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Remarkable perturbations in the stratospheric abundances of chlorine species and ozone were observed over Southern Hemisphere mid-latitudes following the 2020 Australian wildfires1,2. These changes in atmospheric chemical composition suggest that wildfire aerosols affect stratospheric chlorine and ozone depletion chemistry. Here we propose that wildfire aerosol containing a mixture of oxidized organics and sulfate3-7 increases hydrochloric acid solubility8-11 and associated heterogeneous reaction rates, activating reactive chlorine species and enhancing ozone loss rates at relatively warm stratospheric temperatures. We test our hypothesis by comparing atmospheric observations to model simulations that include the proposed mechanism. Modelled changes in 2020 hydrochloric acid, chlorine nitrate and hypochlorous acid abundances are in good agreement with observations1,2. Our results indicate that wildfire aerosol chemistry, although not accounting for the record duration of the 2020 Antarctic ozone hole, does yield an increase in its area and a 3-5% depletion of southern mid-latitude total column ozone. These findings increase concern2,12,13 that more frequent and intense wildfires could delay ozone recovery in a warming world.
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Aerosoles , Cloro , Pérdida de Ozono , Ozono , Incendios Forestales , Aerosoles/efectos adversos , Aerosoles/análisis , Aerosoles/química , Australia , Cloro/análisis , Cloro/química , Ácido Clorhídrico/química , Ozono/análisis , Ozono/química , Calentamiento GlobalRESUMEN
Despite the explosive growth of genomic data, functional annotation of regulatory sequences remains difficult. Here, we introduce "comparative epigenomics"-interspecies comparison of DNA and histone modifications-as an approach for annotation of the regulatory genome. We measured in human, mouse, and pig pluripotent stem cells the genomic distributions of cytosine methylation, H2A.Z, H3K4me1/2/3, H3K9me3, H3K27me3, H3K27ac, H3K36me3, transcribed RNAs, and P300, TAF1, OCT4, and NANOG binding. We observed that epigenomic conservation was strong in both rapidly evolving and slowly evolving DNA sequences, but not in neutrally evolving sequences. In contrast, evolutionary changes of the epigenome and the transcriptome exhibited a linear correlation. We suggest that the conserved colocalization of different epigenomic marks can be used to discover regulatory sequences. Indeed, seven pairs of epigenomic marks identified exhibited regulatory functions during differentiation of embryonic stem cells into mesendoderm cells. Thus, comparative epigenomics reveals regulatory features of the genome that cannot be discerned from sequence comparisons alone.
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Secuencia Conservada , Metilación de ADN , Epigenómica/métodos , Código de Histonas , Elementos Reguladores de la Transcripción , Animales , Secuencia de Bases , Células Madre Embrionarias/metabolismo , Regulación de la Expresión Génica , Humanos , Ratones , Células Madre Pluripotentes/metabolismo , Porcinos , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
Cloud condensation nuclei (CCN) can affect cloud properties and therefore Earth's radiative balance1-3. New particle formation (NPF) from condensable vapours in the free troposphere has been suggested to contribute to CCN, especially in remote, pristine atmospheric regions4, but direct evidence is sparse, and the magnitude of this contribution is uncertain5-7. Here we use in situ aircraft measurements of vertical profiles of aerosol size distributions to present a global-scale survey of NPF occurrence. We observe intense NPF at high altitudes in tropical convective regions over both Pacific and Atlantic oceans. Together with the results of chemical-transport models, our findings indicate that NPF persists at all longitudes as a global-scale band in the tropical upper troposphere, covering about 40 per cent of Earth's surface. Furthermore, we find that this NPF in the tropical upper troposphere is a globally important source of CCN in the lower troposphere, where CCN can affect cloud properties. Our findings suggest that the production of CCN as new particles descend towards the surface is not adequately captured in global models, which tend to underestimate both the magnitude of tropical upper tropospheric NPF and the subsequent growth of new particles to CCN sizes.
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Atmósfera , Material Particulado , Aerosoles , Océano Atlántico , Modelos Químicos , Océano Pacífico , Clima TropicalRESUMEN
SignificanceLarge wildfires have been observed to inject smoke into the stratosphere, raising questions about their potential to affect the stratospheric ozone layer that protects life on Earth from biologically damaging ultraviolet radiation. Multiple observations of aerosol and NO2 concentrations from three independent satellite instruments are used here together with model calculations to identify decreases in stratospheric NO2 concentrations following major Australian 2019 through 2020 wildfires. The data confirm that important chemistry did occur on the smoke particle surfaces. The observed behavior in NO2 with increasing particle concentrations is a marker for surface chemistry that contributes to midlatitude ozone depletion. The results indicate that increasing wildfire activity in a warming world may slow the recovery of the ozone layer.
