , Fenoles/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Estrógenos/metabolismoRESUMEN
Metal oxides with oxygen vacancies have a significant impact on catalytic activity for the transformation of organic pollutants in waste-to-energy (WtE) incineration processes. This study aims to investigate the influence of hematite surface oxygen point defects on the formation of environmentally persistent free radicals (EPFRs) from phenolic compounds based on the first-principles calculations. Two oxygen-deficient conditions were considered: oxygen vacancies at the top surface and on the subsurface. Our simulations indicate that the adsorption strength of phenol on the α-Fe2O3(0001) surface is enhanced by the presence of oxygen vacancies. However, the presence of oxygen vacancies has a negative impact on the dissociation of the phenol molecule, particularly for the surface with a defective point at the top layer. Thermo-kinetic parameters were established over a temperature range of 300-1000 K, and lower reaction rate constants were observed for the scission of phenolic O-H bonds over the oxygen-deficient surfaces compared to the pristine surface. The negative effects caused by the oxygen-deficient conditions could be attributed to the local reduction of FeIII to FeII, which lower the oxidizing ability of surface reaction sites. The findings of this study provide us a promising approach to regulate the formation of EPFRs.
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Compuestos Férricos , Oxígeno , Compuestos Férricos/química , Radicales Libres/química , Fenoles , Fenol/químicaRESUMEN
African swine fever is one of the most serious viral diseases caused by African swine fever virus (ASFV). The metabolic changes induced by ASFV infection remain unknown. Here, porcine alveolar macrophages (PAMs) infected with ASFV was analyzed by ultrahigh-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS) in combination with multivariate statistical analysis. A total of 90 metabolites were significantly changed after ASFV infection, and most of them were amino acids and tricarboxylic acid (TCA) cycle intermediates. ASFV infection induced an increase in most of amino acids in the host during the early stages of infection, and amino acids decreased in the late stages of infection. ASFV infection did not significantly affect the glycolysis pathway, whereas it induced increases in citrate, succinate, α-ketoglutarate, and oxaloacetate levels in the TCA cycle, suggesting that ASFV infection promoted the TCA cycle. The activities of aspartate aminotransferase and glutamate production were significantly elevated in ASFV-infected cells and pigs, resulting in reversible transition between TCA cycle and amino acid synthesis. Aspartate, glutamate, and TCA cycle were essential for ASFV replication. In addition, ASFV infection induced an increase in lactate level using lactate dehydrogenase, which led to low expression of beta interferon (IFN-ß) and increased ASFV replication. Our data, for the first time, indicate that ASFV infection controls IFN-ß production through RIG-I-mediated signaling pathways. These data identified a novel mechanism evolved by ASFV to inhibit host innate immune responses and provide insights for development of new preventive or therapeutic strategies targeting the altered metabolic pathways. IMPORTANCE In order to promote viral replication, viruses often cause severe immunosuppression and seize organelles to synthesize a large number of metabolites required for self-replication. African swine fever virus (ASFV) has developed many strategies to evade host innate immune responses. However, the impact of ASFV infection on host cellular metabolism remains unknown. Here, for the first time, we analyzed the metabolomic profiles of ASFV-infected PAMs. ASFV infection increased host TCA cycle and amino acid metabolism. Aspartate, glutamate, and TCA cycle promoted ASFV replication. ASFV infection also induced the increase of lactate production to inhibit innate immune responses for self-replication. This study identified novel immune evasion mechanisms utilized by ASFV and provided insights into ASFV-host interactions, which is critical for guiding the design of new prevention strategies against ASFV targeting the altered metabolic pathways.
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Virus de la Fiebre Porcina Africana/fisiología , Fiebre Porcina Africana/metabolismo , Aminoácidos/metabolismo , Metabolismo Energético , Replicación Viral/fisiología , Fiebre Porcina Africana/virología , Virus de la Fiebre Porcina Africana/patogenicidad , Animales , Ácido Aspártico/metabolismo , Ciclo del Ácido Cítrico , Ácido Glutámico/metabolismo , Interacciones Huésped-Patógeno , Ácido Láctico/metabolismo , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/virología , Metabolómica , PorcinosRESUMEN
Despite the fact that coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been disrupting human life and health worldwide since the outbreak in late 2019, the impact of exogenous substance exposure on the viral infection remains unclear. It is well-known that, during viral infection, organism receptors play a significant role in mediating the entry of viruses to enter host cells. A major receptor of SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2). This study proposes a deep learning model based on the graph convolutional network (GCN) that enables, for the first time, the prediction of exogenous substances that affect the transcriptional expression of the ACE2 gene. It outperforms other machine learning models, achieving an area under receiver operating characteristic curve (AUROC) of 0.712 and 0.703 on the validation and internal test set, respectively. In addition, quantitative polymerase chain reaction (qPCR) experiments provided additional supporting evidence for indoor air pollutants identified by the GCN model. More broadly, the proposed methodology can be applied to predict the effect of environmental chemicals on the gene transcription of other virus receptors as well. In contrast to typical deep learning models that are of black box nature, we further highlight the interpretability of the proposed GCN model and how it facilitates deeper understanding of gene change at the structural level.
