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Lipid nanoparticles (LNPs)-based messenger RNA (mRNA) therapeutics have emerged with promising potentials in the fields of infectious diseases, cancer vaccines, and protein replacement therapies; however, their therapeutic efficacy and safety can still be promoted by the optimization of LNPs formulations. Unfortunately, current LNPs suffer from increased production of reactive oxygen species during translation, which leads to a decreased translation efficiency and the onset of inflammation and other side effects. Herein, we synthesize a lipid-modified poly(guanidine thioctic acid) polymer to fabricate novel LNPs for mRNA vaccines. The acquired G-LNPs significantly promote the translation efficiency of loaded mRNA and attenuate inflammation after vaccination through the elimination of reactive oxygen species that are responsible for translational inhibition and inflammatory responses. In vivo studies demonstrate the excellent antitumor efficacy of the G-LNPs@mRNA vaccine, and two-dose vaccination dramatically increases the population and infiltration of cytotoxic T cells due to the intense antitumor immune responses, thus generating superior antitumor outcomes compared with the mRNA vaccine prepared from traditional LNPs. By synergy with immune checkpoint blockade, the tumor inhibition of G-LNPs@mRNA is further boosted, indicating that G-LNPs-based mRNA vaccines will be powerful and versatile platforms to combat cancer.
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Vacunas contra el Cáncer , Lípidos , Liposomas , Nanopartículas , ARN Mensajero , Vacunas contra el Cáncer/química , Vacunas contra el Cáncer/inmunología , Nanopartículas/química , Animales , Ratones , ARN Mensajero/genética , ARN Mensajero/inmunología , Lípidos/química , Humanos , Ácido Tióctico/química , Ácido Tióctico/farmacología , Polímeros/química , Guanidinas/química , Guanidinas/farmacología , Línea Celular TumoralRESUMEN
An aperiodic snake-like optical chain has been proposed and generated by using an optical pen technique, whose numbers and positions of focal points are controllable. Moreover, by introducing a fan phase together with a twisted phase into the optical pen technique, a self-rotation optical chain can be obtained; meanwhile, it transforms the bright optical chain into a twisted optical chain with a rotating hollow region in a three-dimensional (3D) space. The properties of the rotatable focal points and the variable diameters of cross-sectional intensities during the propagation of the optical chain are demonstrated in the experimental results. Consequently, this research framework can be applied in the techniques such as deep multiplexing and rotation angle multiplexing while also enabling the realization of multiple capture sites and more intricate manipulations.
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BACKGROUND: Extracellular vesicles (EVs) are membrane-enclosed structures containing lipids, proteins, and RNAs that play a crucial role in cell-to-cell communication. However, the precise mechanism through which circulating EVs disrupt hepatic glucose homeostasis in gestational diabetes mellitus (GDM) remains unclear. RESULTS: Circulating EVs isolated from human plasma were co-cultured with mammalian liver cells to investigate the potential induction of hepatic insulin resistance by GDM-EVs using glucose output assays, Seahorse assays, metabolomics, fluxomics, qRT-PCR, bioinformatics analyses, and luciferase assays. Our findings demonstrated that hepatocytes exposed to GDM-EVs exhibited increased gluconeogenesis, attenuated energy metabolism, and upregulated oxidative stress. Particularly noteworthy was the discovery of miR-1299 as the predominant miRNA in GDM-EVs, which directly targeting the 3'-untranslated regions (UTR) of STAT3. Our experiments involving loss- and gain-of-function revealed that miR-1299 inhibits the insulin signaling pathway by regulating the STAT3/FAM3A axis, resulting in increased insulin resistance through the modulation of mitochondrial function and oxidative stress in hepatocytes. Moreover, experiments conducted in vivo on mice inoculated with GDM-EVs confirmed the development of glucose intolerance, insulin resistance, and downregulation of STAT3 and FAM3A. CONCLUSIONS: These results provide insights into the role of miR-1299 derived from circulating GDM-EVs in the progression of insulin resistance in hepatic cells via the STAT3/FAM3A axis and downstream metabolic reprogramming.