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Altitud , Material Particulado/química , Humo/análisis , Ozono Estratosférico/química , Incendios Forestales , AustraliaRESUMEN
PURPOSE: To explore the predictive value of radiomics in predicting stroke-associated pneumonia (SAP) in acute ischemic stroke (AIS) patients and construct a prediction model based on clinical features and DWI-MRI radiomics features. METHODS: Univariate and multivariate logistic regression analyses were used to identify the independent clinical predictors for SAP. Pearson correlation analysis and the least absolute shrinkage and selection operator with ten-fold cross-validation were used to calculate the radiomics score for each feature and identify the predictive radiomics features for SAP. Multivariate logistic regression was used to combine the predictive radiomics features with the independent clinical predictors. The prediction performance of the SAP models was evaluated using receiver operating characteristics (ROC), calibration curves, decision curve analysis, and subgroup analyses. RESULTS: Triglycerides, the neutrophil-to-lymphocyte ratio, dysphagia, the National Institutes of Health Stroke Scale (NIHSS) score, and internal carotid artery stenosis were identified as clinically independent risk factors for SAP. The radiomics scores in patients with SAP were generally higher than in patients without SAP (P < 0. 05). There was a linear positive correlation between radiomics scores and NIHSS scores, as well as between radiomics scores and infarct volume. Infarct volume showed moderate performance in predicting the occurrence of SAP, with an AUC of 0.635. When compared with the other models, the combined prediction model achieved the best area under the ROC (AUC) in both training (AUC = 0.859, 95% CI 0.759-0.936) and validation (AUC = 0.830, 95% CI 0.758-0.896) cohorts (P < 0.05). The calibration curves and decision curve analysis further confirmed the clinical value of the nomogram. Subgroup analysis showed that this nomogram had potential generalization ability. CONCLUSION: The addition of the radiomics features to the clinical model improved the prediction of SAP in AIS patients, which verified its feasibility.
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Accidente Cerebrovascular Isquémico , Neumonía , Accidente Cerebrovascular , Estados Unidos , Humanos , Estudios de Factibilidad , Radiómica , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/epidemiología , InfartoRESUMEN
The Montreal Protocol was designed to protect the stratospheric ozone layer by enabling reductions in the abundance of ozone-depleting substances such as chlorofluorocarbons (CFCs) in the atmosphere1-3. The reduction in the atmospheric concentration of trichlorofluoromethane (CFC-11) has made the second-largest contribution to the decline in the total atmospheric concentration of ozone-depleting chlorine since the 1990s 1 . However, CFC-11 still contributes one-quarter of all chlorine reaching the stratosphere, and a timely recovery of the stratospheric ozone layer depends on a sustained decline in CFC-11 concentrations 1 . Here we show that the rate of decline of atmospheric CFC-11 concentrations observed at remote measurement sites was constant from 2002 to 2012, and then slowed by about 50 per cent after 2012. The observed slowdown in the decline of CFC-11 concentration was concurrent with a 50 per cent increase in the mean concentration difference observed between the Northern and Southern Hemispheres, and also with the emergence of strong correlations at the Mauna Loa Observatory between concentrations of CFC-11 and other chemicals associated with anthropogenic emissions. A simple model analysis of our findings suggests an increase in CFC-11 emissions of 13 ± 5 gigagrams per year (25 ± 13 per cent) since 2012, despite reported production being close to zero 4 since 2006. Our three-dimensional model simulations confirm the increase in CFC-11 emissions, but indicate that this increase may have been as much as 50 per cent smaller as a result of changes in stratospheric processes or dynamics. The increase in emission of CFC-11 appears unrelated to past production; this suggests unreported new production, which is inconsistent with the Montreal Protocol agreement to phase out global CFC production by 2010.