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COVID-19 , Aprendizaje Profundo , Humanos , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Receptores Virales/química , Receptores Virales/genética , Receptores Virales/metabolismo , Peptidil-Dipeptidasa A/química , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , SARS-CoV-2 , Transcripción GenéticaRESUMEN
African swine fever is a devastating disease of swine caused by African swine fever virus (ASFV). The pathogenesis of the disease remains largely unknown, leaving the spread of the disease uncontrolled in many countries and regions. Here, we identified E120R, a structural protein of ASFV, as a key virulence factor and late-phase-expressed protein of the virus. E120R revealed an activity to suppress the host antiviral response through blocking beta interferon (IFN-ß) production, and the amino acids (aa) at sites 72 and 73 (amino acids 72-73) in the C-terminal domain were essential for this function. E120R interacted with interferon regulatory factor 3 (IRF3) and interfered with the recruitment of IRF3 to TANK-binding kinase 1 (TBK1), which in turn suppressed IRF3 phosphorylation, decreasing interferon production. A recombinant mutant ASFV was further constructed to confirm the claimed mechanism. The ASFV lacking the complete E120R region could not be rescued, whereas the virus could tolerate the deletion of the 72nd and 73rd residues in E120R (ASFV E120R-Δ72-73aa). ASFV E120R with the two-amino-acid deletion failed to interact with IRF3 during ASFV E120R-Δ72-73aa infection, and the viral infection activated IRF3 phosphorylation highly and induced more robust type I interferon production than its parental ASFV. An unbiased transcriptome-wide analysis of gene expression also confirmed that considerably more IFN-stimulated genes (ISGs) were detected in ASFV E120R-Δ72-73aa-infected porcine alveolar macrophages (PAMs) than in wild-type ASFV-infected PAMs. Together, our findings have identified a novel mechanism evolved by ASFV to inhibit the host antiviral response, and they provide a new target for guiding the development of ASFV live-attenuated vaccine. IMPORTANCE African swine fever is a highly contagious animal disease affecting the pig industry worldwide, which has brought enormous economic losses. Infection by the causative agent, African swine fever virus (ASFV), causes severe immunosuppression during viral infection, contributing to serious clinical manifestations. Therefore, identification of the viral proteins involved in immunosuppression is critical for ASFV vaccine design and development. Here, for the first time, we demonstrated that E120R protein, a structural protein of ASFV, played an important role in suppression of interferon regulatory factor 3 (IRF3) phosphorylation and type I interferon production by binding to IRF3 and blocking the recruitment of IRF3 to TANK-binding kinase 1 (TBK1). Deletion of the crucial binding sites in E120R critically increased the interferon response during ASFV infection. This study explored a novel antagonistic mechanism of ASFV, which is critical for guiding the development of ASFV live-attenuated vaccines.
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Virus de la Fiebre Porcina Africana/fisiología , Fiebre Porcina Africana/virología , Interacciones Huésped-Patógeno , Factor 3 Regulador del Interferón/metabolismo , Interferón beta/metabolismo , Mutación , Proteínas Virales/metabolismo , Fiebre Porcina Africana/genética , Fiebre Porcina Africana/metabolismo , Animales , Perfilación de la Expresión Génica , Células HEK293 , Humanos , Factor 3 Regulador del Interferón/genética , Fosforilación , Transducción de Señal , Porcinos , Proteínas Virales/genética , VirulenciaRESUMEN
COVID-19 caused by SARS-COV-2 is continuing to surge globally. The spike (S) protein is the key protein of SARS-COV-2 that recognizes and binds to the host target ACE2. In this study, molecular dynamics simulation was used to elucidate the allosteric effect of the S protein. Binding of ACE2 caused a centripetal movement of the receptor-binding domain of the S protein. The dihedral changes in Phe329 and Phe515 played a key role in this process. Two potential cleavage sites S1/S2 and S2' were exposed on the surface after the binding of ACE2. The binding affinity of SARS-COV-2 S protein and ACE2 was higher than that of SARS-COV. This was mainly due to the mutation of Asp480 in SARS-COV to Ser494 in SARS-COV-2, which greatly weakened the electrostatic repulsion. The result provides a theoretical basis for the SARS-COV-2 infection and aids the development of biosensors and detection reagents.
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Simulación de Dinámica Molecular , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/química , COVID-19 , Humanos , Unión ProteicaRESUMEN
Invited for the cover of this issue are Aiqian Zhang, Jianjie Fu, Guibin Jiang, and co-workers at the Chinese Academy of Sciences. The image depicts the molecular recognition of human angiotensin-converting enzyme 2 by the SARS-COV-2 spike protein. Read the full text of the article at 10.1002/chem.202104215.