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Diabetes Gestacional , Vesículas Extracelulares , Glucosa , Hepatocitos , Homeostasis , Resistencia a la Insulina , Hígado , MicroARNs , Factor de Transcripción STAT3 , Animales , Femenino , Humanos , Ratones , Embarazo , Regiones no Traducidas 3' , Diabetes Gestacional/metabolismo , Diabetes Gestacional/genética , Vesículas Extracelulares/metabolismo , Glucosa/metabolismo , Células Hep G2 , Hepatocitos/metabolismo , Hígado/metabolismo , Ratones Endogámicos C57BL , MicroARNs/metabolismo , MicroARNs/genética , Estrés Oxidativo , Transducción de Señal , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genéticaRESUMEN
Spatialization and analysis of the gross domestic product of second and tertiary industries (GDP23) can effectively depict the socioeconomic status of regional development. However, existing studies mainly conduct GDP spatialization using nighttime light data; few studies specifically concentrated on the spatialization and analysis of GDP23 in a built-up area by combining multi-source remote sensing images. In this study, the NPP-VIIRS-like dataset and Sentinel-2 multi-spectral remote sensing images in six years were combined to precisely spatialize and analyze the variation patterns of the GDP23 in the built-up area of Zibo city, China. Sentinel-2 images and the random forest (RF) classification method based on PIE-Engine cloud platform were employed to extract built-up areas, in which the NPP-VIIRS-like dataset and comprehensive nighttime light index were used to indicate the nighttime light magnitudes to construct models to spatialize GDP23 and analyze their change patterns during the study period. The results found that (1) the RF classification method can accurately extract the built-up area with an overall accuracy higher than 0.90; the change patterns of built-up areas varied among districts and counties, with Yiyuan county being the only administrative region with an annual expansion rate of more than 1%. (2) The comprehensive nighttime light index is a viable indicator of GDP23 in the built-up area; the fitted model exhibited an R2 value of 0.82, and the overall relative errors of simulated GDP23 and statistical GDP23 were below 1%. (3) The year 2018 marked a significant turning point in the trajectory of GDP23 development in the study area; in 2018, Zhoucun district had the largest decrease in GDP23 at -52.36%. (4) GDP23 gradation results found that Zhangdian district exhibited the highest proportion of high GDP23 (>9%), while the proportions of low GDP23 regions in the remaining seven districts and counties all exceeded 60%. The innovation of this study is that the GDP23 in built-up areas were first precisely spatialized and analyzed using the NPP-VIIRS-like dataset and Sentinel-2 images. The findings of this study can serve as references for formulating improved city planning strategies and sustainable development policies.
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Nanofiltration (NF) membrane technology has been widely used in the removal of salts and trace organic pollutants, such as pharmaceuticals and personal care products (PPCPs), due to its superiority. A positive-charged composite NF membrane with an active skin layer was prepared by polyethyleneimine (PEI), trimethyl benzene chloride, and quaternate chitosan (HTCC) through second interfacial polymerization on the polyethersulfone ultrafiltration membrane. The physicochemical properties of the nanocomposite membrane were investigated using surface morphology, hydrophilicity, surface charge, and molecular weight cut-off (MWCO). The influence of the concentration and reaction time of PEI and HTCC was documented. The optimized membrane had a MWCO of about 481 Da and possessed a pure water permeability of 25.37 L·m-2·h-1·MPa-1. The results also exhibited salt rejection ability as MgCl2 > CaCl2 > MgSO4 > Na2SO4 > NaCl > KCl, showing a positive charge on the fabricated membrane. In addition, the membrane had higher rejection to atenolol, carbamazepine, amlodipine, and ibuprofen at 89.46, 86.02, 90.12, and 77.21%, respectively. Moreover, the anti-fouling performance and stability of the NF membrane were also improved.