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BACKGROUND: The symptoms of functional constipation (FC) were obviously affected by mental symptoms, which was consistent with somatic symptoms. However, the characteristics of FC patients with somatic symptom remains unexplored. METHODS: Clinical characteristics including somatic symptom (SOM, PHQ-15), depression (PHQ-9), anxiety (GAD-7), quality of life (PAC-QOL), constipation (KESS), demographic variables, anatomical abnormalities and symptoms were investigated. Subsequent analyses encompassed the comparison of clinical parameters between patients with SOM + group (PHQ-15 ≥ 10) and SOM- group (PHQ-15 < 10), subgroup analysis, correlation analysis, and logistic regression. Lastly, we evaluated the somatic symptom severity (SSS) among FC patients subjected to various stressors. RESULTS: Notable disparities were observed between SOM + and SOM- groups in variety of physiological and psychological variables, including gender, stressful events, sleep disorders, reduced interest, GAD-7, PHQ-15, PHQ-9, PAC-QOL, anterior rectocele, KESS, and internal anal sphincter achalasia (IASA) (P < 0.05). Subgroup analysis affirmed consistent findings across mental symptoms. Correlation analyses revealed significant associations between SSS and KESS, anterior rectocele, GAD-7, PHQ-9, and PAC-QOL (P < 0.05). Logistic regression identified PHQ-9 (OR = 7.02, CI: 2.06-27.7, P = 0.003), GAD-7 (OR = 7.18, CI: 2.00-30.7, P = 0.004), and KESS (OR = 16.8, CI: 3.09-113, P = 0.002) as independent predictors of SSS. Elevated SSS scores were significantly associated with couple, parental, and work-related stressors (P < 0.05). CONCLUSION: A marked heterogeneity was observed between SOM + and SOM- patients of FC, with SOM + accompanied by more severe constipation, anxiety and depression symptoms. This finding underscores the importance of considering somatic symptoms in diagnosis and treatment of FC.
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Síntomas sin Explicación Médica , Calidad de Vida , Humanos , Calidad de Vida/psicología , Estudios Transversales , Rectocele , Encuestas y Cuestionarios , Pacientes Ambulatorios , Ansiedad/diagnóstico , Depresión/diagnóstico , Depresión/psicología , Estreñimiento/diagnósticoRESUMEN
Genomes can be edited by homologous recombination stimulated by CRISPR/Cas9 [clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated peptide 9]-induced DNA double-strand breaks. However, this approach is inefficient for inserting or deleting long fragments in mammalian cells. Here, we describe a simple genome-editing method, termed transcription-coupled Cas9-mediated editing (TEd), that can achieve higher efficiencies than canonical Cas9-mediated editing (CEd) in deleting genomic fragments, inserting/replacing large DNA fragments and introducing point mutations into mammalian cell lines. We also found that the transcription on DNA templates is crucial for the promotion of homology-directed repair, and that tethering transcripts from TEd donors to targeted sites further improves editing efficiency. The superior efficiency of TEd for the insertion and deletion of long DNA fragments expands the applications of CRISPR for editing mammalian genomes.
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Sistemas CRISPR-Cas , Edición Génica , Animales , Edición Génica/métodos , Sistemas CRISPR-Cas/genética , Recombinación Homóloga/genética , Roturas del ADN de Doble Cadena , ADN/genética , Mamíferos/genéticaRESUMEN
BACKGROUND: Many studies have shown that adverse childhood experiences (ACEs) lead to adverse social relations in middle-aged and older adults and harm physical and mental health, but few studies have focused on the impact of ACEs on marital status in middle-aged and older adults and the potential influence of marital status between ACEs and depressive symptoms. PURPOSE: This study aimed to analyze the effect of ACEs on marital status and depressive symptoms in the Chinese middle-aged and older adults, and to explore the mediating role of marital status in the association between ACEs and depressive symptoms in middle-aged and older adults. METHOD: This study used the China Health and Retirement Longitudinal Study (CHARLS) 2014 life history survey and 2015 and 2018 follow-up data to analyze, ten ACEs conditions and marital status were collected by questionnaire, using the Center for Epidemiological Studies Depression Scale (CESD-10) 10-item short form to assess depressive symptoms. The association between cumulative ACEs and marital status was assessed by constructing a multinomial logistic regression (MLR) model, as well as a binary logistic regression model to assess the association between ACEs and depressive symptoms. The mediating role of marital status in the association between ACEs and depressive symptoms was also assessed. RESULTS: A total of 10,246 individuals aged 45 years or older were included in the analysis. Compared to individuals who did not experience ACEs, those who experienced two or more ACEs had a higher risk of being unmarried (seperated/divorced/never married) (OR = 1.67, 95% CI=[1.10,2.51]) and a higher risk of depressive symptoms (OR = 1.66, 95% CI=[1.49,1.84]) in middle and old age. Unmarried status partially mediated the association of ACEs with depressive symptoms. CONCLUSION: Chinese middle-aged and older people who experienced two or more ACEs have higher risks of unmarried status and depressive symptoms, and unmarried status partially mediated the ACEs-depressive symptom association. These findings reveal the fact that we need to develop life-cycle public health strategies to reduce exposure to ACEs and society should give more attention to the marital status of older people, thereby reducing the risk of depression among middle-aged and older adults in China.
