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Candida albicans is a leading cause of intravascular catheter-related infections. The capacity for biofilm formation has been proposed to contribute to the persistence of this fungal pathogen on catheter surfaces. While efforts have been devoted to identifying microbial factors that modulate C. albicans biofilm formation in vitro, our understanding of the host factors that may shape C. albicans persistence in intravascular catheters is lacking. Here, we used multiphoton microscopy to characterize biofilms in intravascular catheters removed from candidiasis patients. We demonstrated that, NETosis, a type of neutrophil cell death with antimicrobial activity, was implicated in the interaction of immune cells with C. albicans in the catheters. The catheter isolates exhibited reduced filamentation and candidalysin gene expression, specifically in the total parenteral nutrition culture environment. Furthermore, we showed that the ablation of candidalysin expression in C. albicans reduced NETosis and conferred resistance to neutrophil-mediated fungal biofilm elimination. Our findings illustrate the role of neutrophil NETosis in modulating C. albicans biofilm persistence in an intravascular catheter, highlighting that C. albicans can benefit from reduced virulence expression to promote its persistence in an intravascular catheter.
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Biopelículas , Candida albicans , Candidiasis , Infecciones Relacionadas con Catéteres , Trampas Extracelulares , Proteínas Fúngicas , Neutrófilos , Humanos , Biopelículas/crecimiento & desarrollo , Proteínas Fúngicas/metabolismo , Candidiasis/microbiología , Candidiasis/inmunología , Infecciones Relacionadas con Catéteres/microbiología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Trampas Extracelulares/inmunología , Catéteres/microbiología , Regulación Fúngica de la Expresión GénicaRESUMEN
Pycnoporus sanguineus is a fungus of the phylum Basidiomycota that has many applications in traditional medicine, modern pharmaceuticals, and agricultural industries. Light plays an essential role in the metabolism, growth, and development of fungi. This study evaluated the mycelial growth and antioxidant and anti-inflammatory activities in P. sanguineus fermentation broth (PFB) cultured under different wavelengths of LED irradiation or in the dark. Compared to the dark cultures, the dry weight of mycelia in red- and yellow-light cultures decreased by 37 and 35% and the yields of pigments increased by 30.92 ± 2.18 mg and 31.75 ± 3.06 mg, respectively. Compared with the dark culture, the DPPH free radical scavenging ability, ABTS+ free radical scavenging capacity, and reducing power of yellow-light cultures increased significantly, and their total phenolic content peaked at 180.0 ± 8.34 µg/mL. However, the reducing power in blue-light cultures was significantly reduced, though the total phenol content did not vary with that of dark cultures. In LPS- and IFN-γ-stimulated RAW 264.7 cells, nitrite release was significantly reduced in the red and yellow light-irradiated PFB compared with the dark culture. In the dark, yellow-, and green-light cultures, TNF-α production in the inflamed RAW 264.7 cells was inhibited by 62, 46, and 14%, respectively. With red-, blue-, and white-light irradiation, TNF-α production was significantly enhanced. Based on these results, we propose that by adjusting the wavelength of the light source during culture, one can effectively modulate the growth, development, and metabolism of P. sanguineus.
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Antioxidantes , Luz , Pycnoporus , Ratones , Animales , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/metabolismo , Células RAW 264.7 , Pycnoporus/metabolismo , Factores Inmunológicos/farmacología , Factores Inmunológicos/química , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Picratos/antagonistas & inhibidores , Picratos/química , Agentes Inmunomoduladores/farmacología , Agentes Inmunomoduladores/química , Compuestos de Bifenilo/antagonistas & inhibidores , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacologíaRESUMEN
In nature, biological nitrogen fixation is accomplished through the π-back-bonding mechanism of nitrogenase, which poses significant challenges for mimic artificial systems, thanks to the activation barrier associated with the N≡N bond. Consequently, this motivates us to develop efficient and reusable photocatalysts for artificial nitrogen fixation under mild conditions. We employ a charge-assisted self-assembly process toward encapsulating one polyoxometalate (POM) within a dehydrated Zr-based metal-organic framework (d-UiO-66) exhibiting nitrogen photofixation activities, thereby constructing an enzyme-mimicking photocatalyst. The dehydration of d-UiO-66 is favorable for facilitating nitrogen chemisorption and activation via the unpaired d-orbital electron at the [Zr6O6] cluster. The incorporation of POM guests enhanced the charge separation in the composites, thereby facilitating the transfer of photoexcited electrons into the π* antibonding orbital of chemisorbed N2 for efficient nitrogen fixation. Simultaneously, the catalytic efficiency of SiW9Fe3@d-UiO-66 is enhanced by 9.0 times compared to that of d-UiO-66. Moreover, SiW9Fe3@d-UiO-66 exhibits an apparent quantum efficiency (AQE) of 0.254% at 550 nm. The tactics of "working-in-tandem" achieved by POMs and d-UiO-66 are extremely vital for enhancing artificial ammonia synthesis. This study presents a paradigm for the development of an efficient artificial catalyst for nitrogen photofixation, aiming to mimic the process of biological nitrogen fixation.