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Quitosano , Membranas Artificiales , Contaminantes Químicos del Agua , Quitosano/química , Contaminantes Químicos del Agua/química , Preparaciones Farmacéuticas/química , Purificación del Agua/métodos , Polimerizacion , Sales (Química)/química , Ultrafiltración/métodos , Filtración/métodosRESUMEN
The JNK signaling pathway plays crucial roles in various physiological processes, including cell proliferation, differentiation, migration, apoptosis, and stress response. Dysregulation of this pathway is closely linked to the onset and progression of numerous major diseases, such as developmental defects and tumors. Identifying and characterizing novel components of the JNK signaling pathway to enhance and refine its network hold significant scientific and clinical importance for the prevention and treatment of associated cancers. This study utilized the model organism Drosophila and employed multidisciplinary approaches encompassing genetics, developmental biology, biochemistry, and molecular biology to investigate the interplay between Tip60 and the JNK signaling pathway, and elucidated its regulatory mechanisms. Our findings suggest that loss of Tip60 acetyltransferase activity results in JNK signaling pathway activation and subsequent induction of JNK-dependent apoptosis. Genetic epistasis analysis reveals that Tip60 acts downstream of JNK, paralleling with the transcription factor FOXO. The biochemical results confirm that Tip60 can bind to FOXO and acetylate it. Introduction of human Tip60 into Drosophila effectively mitigates apoptosis induced by JNK signaling activation, underscoring conserved regulatory role of Tip60 in the JNK signaling pathway from Drosophila to humans. This study further enhances our understanding of the regulatory network of the JNK signaling pathway. By revealing the role and mechanism of Tip60 in JNK-dependent apoptosis, it unveils new insights and potential therapeutic avenues for preventing and treating associated cancers.
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Apoptosis , Proteínas de Drosophila , Factores de Transcripción Forkhead , Animales , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Histona Acetiltransferasas/metabolismo , Histona Acetiltransferasas/genética , Drosophila/genética , Drosophila/metabolismo , Sistema de Señalización de MAP Quinasas , Humanos , Transducción de Señal , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/genéticaRESUMEN
As the most advanced non-viral delivery system, lipid nanoparticles (LNPs) were approved by the FDA, propelling the advancements of gene therapy. However, their clinical applications are hampered by the potential immunogenicity of the lipid components that trigger immune-related adverse events, like inflammation and allergy. Herein, we formulate various dLNPs with diminished immunogenicity by incorporating dexamethasone (Dex) into liver-, spleen-, and lung-targeting LNPs formulations that exhibit excellent abilities to target specific organs and deliver various types of RNA, such as mRNA and siRNA. In vivo investigations demonstrate unparalleled advantages in safety as compared to conventional LNPs, showing promising potential in the development of RNA therapeutics. Intriguingly, the encapsulation of runt-related transcription factor-1 siRNA (siRUNX1) into lung-targeting dLNPs (dLNPs@siRUNX1) demonstrates remarkable advantages in the treatment of pulmonary fibrosis through the synergy of gene therapy and drug therapy. This research establishes secure and universal platforms for the precise delivery of nucleic acid therapeutics, showcasing promising clinical applications in gene therapy.
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Dexametasona , Lípidos , Nanopartículas , Fibrosis Pulmonar , ARN Interferente Pequeño , Nanopartículas/química , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Animales , Ratones , ARN Interferente Pequeño/química , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/uso terapéutico , Dexametasona/química , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Lípidos/química , Humanos , Pulmón/metabolismo , Pulmón/patología , Pulmón/inmunología , Pulmón/efectos de los fármacos , Terapia Genética , LiposomasRESUMEN
Insufficient accumulation of lipid nanoparticles (LNPs)-based mRNA vaccines in antigen presenting cells remains a key barrier to eliciting potent antitumor immune responses. Herein, we develop dendritic cells (DCs) targeting LNPs by taking advantage of mannose receptor-mediated endocytosis. Efficient delivery of mRNA to DCs is achieved in vitro and in vivo utilizing the sweet LNPs (STLNPs-Man). Intramuscular injection of mRNA vaccine (STLNPs-Man@mRNAOVA ) results in a four-fold higher uptake by DCs in comparison with commercially used LNPs. Benefiting from its DCs targeting ability, STLNPs-Man@mRNAOVA significantly promotes the antitumor performances, showing a comparable therapeutic efficacy by using one-fifth of the injection dosage as the vaccine prepared from normal LNPs, thus remarkably avoiding the side effects brought by conventional mRNA vaccines. More intriguingly, STLNPs-Man@mRNAOVA exhibits the ability to downregulate the expression of cytotoxic T-lymphocyte-associated protein 4 on T cells due to the blockade of CD206/CD45 axis, showing brilliant potentials in promoting antitumor efficacy combined with immune checkpoint blockade therapy.