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Experiencias Adversas de la Infancia , Depresión , Estado Civil , Humanos , China/epidemiología , Femenino , Masculino , Depresión/epidemiología , Depresión/psicología , Persona de Mediana Edad , Estado Civil/estadística & datos numéricos , Anciano , Estudios Longitudinales , Experiencias Adversas de la Infancia/estadística & datos numéricos , Experiencias Adversas de la Infancia/psicología , Encuestas y Cuestionarios , Pueblos del Este de AsiaRESUMEN
The utilization of assisted reproductive technologies (ART) is on the rise, resulting in a growing population of ART-conceived offspring. The health concerns of this unique population have attracted significant attention. During ART procedures, gametes and early-stage embryos are exposed to various non-physiological conditions, such as manipulation, culture media, and cryopreservation, which may disrupt embryonic development and potentially impact the health of offspring. Notably, the potential impact of ART on neurodevelopment and its association with an increased risk of neurodevelopmental disorders (NDD) later in life remains a subject of debate. This review aims to summarize the current research advancements concerning the effects of ART on neurodevelopment, specifically focusing on the evidence of the relationship between ART, epigenetic modifications, and NDD, including autism spectrum disorder, intellectual disability, attention deficit hyperactivity disorder, and cerebral palsy. Future studies should prioritize large sample sizes, rigorous adjustment for confounding factors, and the use of interdisciplinary approaches to effectively monitor the neurodevelopmental outcomes of ART-conceived children.
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Trastorno del Espectro Autista , Trastornos del Neurodesarrollo , Embarazo , Femenino , Niño , Humanos , Trastorno del Espectro Autista/etiología , Técnicas Reproductivas Asistidas/efectos adversos , Epigénesis Genética , Trastornos del Neurodesarrollo/etiologíaRESUMEN
DNA-PKcs is a crucial protein target involved in DNA repair and response pathways, with its abnormal activity closely associated with the occurrence and progression of various cancers. In this study, we employed a deep learning-based screening and molecular dynamics (MD) simulation-based pipeline, identifying eight candidates for DNA-PKcs targets. Subsequent experiments revealed the effective inhibition of DNA-PKcs-mediated cell proliferation by three small molecules (5025-0002, M769-1095, and V008-1080). These molecules exhibited anticancer activity with IC50 (inhibitory concentration at 50%) values of 152.6 µM, 30.71 µM, and 74.84 µM, respectively. Notably, V008-1080 enhanced homology-directed repair (HDR) mediated by CRISPR/Cas9 while inhibiting non-homologous end joining (NHEJ) efficiency. Further investigations into the structure-activity relationships unveiled the binding sites and critical interactions between these small molecules and DNA-PKcs. This is the first application of DeepBindGCN_RG in a real drug screening task, and the successful discovery of a novel DNA-PKcs inhibitor demonstrates its efficiency as a core component in the screening pipeline. Moreover, this study provides important insights for exploring novel anticancer therapeutics and advancing the development of gene editing techniques by targeting DNA-PKcs.
