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The self-assembly of the lanthanide metal-organic frameworks presents a formidable challenge but profound significance. Compared with the metal-organic frameworks based on 4f-3d ions, the chemistry of 4f-3p metal-organic frameworks has not been fully explored so far. In this study, two lanthanide-aluminum-based clusters [Ln6Al(IN)10(µ3-OH)5(µ3-O)3(H2O)8]·xH2O (x = 2, Ln = Gd, abbreviated as Gd6Al; x = 2.5, Ln = Eu, abbreviated as Eu6Al; HIN = isonicotinic acid) have been meticulously designed and obtained by hydrothermal reaction at low pH. The crystallographic study revealed that both Gd6Al and Eu6Al clusters exhibit an unprecedented sandwiched metal-organic framework holding a highly ordered honeycomb network. To our knowledge, it is the first case of Ln-Al-based cluster-organic frameworks. Furthermore, magnetic investigation of Gd6Al manifests a decent magnetic entropy change of -ΔSmmax = 28.8 J kg-1 K-1 at 2 K for ΔH = 7.0 T. Significantly, the introduction of AlIII ions into the lanthanide metal-organic frameworks displays excellent solid-state luminescent capability with a lifetime of 371.6 µs and quantum yield of 6.64%. The construction and investigation of these two Ln-Al clusters represent great progress in the 4f-3p metal-organic framework.
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Joint profiling of transcriptome and chromatin accessibility within single cells allows for the deconstruction of the complex relationship between transcriptional states and upstream regulatory programs determining different cell fates. Here, we developed an automated method with high sensitivity, assay for single-cell transcriptome and accessibility regions (ASTAR-seq), for simultaneous measurement of whole-cell transcriptome and chromatin accessibility within the same single cell. To show the utility of ASTAR-seq, we profiled 384 mESCs under naive and primed pluripotent states as well as a two-cell like state, 424 human cells of various lineage origins (BJ, K562, JK1, and Jurkat), and 480 primary cord blood cells undergoing erythroblast differentiation. With the joint profiles, we configured the transcriptional and chromatin accessibility landscapes of discrete cell states, uncovered linked sets of cis-regulatory elements and target genes unique to each state, and constructed interactome and transcription factor (TF)-centered upstream regulatory networks for various cell states.
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Cromatina/metabolismo , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Análisis de la Célula Individual/métodos , Animales , Diferenciación Celular , Línea Celular , Células Cultivadas , Células Madre Embrionarias , Epigénesis Genética , Eritroblastos/citología , Eritroblastos/metabolismo , Humanos , Ratones , Elementos Reguladores de la Transcripción , Factores de Transcripción/metabolismo , TranscriptomaRESUMEN
Acute exacerbation (AE) is the main cause of increased disability and mortality for patients with Chronic Obstructive Pulmonary Disease (COPD). Short-term re-exacerbation after discharge is common for in-hospital patients with AECOPD. Thus, we aimed to design a scoring system to effectively predict the 30-day re-exacerbation using simple and easily accessible variables. We retrospectively enrolled 686 cases hospitalized for AECOPD in two Chinese hospitals from 2005 to 2017. A variety of parameters were collected like demographics, clinical manifestations and treatments in stable and AE period. The optimal subset of covariates in the multivariate logistic analysis was identified by the smallest Akaike Information Criterion (AIC) and was further used to develop a practical and reliable nomogram to predict the 30-day re-exacerbation. The efficacy of the nomogram was internally validated by concordance index (C-index) and a calibration plot. The incidence of 30-day re-exacerbation was 15.8%. Based on the smallest AIC, eight easily-accessible parameters were included in the nomogram, including sex, COPD assessment test (CAT) scores, AE with respiratory failure in the previous year, new purulent sputum, new cardiovascular events, combined antibiotic therapy, theophylline therapy for AE and ICU admission. Our nomogram revealed good discriminative ability with the C-index of 0.702. The calibration curve showed good agreement between nomogram-predicted probability and actual observation. Incorporating eight common variables, a nomogram for 30-day re-exacerbation after discharge with high predictive performance was constructed for patients with AECOPD, which was helpful in predicting individualized risk of re-exacerbation and offering individualized post-discharge support.
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Reglas de Decisión Clínica , Hospitalización , Nomogramas , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Glucocorticoids are commonly used for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Inhaled corticosteroids are associated with a significantly increased risk of pneumonia. Syndecan-1 (SDC1) located in the cell membrane of airway epithelial cell is the crucial molecule mediating infections by P. aeruginosa (PA). In the present study, we found that SDC1 expression was upregulated and the adhesion of PA to human bronchial epithelial (HBE) cells increased to 125 and 138%, respectively, after stimulation by dexamethasone or budesonide. The HBE cells knocking down SDC1 showed lower affinity to PA compared with control. CCAAT-enhancer-binding protein ß (C/EBP ß) and its phosphorylated form participated in the regulation of glucocorticoid to SDC1 for interfering C/EBP ß or inhibiting phosphorylation of C/EBP ß by LiCl and BIO, which are inhibitors of glycogen synthase kinase 3ß (GSK-3ß), and could prevent glucocorticoids from upregulating SDC1 expression. One should be cautious in administering glucocorticoids in chronic lung disease because of their property of increasing the expression of SDC1 and PA binding to the airway epithelium.