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Vacunas contra el Cáncer , Liposomas , Nanopartículas , Neoplasias , Humanos , Presentación de Antígeno , Vacunas de ARNm , ARN Mensajero/genética , ARN Mensajero/metabolismo , Células Dendríticas/metabolismo , Neoplasias/terapia , Neoplasias/metabolismoRESUMEN
Despite the tremendous breakthrough of immunotherapy, the low response rate and resistance of immune checkpoint inhibitors (ICIs) toward solid tumors occur frequently. A highly hypoxic tumor microenvironment (TME) provides tumor cells with high concentrations of HIF-1α and polyamines to evade immune cell destruction. Reprogramming of an immunogenic TME has exhibited a brilliant future to boost immunotherapeutic performances. Herein, a supramolecular nanomedicine (TAPP) is developed on the basis of host-guest molecular recognition and metal coordination, showing the capability to remodel the immunosuppressive TME. Tamoxifen (Tmx) and Fe3+ are encapsulated into TAPP to achieve the combination of chemotherapy and chemodynamic therapy (CDT). Tmx directly downregulates HIF-1α, and a pillar[5]arene-based macrocyclic host successfully eliminates polyamines in tumors. Enhanced immunogenic cell death is achieved by Tmx and Fe3+, and the therapeutic efficacy is further synergized by immune checkpoint blockade (ICB) therapy. This supramolecular reprogramming modality encourages cytotoxic T lymphocyte infiltration, achieving pre-eminent immune response and long-term tumor suppression.
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Calixarenos , Gastrópodos , Neoplasias , Animales , Microambiente Tumoral , Inmunoterapia , Neoplasias/tratamiento farmacológico , Línea Celular TumoralRESUMEN
BACKGROUND: Gestational diabetes Mellitus (GDM) is a common pregnancy-specific disease with high morbidity, which is linked to a high risk of obesity and diabetes in offspring. N6-methyladenosine modification of RNA is emerging as an important epigenetic mechanism that is widely manifested in many diseases. This study aimed to investigate the mechanism of m6A methylation in metabolic syndrome in offspring result from intrauterine hyperglycemia. METHODS: GDM mice were established by feeding a high-fat diet 1 weeks before pregnancy. The m6A RNA methylation quantification kit was used to detect liver tissue methylation levels. PCR array was used to determine the expression of the m6A methylation modification enzyme. Immunohistochemistry, qRT-PCR, and western blot were used to examine the expression of RBM15, METTL13, IGF2BP1, and IGF2BP2. Subsequently, methylated RNA immunoprecipitation sequencing combined with mRNA sequencing, followed by dot blot and glucose uptake tests, were performed. RESULTS: In this study, we found that offspring from a GDM mother were more vulnerable to glucose intolerance and insulin resistance. GC-MS revealed significant metabolic changes including saturated fatty acids and unsaturated fatty acids in liver of GDM offspring. We also demonstrated that global mRNA m6A methylation level was significantly increased in the fetal liver of GDM mice, indicating epigenetic change may have a strong relationship with the mechanism of metabolism syndrome. Concordantly, RBM15, the RNA binding methyltransferase, was upregulated in the liver. In vitro, RBM15 suppressed insulin sensitivity and increased insulin resistance through m6A-regulated epigenetic inhabitation of CLDN4. Moreover, MeRIP-sequencing and mRNA-sequencing revealed that differently regulated genes with differential m6A peaks were enriched in metabolic pathways. CONCLUSION: Our study revealed the essential role of RBM15 in insulin resistance and the effect of RBM15-regulated m6A modification in the metabolic syndrome of offspring of GDM mice.
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Diabetes Gestacional , Resistencia a la Insulina , Síndrome Metabólico , Animales , Femenino , Humanos , Ratones , Embarazo , Claudina-4/metabolismo , Diabetes Gestacional/genética , Diabetes Gestacional/metabolismo , Hígado/metabolismo , Síndrome Metabólico/metabolismo , Metiltransferasas/metabolismo , ARN/metabolismo , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
Hepatic ischemia-reperfusion injury (HIRI) is a critical complication after liver surgery that negatively affects surgical outcomes of patients with the end-stage liver-related disease. Reactive oxygen species (ROS) are responsible for the development of ischemia-reperfusion injury and eventually lead to hepatic dysfunction. Selenium-doped carbon quantum dots (Se-CQDs) with an excellent redox-responsive property can effectively scavenge ROS and protect cells from oxidation. However, the accumulation of Se-CQDs in the liver is extremely low. To address this concern, the fabrication of Se-CQDs-lecithin nanoparticles (Se-LEC NPs) is developed through self-assembly mainly driven by the noncovalent interactions. Lecithin acting as the self-assembly building block also makes a pivotal contribution to the therapeutic performance of Se-LEC NPs due to its capability to react with ROS. The fabricated Se-LEC NPs largely accumulate in the liver, effectively scavenge ROS and inhibit the release of inflammatory cytokines, thus exerting beneficial therapeutic efficacy on HIRI. This work may open a new avenue for the design of self-assembled Se-CQDs NPs for the treatment of HIRI and other ROS-related diseases.