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Proteína Quinasa Activada por ADN , Simulación de Dinámica Molecular , Humanos , Proteína Quinasa Activada por ADN/antagonistas & inhibidores , Proteína Quinasa Activada por ADN/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Ensayos Analíticos de Alto Rendimiento/métodos , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Reparación del ADN por Unión de Extremidades/efectos de los fármacos , Simulación del Acoplamiento Molecular , Sitios de UniónRESUMEN
BACKGROUND: The increasing demand for sustainable alternatives to traditional protein sources, driven by population growth, underscores the importance of protein in a healthy diet. Pecan (Carya illinoinensis (Wangenh.) K. Koch) nuts are currently underutilized as plant-based proteins but hold great potential in the food industry. However, there is insufficient information available on pecan protein, particularly its protein fractions. This study aimed to explore the physicochemical and functional properties of protein isolate and the main protein fraction glutelin extracted from pecan nuts. RESULTS: The results revealed that glutelin (820.67 ± 69.42 g kg-1) had a higher crude protein content compared to the protein isolate (618.43 ± 27.35 g kg-1), while both proteins exhibited amino acid profiles sufficient for adult requirements. The isoelectric points of protein isolate and glutelin were determined to be pH 4.0 and pH 5.0, respectively. The denaturation temperature of the protein isolate (90.23 °C) was higher than that of glutelin (87.43 °C), indicating a more organized and stable conformation. This is further supported by the fact that the protein isolate had a more stable main secondary structure than glutelin. Both proteins demonstrated improved solubility, emulsifying, and foaming properties at pH levels deviating from their isoelectric points in U-shaped curves. Compared to the protein isolate, glutelin displayed superior water and oil absorption capacity along with enhanced gelling ability. CONCLUSION: The protein isolate and glutelin from pecan nuts exhibited improved stability and competitive functional properties, respectively. The appropriate utilization of these two proteins will support their potential as natural ingredients in various food systems. © 2024 Society of Chemical Industry.
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Charge compensation from cationic and anionic redox couples accompanying Na+ (de)intercalation in layered oxide cathodes contributes to high specific capacity. However, the engagement level of different redox couples remains unclear and their relationship with Na+ content is less studied. Here we discover that it is possible to take full advantage of the high-voltage transition metal (TM) redox reaction through low-valence cation substitution to tailor the electronic structure, which involves an increased ratio of Na+ content to available charge transfer number of TMs. Taking NaxCu0.11Ni0.11Fe0.3Mn0.48O2 as the example, the Li+ substitution increases the ratio to facilitate the high-voltage TM redox activity, and further F-ion substitution decreases the covalency of the TM-O bond to relieve structural changes. As a consequence, the final high-entropy Na0.95Li0.07Cu0.11Ni0.11Fe0.3Mn0.41O1.97F0.03 cathode demonstrates â¼29% capacity increase contributed by the high-voltage TMs and exhibits excellent long-term cycling stability due to the improved structural reversibility. This work provides a paradigm for the design of high-energy-density electrodes by simultaneous electronic and crystal structure modulation.
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A growing number of studies have shown that tumor cells secrete extracellular vesicles (EVs) containing programmed death-ligand 1 (PD-L1) protein. These vesicles can travel to lymph nodes and remotely inactivate T cells, thereby evading immune system attack. Therefore, the simultaneous detection of PD-L1 protein expression in cells and EVs is of great significance in guiding immunotherapy. Herein, we developed a method based on qPCR for the simultaneous detection of PD-L1 protein and mRNA in EVs and their parental cells (PREC-qPCR assay). Lipid probes immobilized on magnetic beads were used to capture EVs directly from samples. For RNA assay, EVs were directly broken by heating and quantified with qPCR. As to protein assay, EVs were recognized and bound with specific probes (such as aptamers), which were used as templates in subsequent qPCR analysis. This method was used to analyze EVs of patient-derived tumor clusters (PTCs) and plasma samples from patients and healthy volunteers. The results revealed that the expression of exosomal PD-L1 in PTCs was correlated with tumor types and significantly higher in plasma-derived EVs from tumor patients than that of healthy individuals. When extended to cells and PD-L1 mRNAs, the results showed that the expression of PD-L1 protein was consistent with mRNA in cancer cell lines, while PTCs demonstrated significant heterogeneity. This comprehensive detection of PD-L1 at four levels (cell, EVs, protein, and mRNA) is believed to enhance our understanding of the relationship among PD-L1, tumors, and the immune system and to provide a promising tool for predicting the benefits of immunotherapy.