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Toll-like receptor (TLR) is essential for the immune response to Mycobacterium tuberculosis (MTB) infection. However, the mechanism whereby TLR mediates the MTB-induced pleural mesothelial hyperpermeability in tuberculous pleural effusion (TBPE) remains unclear. Pleural effusion size and pleural fluid levels of vascular endothelial growth factor (VEGF) and soluble TLR2 (sTLR2) in patients with TBPE (n = 36) or transudative pleural effusion (TPE, n = 16) were measured. The effects of MTB H37Ra (MTBRa) on pleural mesothelial permeability and the expression of VEGF and zonula occludens (ZO)-1 in human pleural mesothelial cells (PMCs) were assessed. Levels of VEGF and sTLR2 were significantly elevated in TBPE compared to TPE. Moreover, effusion VEGF levels correlated positively, while sTLR2 values correlated negatively, with pleural effusion size in TBPE. In human PMCs, MTBRa substantially activated JNK/AP-1 signaling and upregulated VEGF expression, whereas knockdown of TLR2 remarkably inhibited MTBRa-induced JNK phosphorylation and VEGF overexpression. Additionally, both MTBRa and VEGF markedly reduced ZO-1 expression and induced pleural mesothelial permeability, while TLR2 silencing or pretreatment with anti-VEGF antibody significantly attenuated the MTBRa-triggered effects. Collectively, TLR2 mediates VEGF overproduction and downregulates ZO-1 expression in human PMCs, leading to mesothelial hyperpermeability in TBPE. Targeting TLR2/VEGF pathway may confer a potential treatment strategy for TBPE.
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Derrame Pleural , Tuberculosis , Humanos , Factor A de Crecimiento Endotelial Vascular/genética , Receptor Toll-Like 2/genética , Factores de Crecimiento Endotelial VascularRESUMEN
Despite extensive research documenting associations between adverse early-life experiences and negative outcomes in later life, little is known about how adverse experiences in late adolescence relate to young adulthood disadvantages. This study examines the role of adverse experiences during late adolescence on young adults' education and work trajectories in Taiwan. Drawing theories and research from human development and sociology, the study links indicators of disadvantages in young adulthood to measures of adverse experiences in late adolescence using data from the Taiwan Youth Project data (n = 1221; median ages 18, 20, and 22; 49.4% female). The analysis found that running away from home was associated with instability in education or employment and that having cumulative adverse experiences was associated with graduating with debt and instability in education or employment. Some associations were explained by financial pressure, however, taken together, the findings suggest that certain adverse experiences in late adolescence have a significant impact on disadvantaged education and work trajectories in young adulthood.
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Empleo , Adulto Joven , Humanos , Adolescente , Femenino , Adulto , Masculino , Escolaridad , Estudios LongitudinalesRESUMEN
This study aims to investigate the impact of the invasive pest Corythucha marmorata on the growth and quality of Artemi-sia argyi. The signs of insect damage at the cultivation base of A. argyi in Huanggang, Hubei were observed. The pests were identified based on morphological and molecular evidence. The pest occurrence pattern and damage mechanism were investigated. Electron microscopy, gas chromatography-mass spectrometry(GC-MS), and high performance liquid chromatography(HPLC) were employed to analyze the microstructure, volatile oils, and flavonoid content of the pest-infested leaves. C. marmorata can cause destructive damage to A. argyi. Small decoloring spots appeared on the leaf surface at the initial stage of infestation. As the damage progressed, the spots spread along the leaf veins and aggregated into patches, causing yellowish leaves and even brownish yellow in the severely affected areas. The insect frequently appeared in summer because it thrives in hot dry conditions. After occurrence on the leaves, microscopic examination revealed that the front of the leaves gradually developed decoloring spots, with black oily stains formed by the black excrement attaching to the glandular hairs. The leaf flesh was also severely damaged, and the non-glandular hairs were broken, disor-ganized, and sticky. The content of neochlorogenic acid, cryptochlorogenic acid, isochlorogenic acids A and B, hispidulin, jaceosidin, and eupatilin at the early stage of infestation was significantly higher than that at the middle stage, and the content decreased at the last stage of infestation. The content of eucalyptol, borneol, terpinyl, and caryophyllin decreased in the moderately damaged leaves and increased in the severely damaged leaves. C. marmorata was discovered for the first time on A. argyi leaves in this study, and its prevention and control deserves special attention. The germplasm materials resistant to this pest can be used to breed C. marmorata-resis-tant A. argyi varieties.