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Puntos Cuánticos , Daño por Reperfusión , Selenio , Humanos , Antioxidantes/farmacología , Especies Reactivas de Oxígeno , Carbono , Lecitinas , Hígado , Daño por Reperfusión/tratamiento farmacológicoRESUMEN
A new type of versatile spiral beam (VSB) is generated based on the competition mechanism between the self-focusing property of ring Airy beam and metalens phase distribution, which exhibits twisted properties and optical bottle structure along the propagation direction. The number of spiral lobes, rotation direction, shape and magnification times on the cross section of the proposed beam can be customized by flexibly tuning diffraction distance, topological charge and constant parameter. Therefore, the VSB can be viewed as tunable three-dimensional (3D) spiral beam, and our scheme has the superiority with more diverse and tunable intensity distribution. The properties of intensity distribution variation depended on the propagation distance and topological charge are demonstrated convincingly by employing the Poynting vector intuitive presentation the energy flow. The VSBs with the aid of above-mentioned properties are beneficial for guiding microparticles along the designed spiral path and capturing multiple microparticles into the closed dark regions. Finally, the modulated spiral beams are implemented as tool for particle manipulation in the three dimensional space to demonstrate the advantages of the modulated spiral beam and we can observe the stable trapping of the particles.
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The hydroxylamine method involves the synthesis of a new hydroxamic acid collector, i.e., phenylpropyl hydroxamic acid (PHA), from methyl cinnamic hydroxamic acid. Flotation test results show that PHA exhibits good selective collection ability. The adsorption mechanism of PHA is investigated using the zeta potential, Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). The results show that PHA formed a new Ca-O bond with Ca2+ on the fluorite surface via chemical adsorption. A new five-element chelated hydroxamate group may have formed in Ca on the fluorite surface. The PHA selectivity is fully explained via density functional theory (DFT) calculations, and an adsorption model is established.
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Precise identification and spatial analysis of land salinity in China's Yellow River Delta are essential for the rational utilization and sustainable development of land resources. However, the accurate retrieval model construction for monitoring land salinity remains challenging. This study constructed a land salinity retrieval framework using a harmonized UAV and Landsat-9 multi-spectral dataset. The Kenli district of the Yellow River Delta was selected as the case study area, and a land salinity monitoring index (LSMI) was proposed based on field survey data and UAV multi-spectral image and applied to the reflectance-corrected Landsat-9 OLI image. The land salinity distribution patterns were then mapped and spatially analyzed using Moran's I and Getis-Ord GI* analysis. The results demonstrated the following: (1) The LSMI-based method can accurately retrieve land salinity content with a validation determination coefficient (R2), root mean square error (RMSE), and residual predictive deviation (RPD) of 0.75, 1.89, and 2.11, respectively. (2) Land salinization affected 93.12% of the cultivated land in the study area, and the severely saline soil grade (with a salinity content of 6-8 g/kg) covered 38.41% of the total cultivated land area and was widely distributed throughout the study area. (3) Saline land exhibited a positive spatial autocorrelation with a value of 0.311 at the p = 0.000 level; high-high cluster types occurred mainly in the Kendong and Huanghekou towns (80%), while low-low cluster types were mainly located in the Dongji, Haojia, Kenli, and Shengtuo towns (88.46%). The spatial characteristics of various salinity grades exhibit significant variations, and conducting separate spatial analyses is recommended for future studies.