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Reacción en Cadena en Tiempo Real de la Polimerasa , Humanos , Neoplasias/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , ARN Mensajero/análisis , ARN Mensajero/genética , Vesículas Extracelulares/genética , Línea Celular TumoralRESUMEN
BACKGROUND: The incidence and mortality of gastric cancer ranks fifth and fourth worldwide among all malignancies, respectively. Accumulating evidences have revealed the close relationship between mitochondrial dysfunction and the initiation and progression of stomach cancer. However, rare prognostic models for mitochondrial-related gene risk have been built up in stomach cancer. METHODS: In current study, the expression and prognostic value of mitochondrial-related genes in stomach adenocarcinoma (STAD) patients were systematically analyzed to establish a mitochondrial-related risk model based on available TCGA and GEO databases. The tumor microenvironment (TME), immune cell infiltration, tumor mutation burden, and drug sensitivity of gastric adenocarcinoma patients were also investigated using R language, GraphPad Prism 8 and online databases. RESULTS: We established a mitochondrial-related risk prognostic model including NOX4, ALDH3A2, FKBP10 and MAOA and validated its predictive power. This risk model indicated that the immune cell infiltration in high-risk group was significantly different from that in the low-risk group. Besides, the risk score was closely related to TME signature genes and immune checkpoint molecules, suggesting that the immunosuppressive tumor microenvironment might lead to poor prognosis in high-risk groups. Moreover, TIDE analysis demonstrated that combined analysis of risk score and immune score, or stromal score, or microsatellite status could more effectively predict the benefit of immunotherapy in STAD patients with different stratifications. Finally, rapamycin, PD-0325901 and dasatinib were found to be more effective for patients in the high-risk group, whereas AZD7762, CEP-701 and methotrexate were predicted to be more effective for patients in the low-risk group. CONCLUSIONS: Our results suggest that the mitochondrial-related risk model could be a reliable prognostic biomarker for personalized treatment of STAD patients.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Microambiente Tumoral/genética , Mitocondrias/genética , Adenocarcinoma/genética , PronósticoRESUMEN
Asphaltenes are a group of compounds that are soluble in benzene and toluene but insoluble in nonpolar small molecule n-alkanes. The asphaltene aggregation in the asphaltene-heptane-toluene system was studied using molecular dynamics (MD) simulation, and the interaction between asphaltene molecules during this process was also revealed from the evolution of the density field, radial distribution function (RDF), and intermolecular distance of asphaltenes. Three main findings were made: (1) more asphaltene precipitates (heptane) were contained, and more asphaltene dimers or trimers were formed during the MD simulation; (2) asphaltene molecules interacted with each other to form aggregates in the form of π-π or H-bond interaction. The stable distance of the π-π interaction was 3.3-3.5 Å, and the stable distance of the H-bond connection was 1.7-1.9 Å. (3) The asphaltene interaction in the heptane-rich system was dominated by π-π interaction between asphaltene molecules. However, the asphaltene interactions in the toluene-rich system were mainly the π-π interaction between asphaltene molecules and toluene and the H-bond interaction between the side chains of asphaltene molecules. The results of this study can aid in understanding how asphaltene molecules aggregate and self-associate and can also offer theoretical support for flow assurance in systems used to produce crude oil.
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Immortalization-upregulated protein (IMUP) plays a vital role in cell proliferation and tumor progression. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we select IMUP as an alternative gene based on GeneChip analysis of clinical PDAC tissues and transcriptome data from The Cancer Genome Atlas. IMUP expression is upregulated in PDAC tumor tissues. Moreover, high IMUP expression correlates with poor prognosis, while IMUP depletion inhibits PDAC cell proliferation and colony formation capacity in vitro, and decreases xenograft tumor growth in vivo. IMUP downregulation leads to cell-cycle arrest in the S phase. IMUP knockdown increases the expression of four-and-a-half LIM domain protein 1 (FHL1), which regulates the phosphorylation of cell division cycle 25A (CDC25A) by cycle checkpoint kinase 1 (CHK1) and promotes cytoplasmic distribution of CDC25A by interaction with 14-3-3ξ. Furthermore, FHL1 knockdown restores the effects induced by IMUP depletion. Liquid chromatography tandem mass spectrometry and immunoprecipitation analysis further show that IMUP interacts directly with nucleophosmin (NPM1) and enhances its stability. DNA methylation sequencing shows that FHL1 promoter methylation decreases when IMUP is downregulated. Overexpression of NPM1 can increase the methylation level of FHL1, thereby decreasing its expression. Our study provides a novel perspective on IMUP/NPM1/FHL1-mediated cell-cycle arrest by regulating CDC25A phosphorylation in PDAC. These findings may provide a new therapeutic target for PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas con Dominio LIM/genética , Proteínas con Dominio LIM/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias PancreáticasRESUMEN