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Artemisia , Aceites Volátiles , Artemisia/química , Fitomejoramiento , Cromatografía de Gases y Espectrometría de Masas , Aceites Volátiles/análisis , Cromatografía Líquida de Alta Presión , Hojas de la Planta/químicaRESUMEN
A Positive Youth Development (PYD) perspective emphasizes adolescents' potential for healthy, successful development. Researchers have introduced a variety of constructs that may promote PYD. For example, Intentional Self-Regulation (ISR) enables youth to seek out and use resources in the environment; purpose can help youth navigate and overcome obstacles. We examine connections between ISR, purpose and two PYD outcomes: confidence and connection. Data come from 763 Scottish youth (ages 12-14). We estimated fixed-effects regression models predicting confidence and connection from both ISR and purpose, confirming outcomes were independently associated with one or both predictors. Our findings are especially salient to the field of youth purpose, linking purpose with specific PYD outcomes.
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Desarrollo del Adolescente , Autocontrol , Adolescente , Humanos , Niño , Intención , Psicología del Adolescente , LogroRESUMEN
The establishment of a heterojunction is a crucial strategy to design highly effective nonnoble metal nanocatalysts for the photocatalytic nitrogen reduction reaction (PNRR). Heteropoly blues (r-POMs) can act as electron-transfer mediators in PNRR, but its agglomeration limits the further promotion of PNRR productivity. In this work, we construct a protonation-modified surface of N-vacancy g-C3N4 (HV-C3N4), achieving the high dispersion of r-POMs via the surface modification strategy. Enlightened by the synergy effect of the nitrogenase, r-POMs were anchored onto HV-C3N4 nanosheets through an electrostatic self-assembly method for preparing r-POMs-based protonation-defective graphitic carbonitride (HV-C3N4/r-POMs). As an electron donor, r-PW12 can match with the energy level of HV-C3N4 to build a heterojunction. The electron redistribution of the heterojunction facilitates the optimization of the electronic structure for enhancing the performance of PNRR. HV-C3N4/r-PW12 exhibits the best PNRR efficiency of 171.4 µmol L-1 h-1, which is boosted by 94.39% (HV-C3N4) and 86.98% (r-PW12). The isotope 15NH4+ experiment proves that ammonia is derived from N2, not carbon nitride. This study opens up a crucial view to achieve the high dispersion of r-POMs nanoparticles and develop high-efficiency nonnoble metal photocatalysts for the PNRR.
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INTRODUCTION: Adolescence to emerging adulthood is a developmental period when individuals experience substantial biological changes and social transitions. In East Asian societies, this period is also marked by high pressure around college entrance exams. However, little is known about how young people's sleep changes over time, or how it is impacted by social institutions in the cultural context. This study fills this gap in the literature by examining sleep trajectories from adolescence to emerging adulthood using a population-based, longitudinal sample from Taiwan. METHODS: Multilevel models were applied to longitudinal data from the Taiwan Youth Project (N = 1,489) to estimate sleep trajectories from age 14 to 22 for total time in bed, bedtime, and wake-up time by gender and by educational pathway, controlling for family background. RESULTS: Analysis revealed that Taiwanese youth sleep less as adolescents than as emerging adults. Gender differences exist in adolescents' sleep trajectories but narrow after age 18. Differences in weekday and weekend time in bed vary by gender and change as individuals emerge into adulthood. Finally, college attendees and high school only attendees display differences in sleep that begin in high school and continue through college. CONCLUSIONS: The findings provide evidence of developmental changes in sleep from adolescence to emerging adulthood and demonstrate that sleep trajectories are gendered and socially patterned. The study is also one of the first to examine the sleep trajectories of East Asian youth and, as such, sheds light on the role of educational and cultural context as an influential factor.