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The hepatic disposition of estradiol 17beta-D-glucuronide (E(2)17G), a substrate of the organic anion-transporting polypeptides Oatp1a1, Oatp1a4, and Oatp1b2, was investigated in Wistar and TR(-) [multidrug resistance-associated protein (Mrp) 2-mutant] rats to elucidate how absence of Mrp2, the major excretory transporter for both E(2)17G and its 3-sulfate metabolite (E(2)3S17G), affected the net sulfation. With absence of Mrp2, lower microsomal desulfation activity and higher Mrp3 but unchanged immunoreactive protein expression of other transporters (Oatps and Mrp4) and estrogen sulfotransferase were found in TR(-) rats. In recirculating, perfused liver preparations, the rapid decay of E(2)17G and sluggish appearance of low levels of E(2)3S17G in perfusate for Wistar livers were replaced by a protracted, biexponential decay of E(2)17G and greater accumulation of E(2)3S17G, whose levels reached plateaus upon the almost complete obliteration of biliary excretion of E(2)17G and E(2)3S17G in the TR(-) liver. Much higher amounts of E(2)17G (28x) and E(2)3S17G (11x) in liver and reduced net sulfation (40 +/- 6 from 77 +/- 6% dose, P < 0.05) were observed at 2 h for the TR(-) versus the Wistar rats. With use of a physiologically based pharmacokinetic model, analytical solutions for the areas under the curve for the precursor and metabolite were obtained to reveal how enzyme- and transporter-mediated processes affected the hepatic disposition of the precursor and metabolite in futile cycling. The analytical solutions were useful to explain transporter-enzyme interplay in futile cycling and predicted that a shutdown of Mrp2 function led to decreased net sulfation of E(2)17G by raising the intracellular concentration of the metabolite, E(2)3S17G, which readily refurnished E(2)17G via desulfation.
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Estradiol/análogos & derivados , Hígado/metabolismo , Fase II de la Desintoxicación Metabólica/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Ciclo del Sustrato/genética , Ésteres del Ácido Sulfúrico/metabolismo , Animales , Área Bajo la Curva , Arilsulfotransferasa/metabolismo , Bilis/metabolismo , Simulación por Computador , Estradiol/metabolismo , Estradiol/farmacocinética , Masculino , Microsomas Hepáticos/metabolismo , Modelos Biológicos , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Transportadores de Anión Orgánico/metabolismo , Perfusión , Farmacocinética , Ratas , Ratas Transgénicas , Ratas Wistar , Sulfotransferasas/metabolismo , Ésteres del Ácido Sulfúrico/farmacocinéticaRESUMEN
BACKGROUND: Despite the release of a national guideline in 2016, the actual practices with respect to adult community-acquired pneumonia (CAP) remain unknown in China. We aimed to investigate CAP patient management practices in Shanghai to identify potential problems and provide evidence for policy making. METHODS: A short-period, 5-day prospective cross-sectional study was performed with sampled pulmonologists from 36 hospitals, encompassing all the administrative districts of Shanghai, during January 8-12, 2018. The medical information was recorded and analyzed for the patients with the diagnosis of CAP who were cared for by 46 pulmonologists during the study period. RESULTS: Overall, 435 patients were included in the final analysis, and 94.3% had a low risk of death in terms of CRB-65 criteria (C: disturbance of consciousness, R: respiratory rate, B: blood pressure, 65: age). When diagnosed with CAP, 70.1% of patients were not evaluated using the CURB-65 score (CRB-65 + U: urea nitrogen), but most patients (95.4%) were evaluated using CRB-65. Time to achieve clinical stability was longer in patients with hypoxemia than in those without hypoxemia (8.42±6.36 vs. 5.53±4.12 days, P=0.004). Overall, 84.4% of patients with a CRB-65 score of 0 were administered antibiotics intravenously, and 19.4% were still hospitalized after excluding hypoxemia and comorbidities. The average duration of antibiotic treatment was 10.4±4.9 days. Overall, 72.6% of patients received antibiotics covering atypical pathogens whose time to clinical stability was significantly shortened compared with those without coverage, but the antibiotic duration was similar and not correspondingly shortened. CONCLUSIONS: CRB-65 seems to be more practical than CURB-65 for the initial evaluation of CAP in the context of local practice, and oxygenation assessment should be included in the evaluation of severity. Overtreatment may be relatively common in patients at low risk of death, including unreasonable hospitalization, intravenous administration, and antibiotic duration.