OBJECTIVES: To evaluate the efficacy of SOX combined with a programmed cell death protein-1 (PD-1) inhibitor compared with SOX alone in the perioperative management of locally advanced gastric cancer and to explore biomarkers that may predict response to anti-PD-1 therapy. METHODS: Data of patients with clinical stage T3-4aN0-3M0 (IIb-III) gastric cancer were reviewed to create a primary database. Patients treated with perioperative SOX combined with sintilimab were included in Group A, while those treated with SOX alone were included in Group B. After one-to-one propensity score matching, pathological response and short-term survival outcomes were compared between the two groups. In addition, potential efficacy-related biomarkers were analyzed. RESULTS: Between January 2018 and December 2022, a total of 150 patients were included in the analysis, with 75 patients in each group. The rates of pathological complete response (21.3% vs. 4.0%; P = 0.001) and major pathological response (45.3% vs. 22.7%; P = 0.003) in Group A were statistically higher than those in Group B. There was no significant difference in 1-year overall survival (92.8% vs. 92.0%; P = 0.392) and disease-free survival (88.9% vs. 88.0%; P = 0.357) between the two groups. Subgroup analysis of Group A showed that the pathological complete response (40.6% vs. 8.6%; P = 0.002) and major pathological response (65.6% vs. 28.6%; P = 0.002) rates were significantly higher in programmed death ligand-1-positive patients with a combined positive score of ≥ 5. A pathological complete response was achieved in 42.9% patients (3/7) with mismatch repair deficiency. For the two patients confirmed as Epstein-Barr virus-positive, one patient achieved a pathological complete response and the other achieved a major pathological response. CONCLUSIONS: The adoption of SOX combined with a PD-1 inhibitor may improve the pathological response rate of patients with locally advanced gastric cancer, especially those with programmed death ligand-1 combined positive score ≥ 5, Epstein-Barr virus-positivity and mismatch repair deficiency. However, further prospective studies are still warranted to confirm the long-term survival benefit.
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Infecciones por Virus de Epstein-Barr , Neoplasias Primarias Secundarias , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Estudios Prospectivos , Puntaje de Propensión , Herpesvirus Humano 4 , Neoplasias Primarias Secundarias/tratamiento farmacológico , Biomarcadores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Machine learning (ML) models were developed for understanding the root uptake of per- and polyfluoroalkyl substances (PFASs) under complex PFAS-crop-soil interactions. Three hundred root concentration factor (RCF) data points and 26 features associated with PFAS structures, crop properties, soil properties, and cultivation conditions were used for the model development. The optimal ML model, obtained by stratified sampling, Bayesian optimization, and 5-fold cross-validation, was explained by permutation feature importance, individual conditional expectation plot, and 3D interaction plot. The results showed that soil organic carbon contents, pH, chemical logP, soil PFAS concentration, root protein contents, and exposure time greatly affected the root uptake of PFASs with 0.43, 0.25, 0.10, 0.05, 0.05, and 0.05 of relative importance, respectively. Furthermore, these factors presented the key threshold ranges in favor of the PFAS uptake. Carbon-chain length was identified as the critical molecular structure affecting root uptake of PFASs with 0.12 of relative importance, based on the extended connectivity fingerprints. A user-friendly model was established with symbolic regression for accurately predicting RCF values of the PFASs (including branched PFAS isomerides). The present study provides a novel approach for profound insight into the uptake of PFASs by crops under complex PFAS-crop-soil interactions, aiming to ensure food safety and human health.
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Fluorocarburos , Contaminantes Químicos del Agua , Humanos , Suelo/química , Carbono , Teorema de Bayes , Fluorocarburos/análisis , Aprendizaje Automático , Contaminantes Químicos del Agua/análisisRESUMEN
Hydrogen (H) removal in plasma-facing materials (PFMs) has been an important issue in the field of manually controllable fusion reactions. The tungsten nitride (WNx) film, as a by-product on the divertor surface in the fusion reactor after nitrogen seeding, has rich H retention, and much attention should be given to hydrogen removal from WNx. In this paper, by using density functional theory calculations, we predicted a novel W24N48 crystal, which possesses nanoscale cavities and channels inside, and studied the interaction between it and hydrogen. We found that the N atoms inside the crystal are favorable for the adsorption of atomic hydrogen. When more hydrogen atoms are injected, the hydrogen atoms adsorbed in the crystal react with the newly entered hydrogen atoms to form hydrogen molecules. These newly formed H2 molecules can easily move through the nanochannels in W24N48 and serve to remove hydrogen. Our calculations suggest that when this new W24N48 material is embedded in the WNx film on the surface of the PFMs, the nanochannels will be helpful in removing and recycling hydrogen isotopes in the PFMs.