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Trastornos del Sueño-Vigilia , Sueño , Adolescente , Adulto , Escolaridad , Humanos , Estudios Longitudinales , Instituciones Académicas , Adulto JovenRESUMEN
BACKGROUND: Numerous studies have documented factors that are associated with substance use behaviors among college-aged individuals. However, relatively few studies have considered the heterogeneity of the college experience by field of study (i.e., college major) and how that educational context might affect students' health behaviors differently. Drawing from theories and prior research, this study investigates whether college majors are associated with different substance use behaviors, both during college and upon graduation. METHODS: The study analyzed longitudinal data from the National Longitudinal Survey of Youth 97 (N = 1031), specifically data on individuals who obtained a bachelor's degree, to examine the associations between college fields of study and trajectories of three substance use behaviors: smoking, heavy alcohol use, and marijuana use. RESULTS: The results indicate that social science and business majors were associated with more substance use behaviors than arts and humanities and STEM majors. However, social science majors were associated with a faster decrease in substance use behaviors over time. Importantly, the differences we found in mean levels of substance use behaviors and trajectories were not explained by demographic characteristics, family SES background, childhood health conditions, and employment experience. Further analysis that examined college major and each substance use behavior individually suggests that the associations were stronger for heavy alcohol use and marijuana use. Moreover, we found the associations were more pronounced in men than women. CONCLUSIONS: The study finds that not all college majors show the same level of engagement in substance use behaviors over time, and that the associations also vary by (1) the specific substance use behavior examined and (2) by gender. These findings suggest it is important to consider that the different learning and educational contexts that college majors provide may also be more or less supportive of certain health behaviors, such as substance use. Practical implications are discussed.
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Humanidades , Trastornos Relacionados con Sustancias , Adolescente , Niño , Escolaridad , Femenino , Humanos , Masculino , Estudiantes , Trastornos Relacionados con Sustancias/epidemiología , Universidades , Adulto JovenRESUMEN
Dye-sensitized solar cells (DSSCs) are the third generation of photovoltaic cells developed by Grätzel and O'Regan. They have the characteristics of low cost, simple manufacturing process, tunable optical properties, and higher photoelectric conversion efficiency (PCE). With an ever increasing energy crisis, there is an urgent need to develop highly efficient, environmentally benign, and energy-saving cell materials. Polyoxometalates (POMs), a kind of molecular inorganic quasi-semiconductor, are promising candidates for use in different parts of DSSCs due to their excellent photosensitivity, redox, and catalytic properties, as well as their relative stability. Following a brief introduction to the development of DSSCs and the potential virtues of POMs in DSSCs, we attempt to make some generalizations about the energy level regulation of POMs that is the underlying theoretical basis for their application in DSSCs, and then we summarize the research progress of POMs in DSSCs in recent years. This is organized in terms of the properties of POMs, namely, electron acceptor, photosensitivity, redox and catalysis, based on the accumulation of our research into POMs over many years. Meanwhile, in view of the fact that the properties of POMs depend primarily on their electronic structural diversity, we keep this point in mind throughout the article with a view to revealing their structure-property relationships. Finally we provide a short summary and remarks on the future outlook. This review may be of interest to synthetic chemists devoted to designing POMs with specific structures, and researchers engaged in the extension of POMs to photoelectric materials.
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Background Nasopharyngeal carcinoma (NPC) may be cured with radiation therapy. Tumor proximity to critical structures demands accuracy in tumor delineation to avoid toxicities from radiation therapy; however, tumor target contouring for head and neck radiation therapy is labor intensive and highly variable among radiation oncologists. Purpose To construct and validate an artificial intelligence (AI) contouring tool to automate primary gross tumor volume (GTV) contouring in patients with NPC. Materials and Methods In this retrospective study, MRI data sets covering the nasopharynx from 1021 patients (median age, 47 years; 751 male, 270 female) with NPC between September 2016 and September 2017 were collected and divided into training, validation, and testing cohorts of 715, 103, and 203 patients, respectively. GTV contours were delineated for 1021 patients and were defined by consensus of two experts. A three-dimensional convolutional neural network was applied to 818 training and validation MRI data sets to construct the AI tool, which was tested in 203 independent MRI data sets. Next, the AI tool was compared against eight qualified radiation oncologists in a multicenter evaluation by using a random sample of 20 test MRI examinations. The Wilcoxon matched-pairs signed rank test was used to compare the difference of Dice similarity coefficient (DSC) of pre- versus post-AI assistance. Results The AI-generated contours demonstrated a high level of accuracy when compared with ground truth contours at testing in 203 patients (DSC, 0.79; 2.0-mm difference in average surface distance). In multicenter evaluation, AI assistance improved contouring accuracy (five of eight oncologists had a higher median DSC after AI assistance; average median DSC, 0.74 vs 0.78; P < .001), reduced intra- and interobserver variation (by 36.4% and 54.5%, respectively), and reduced contouring time (by 39.4%). Conclusion The AI contouring tool improved primary gross tumor contouring accuracy of nasopharyngeal carcinoma, which could have a positive impact on tumor control and patient survival. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Chang in this issue.