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OBJECTIVE: Niacin therapy fails to reduce cardiovascular events in statin-treated subjects even though it increases plasma HDL-C (HDL [high-density lipoprotein] cholesterol) and decreases LDL-C (LDL [low-density lipoprotein] cholesterol) and triglyceride levels. To investigate potential mechanisms for this lack of cardioprotection, we quantified the HDL proteome of subjects in 2 niacin clinical trials: the CPC study (Carotid Plaque Composition) and the HDL Proteomics substudy of the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides). APPROACH AND RESULTS: Using targeted proteomics, we quantified levels of 31 HDL proteins from 124 CPC subjects and 120 AIM-HIGH subjects. The samples were obtained at baseline and after 1 year of statin monotherapy or niacin-statin combination therapy. Compared with statin monotherapy, niacin-statin combination therapy did not reduce HDL-associated apolipoproteins APOC1, APOC2, APOC3, and APOC4, despite significantly lowering triglycerides. In contrast, niacin markedly elevated HDL-associated PLTP (phospholipid transfer protein), CLU (clusterin), and HP/HPR (haptoglobin/haptoglobinrelated proteins; P≤0.0001 for each) in both the CPC and AIM-HIGH cohorts. CONCLUSIONS: The addition of niacin to statin therapy resulted in elevated levels of multiple HDL proteins linked to increased atherosclerotic risk, which might have compromised the cardioprotective effects associated with higher HDL-C levels and lower levels of LDL-C and triglycerides. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00715273; NCT00880178; NCT00120289.
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Aterosclerosis/tratamiento farmacológico , Cardiotónicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lipoproteínas HDL/química , Niacina/uso terapéutico , Adulto , Aterosclerosis/sangre , Cardiotónicos/farmacología , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/prevención & control , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Lipoproteínas HDL/sangre , Masculino , Persona de Mediana Edad , Niacina/farmacología , ProteómicaRESUMEN
BACKGROUND: The roles of PD-1+ CXCR5+ follicular helper CD8+ T cell were reported in different disease conditions, but their roles in transplantation are unclear. In this study, the association between PD-1+ CXCR5+ follicular helper CD8+ T cell and renal allograft dysfunction in kidney transplant recipients (KTRs) was investigated. METHODS: 82 KTRs were enrolled in this study. 45 KTRs were included in the chronic allograft dysfunction (CAD) group, and 37 KTRs were included in the stable recipients group. Among the CAD group, 12 cases of antibody-mediated rejection (ABMR) and 4 cases of T cell-mediated rejection (TCMR) were diagnosed by biopsy. The percentage of CXCR5+ CD8+ T cells and the co-expression of signal transducers and activators of transcription 4 (STAT4), STAT5, and PD-1 in peripheral blood were determined by flow cytometry. RESULTS: The expression of CXCR5 on CD3+ CD8+ T cells and the percentage of STAT5+ CXCR5+ cells in the CD3+ CD8+ T-cell population were significantly lower in the CAD group (p < 0.05), while the expression of PD-1+ CXCR5+ CD8+ T cells was significantly higher (p < 0.05). Through logistic regression analysis, we concluded that the percentage of PD-1+ CXCR5+ CD8+ T cells was an independent risk factor for renal dysfunction. Grouping by pathological type, PD-1+ CXCR5+ CD8+ T cells showed relatively good diagnostic efficacy for ABMR by ROC analysis. CONCLUSIONS: Our results suggested that PD-1+ CXCR5+ CD8+ T cells were a promising biomarker for distinguishing renal allograft dysfunction and different allograft pathological types. Also, our findings may provide new ways of identifying and treating allograft rejection.
Asunto(s)
Trasplante de Riñón , Riñón/fisiopatología , Receptor de Muerte Celular Programada 1/metabolismo , Células T Auxiliares Foliculares/fisiología , Adulto , Aloinjertos , Biomarcadores , Linfocitos T CD8-positivos/fisiología , Femenino , Rechazo de Injerto/diagnóstico , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/fisiología , Curva ROC , Receptores CXCR5/metabolismo , Células T Auxiliares Foliculares/metabolismoRESUMEN
Molecular docking is a widely used method to predict the binding modes of small-molecule ligands to the target binding site. However, it remains a challenge to identify the correct binding conformation and the corresponding binding affinity for a series of structurally similar ligands, especially those with weak binding. An understanding of the various relative attributes of popular docking programs is required to ensure a successful docking outcome. In this study, we systematically compared the performance of three popular docking programs, Autodock, Autodock Vina, and Surflex-Dock for a series of structurally similar weekly binding flavonoids (22) binding to the estrogen receptor alpha (ERα). For these flavonoids-ERα interactions, Surflex-Dock showed higher accuracy than Autodock and Autodock Vina. The hydrogen bond overweighting by Autodock and Autodock Vina led to incorrect binding results, while Surflex-Dock effectively balanced both hydrogen bond and hydrophobic interactions. Moreover, the selection of initial receptor structure is critical as it influences the docking conformations of flavonoids-ERα complexes. The flexible docking method failed to further improve the docking accuracy of the semi-flexible docking method for such chemicals. In addition, binding interaction analysis revealed that 8 residues, including Ala350, Glu353, Leu387, Arg394, Phe404, Gly521, His524, and Leu525, are the key residues in ERα-flavonoids complexes. This work provides reference for assessing molecular interactions between ERα and flavonoid-like chemicals and provides instructive information for other environmental chemicals.