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OBJECTIVE: Functional neuroimaging studies have found differential neural activation patterns during anticipation-related paradigms in participants with eating disorders (EDs) compared to controls. However, publications reported conflicting results on the directionality and location of the abnormal activations. There is an urgent need to integrate our existing knowledge of anticipation, both rewarding and aversive, to elucidate these differences. METHOD: We conducted an activation likelihood estimation (ALE) meta-analysis to quantitatively review functional neuroimaging studies that evaluated differences between brain correlates of anticipation in participants with and without disordered eating. PubMed, Web of Sciences, PsycINFO, Medline and EMBASE were searched for studies published up to November 2022. Exploratory sub-analyses to check for differences between reward and non-reward anticipation among all anticipation paradigms. RESULTS: Twenty-one references met the inclusion criteria for meta-analysis. The meta-analysis across anticipation all tasks identified a significant hyperactivation cluster in the right putamen in participants with disordered eating (n = 17 experiments) and a significant hypoactivation cluster in the left inferior parietal lobule (n = 13 experiments), in participants with disordered eating compared to controls. CONCLUSIONS: These findings and sub-analyses of reward- and non-reward-related cues suggest potential pathophysiological mechanisms underlying anticipatory responses to rewarding and aversive cues in ED.
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Trastornos de Alimentación y de la Ingestión de Alimentos , Imagen por Resonancia Magnética , Humanos , Encéfalo , Neuroimagen Funcional , Afecto , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico por imagenRESUMEN
BACKGROUND: The forkhead box O3a protein (FoxO3a) has been reported to be involved in the migration and invasion of trophoblast, but its underlying mechanisms unknown. In this study, we aim to explore the transcriptional and metabolic regulations of FoxO3a on the migration and invasion of early placental development. METHODS: Lentiviral vectors were used to knock down the expression of FoxO3a of the HTR8/SVneo cells. Western blot, matrigel invasion assay, wound healing assay, seahorse, gas-chromatography-mass spectrometry (GC-MS) based metabolomics, fluxomics, and RNA-seq transcriptomics were performed. RESULTS: We found that FoxO3a depletion restrained the migration and invasion of HTR8/SVneo cells. Metabolomics, fluxomics, and seahorse demonstrated that FoxO3a knockdown resulted in a switch from aerobic to anaerobic respiration and increased utilization of aromatic amino acids and long-chain fatty acids from extracellular nutrients. Furthermore, our RNA-seq also demonstrated that the expression of COX-2 and MMP9 decreased after FoxO3a knockdown, and these two genes were closely associated with the migration/invasion progress of trophoblast cells. CONCLUSIONS: Our results suggested novel biological roles of FoxO3a in early placental development. FoxO3a exerts an essential effect on trophoblast migration and invasion owing to the regulations of COX2, MMP9, aromatic amino acids, energy metabolism, and oxidative stress.
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Proteína Forkhead Box O3/metabolismo , Preeclampsia , Trofoblastos , Aminoácidos Aromáticos/metabolismo , Línea Celular , Movimiento Celular/genética , Femenino , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Placenta/metabolismo , Preeclampsia/genética , Embarazo , Trofoblastos/metabolismoRESUMEN
Accurate gene expression requires the targeting of transcription factors (TFs) to regulatory sequences often occluded within nucleosomes. The ability to target a TF binding site (TFBS) within a nucleosome has been the defining characteristic for a special class of TFs known as pioneer factors. Recent studies suggest TP53 functions as a pioneer factor that can target its TFBS within nucleosomes, but it remains unclear how TP53 binds to nucleosomal DNA. To comprehensively examine TP53 nucleosome binding, we competitively bound TP53 to multiple in vitro-formed nucleosomes containing a high- or low-affinity TP53 TFBS located at differing translational and rotational positions within the nucleosome. Stable TP53-nucleosome complexes were isolated and quantified using next-generation sequencing. Our results demonstrate TP53 binding is limited to nucleosome edges with significant binding inhibition occurring within 50 bp of the nucleosome dyad. Binding site affinity only affects TP53 binding for TFBSs located at the same nucleosomal positions; otherwise, nucleosome position takes precedence. Furthermore, TP53 has strong nonspecific nucleosome binding facilitating its interaction with chromatin. Our in vitro findings were confirmed by examining TP53-induced binding in a cell line model, showing induced binding at nucleosome edges flanked by a nucleosome-free region. Overall, our results suggest that the pioneering capabilities of TP53 are driven by nonspecific nucleosome binding with specific binding at nucleosome edges.