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BACKGROUND: COPD, characterized by chronic inflammation and airway remodeling, has significant pathological alterations in composition and deposition of the extracellular matrix. The expression of procollagen 1 C-terminal peptide (PICP) and collagen type 1 C-terminal telopeptide (ICTP), two major by-products in the synthesis and degradation of collagen, was shown to be positively correlated with inflammatory mediator levels in previous studies. PURPOSE: In this study, we investigated whether the serum concentrations of PICP and ICTP were associated with the inflammation level for patients with stable COPD. PATIENTS AND METHODS: We collected serum samples from 25 control subjects and 20 patients with stable COPD from December 2011 to October 2012 in Shanghai Zhongshan Hospital and Shanghai Dahua Hospital. We determined concentrations of PICP, ICTP, C-reactive protein (CRP), IL-6, IL-8, and tumor necrosis factor (TNF)-α by using enzyme-linked immunosorbent assay methods. RESULTS: Demographic characteristics were comparable between the two groups. In patients with stable COPD, serum levels of CRP, IL-6, IL-8, and TNF-α were all elevated compared to control subjects, but only changes of IL-6 achieved statistical significance. Serum concentration of PICP was significantly elevated in patients with COPD, and level of ICTP was slightly decreased. Moreover, serum concentrations of PICP were positively correlated with the levels of both IL-6 and IL-8. CONCLUSION: The increased levels of serum PICP in COPD might indicate the condition of airway remodeling, and IL-6 and/or IL-8 might play an important role in stimulating collagen synthesis.
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Colágeno Tipo I/sangre , Mediadores de Inflamación/sangre , Interleucina-6/sangre , Interleucina-8/sangre , Fragmentos de Péptidos/sangre , Péptidos/sangre , Procolágeno/sangre , Enfermedad Pulmonar Obstructiva Crónica/sangre , Anciano , Remodelación de las Vías Aéreas (Respiratorias) , Biomarcadores/sangre , Estudios de Casos y Controles , China , Femenino , Volumen Espiratorio Forzado , Humanos , Pulmón/metabolismo , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Índice de Severidad de la Enfermedad , Regulación hacia Arriba , Capacidad VitalRESUMEN
PURPOSE: By reanalyzing the gene expression profile GSE76925 in the Gene Expression Omnibus database using bioinformatic methods, we attempted to identify novel candidate genes promoting the development of emphysema in patients with COPD. PATIENTS AND METHODS: According to the Quantitative CT data in GSE76925, patients were divided into mild emphysema group (%LAA-950<20%, n=12) and severe emphysema group (%LAA-950>50%, n=11). Differentially expressed genes (DEGs) were identified using Agilent GeneSpring GX v11.5 (corrected P-value <0.05 and |Fold Change|>1.3). Known driver genes of COPD were acquired by mining literatures and retrieving databases. Direct protein-protein interaction network (PPi) of DEGs and known driver genes was constructed by STRING.org to screen the DEGs directly interacting with driver genes. In addition, we used STRING.org to obtain the first-layer proteins interacting with DEGs' products and constructed the indirect PPi of these interaction proteins. By merging the indirect PPi with driver genes' PPi using Cytoscape v3.6.1, we attempted to discover potential pathways promoting emphysema's development. RESULTS: All the patients had COPD with severe airflow limitation (age=62±8, FEV1%=28±12). A total of 57 DEGs (including 12 pseudogenes) and 135 known driving genes were identified. Direct PPi suggested that GPR65, GNB4, P2RY13, NPSR1, BCR, BAG4, and IMPDH2 were potential pathogenic genes. GPR65 could regulate the response of immune cells to the acidic microenvironment, and NPSR1's expression on eosinophils was associated with asthma's severity and IgE level. Indirect merging PPi demonstrated that the interacting network of TP53, IL8, CCR2, HSPA1A, ELANE, PIK3CA was associated with the development of emphysema. IL8, ELANE, and PIK3CA were molecules involved in the pathological mechanisms of emphysema, which also in return proved the role of TP53 in emphysema. CONCLUSION: Candidate genes such as GPR65, NPSR1, and TP53 may be involved in the progression of emphysema.
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Biología Computacional , Redes Reguladoras de Genes , Enfisema Pulmonar/genética , Anciano , Bases de Datos Genéticas , Progresión de la Enfermedad , Femenino , Volumen Espiratorio Forzado , Perfilación de la Expresión Génica/métodos , Estudios de Asociación Genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Enfisema Pulmonar/diagnóstico por imagen , Enfisema Pulmonar/fisiopatología , Receptores Acoplados a Proteínas G/genética , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X , Transcriptoma , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Glucocorticoids (GCs) are vital multi-faceted hormones with recognized effects on carbohydrate, protein and lipid metabolism. Previous studies with the steroid antagonist, RU486 have underscored the essential role of GCs in the regulation of these metabolic pathways. This article describes the discovery and characterization of novel GRalpha selective nonsteroidal antagonists (NSGCAs). NSGCAs 2 and 3 are spirocyclic dihydropyridine derivatives that selectively bind the GRalpha with IC(50s) of 2 and 1.5 nM, respectively. Importantly, these compounds are full antagonists of the induction by dexamethasone (Dex) of marker genes for glucose and glutamine metabolism; the tyrosine amino transferase (TAT) and glutamine synthetase (GS) enzymes, respectively. In contrast, GC-dependent transcriptional repression of the collagenase 1 (MMP-1) enzyme, an established GRalpha responsive proinflammatory gene; is poorly antagonized by these compounds. These NSGCAs might have useful applications as tools in metabolic research and drug discovery.