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Nucleosomas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular , Humanos , Nucleosomas/genética , Unión Proteica , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Lepidolite is an important mineral resource of lithium. With the increase in awareness of low-carbon and green travel, the demand for lithium has increased dramatically. Therefore, how to increase the output of lithium has to turn into high precedence. In this paper, amidoxime (DPA) was synthesized and used for the efficient collection of lepidolite. Dodecylamine (DA), a commonly used collector of lepidolite ore, was used for comparison. The collecting performances of DA and DPA for lepidolite were studied by the micro-flotation experiment, and the adsorption mechanism of DPA on lepidolite was verified by contact angle, zeta potential tests, FTIR spectra, and density functional theory (DFT) calculations. The results of flotation experiments showed that at the same collector dosage (3 × 10-4 mol/L), the recovery of lepidolite could reach 90%, while the recovery of lepidolite with DA was only 52.5%, and to achieve the maximum recovery of DA (77.5%), only half of the DPA was added. The contact angle test results showed that DPA could effectively improve the hydrophobicity of lepidolite than DA. FTIR spectra and zeta potential tests suggested that DPA molecules were adsorbed on the lepidolite surface by electrostatic attraction. DFT calculations revealed that DPA reacted with the nucleophilic reagent (lepidolite) by the reactive site of the -CH2NH(CH2)2C(NOH)N+H3 group and more easily absorbed on the surface of lepidolite than DA. Therefore, our new finding will provide an important prospect for the sustainable development and utilization of lithium resources.
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The separation and enrichment of scheelite from calcite are hindered by the similar active Ca2+ sites of scheelite and the calcite with calciferous gangue. Herein, a novel trisiloxane surfactant, N-(2-aminoethyl)-3-aminopropyltrisiloxane (AATS), was first explored and synthesized and recommended as the collector for the flotation separation of scheelite from calcite. The micro-flotation and mixed binary mineral flotation tests showed that AATS had excellent collection performance for scheelite and high selectivity for calcite within a wide pH range. At the same time, contact angle and zeta-potential measurements, Fourier transform infrared (FTIR) analysis, and density functional theory (DFT) calculations revealed the relevant adsorption mechanism. The contact angle measurement showed that AATS can increase the contact angle of the scheelite surface from 41.7 to 95.8°, greatly enhancing the hydrophobicity of the mineral surface. The results of FTIR analysis and zeta-potential measurement explained that AATS was electrostatically adsorbed on the mineral surface, and DFT calculation further verified that the -N+H3-positive group in AATS was adsorbed on the negatively charged scheelite surface. Therefore, AATS can realize the expectation of high efficiency and selectivity of minerals and enhance the adhesion between the surface of scheelite minerals and bubbles, providing a fresh approach to industrial production.
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BACKGROUND: Pregnant women expecting twins are more likely to experience stress, which can lead to anxiety and depression. Our aim was to investigate the prevalence of prenatal anxiety and depressive symptoms in women with twin pregnancies and the associated factors. METHODS: In a cross-sectional survey, 210 women with twin pregnancies who satisfied the inclusion and exclusion criteria in two tertiary centers in Southwestern China were asked to complete a basic information form, the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS). To compare statistics with normal distribution in distinct characteristic groups, a paired t-test, and one-way ANOVA were utilized. Binary logistic step regression was used to analyze the associated factors of antenatal anxiety and depressive symptoms. RESULTS: The 210 women with twin pregnancies (age = 30.8 ± 4.2 years) were between 7 and 37 gestational weeks (29.2 ± 1.2 weeks), were typically well-educated (72.4% had a post-high-school degree), and reasonably affluent (88.1% were above the low-income cutoff). Among them, 34.8% had symptoms associated with clinical levels of anxiety, and 37.1% had symptoms indicating possible depression. The prevalence of co-morbid anxiety and depressive symptoms was 24.3%. Binary stepwise logistic regression analysis showed that previous health status and sleep disturbance during pregnancy were the associated factors of anxiety symptoms in women with twin pregnancies (P < 0.05), whereas age, previous health status, negative life events, and physical activity during pregnancy were the associated factors of depressive symptoms in women with twin pregnancies (P < 0.05). CONCLUSION: About one-third of women with twin pregnancies had symptoms of anxiety or depression; these were most strongly predicted by some modifiable factors, suggesting that early preventive mind-body interventions may be a promising strategy to protect against mental health issues for women with twin pregnancies.