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Aprendizaje Profundo , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/métodos , Carcinoma Nasofaríngeo/diagnóstico por imagen , Neoplasias Nasofaríngeas/diagnóstico por imagen , Adolescente , Adulto , Algoritmos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nasofaringe/diagnóstico por imagen , Estudios Retrospectivos , Adulto JovenRESUMEN
Sleep deprivation can have substantial consequences for college learning and achievement. However, prior studies on this topic are limited due to the reliance on small and convenience samples, the use of cross-sectional data, inadequate control for confounders, and the lack of outcome data from official school records. The present study used two waves of longitudinal data from the U.S. Wabash National Study (Nâ¯=â¯3549) to examine the relationships between sleep deprivation and school-record grade point average (GPA) and college graduation. Random-effects and fixed-effects models were used to link sleep deprivation and GPA. Logistic regression was used to link sleep deprivation during the college years and college graduation. Results from the random-effects and fixed-effects models suggest that chronic sleep deprivation is associated with lower GPA. Students who experienced sleep deprivation from their freshman to senior years had a lower chance of graduation than students who were not sleep deprived. Furthermore, sleep deprivation during students' senior year was found to be more consequential for college graduation than sleep deprivation during their freshman year. Findings suggest that the ramifications of chronic sleep deprivation extend beyond short-term GPA; sleep deprivation predicts the likelihood of obtaining a college degree.
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Logro , Privación de Sueño , Estudiantes/estadística & datos numéricos , Universidades , Estudios Transversales , Femenino , Humanos , Estudios Longitudinales , Masculino , Sueño/fisiologíaRESUMEN
INTRODUCTION: The epidemic of sleep deprivation among college students is alarming. Prior studies of college students' sleep deprivation have focused on academic outcomes and mental health problems. This study considers the impact of college students' sleep deprivation on two key, developmental outcomes: leadership and need for cognition. METHODS: This study is a secondary analysis of longitudinal data from the Wabash National Study of Liberal Arts Education (Nâ¯=â¯3,690), using random-effects and fixed-effects models to estimate the association between chronic sleep deprivation from freshman year to senior year and developmental outcomes. RESULTS: Results from the random-effects model show that chronic sleep deprivation is negatively associated with lower scores in leadership skills (ß=-.09P<.001) and need for cognition (ß=-.08P<.001), after accounting for potential confounders. Results from the fixed-effects model that accounts for time-invariant unobserved variables show similar patterns for leadership skills (ß=-.09P<.01) and need for cognition (ß=-.06P<.01). CONCLUSIONS: This study demonstrates that chronic sleep deprivation has consequences for critical skills, suggesting that steps to promote college students' sleep health may also enhance their positive development in leadership skills and need for cognition.
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Cognición/fisiología , Liderazgo , Privación de Sueño/psicología , Adulto , Femenino , Humanos , Estudios Longitudinales , Masculino , Estudiantes/psicología , Adulto JovenRESUMEN
Thrombin is an essential procoagulant and profibrotic mediator. However, its implication in tuberculous pleural effusion (TBPE) remains unknown. The effusion thrombin and plasminogen activator inhibitor-1 (PAI-1) levels were measured among transudative pleural effusion (TPE, n = 22) and TBPE (n = 24) patients. Pleural fibrosis, identified as radiological residual pleural thickening (RPT) and shadowing, was measured at 12-month follow-up. Moreover, in vivo and in vitro effects of thrombin on PAI-1 expression and mesothelial-mesenchymal transition (MMT) were assessed. We demonstrated the effusion thrombin levels were significantly higher in TBPE than TPE, especially greater in TBPE patients with RPT > 10mm than those without, and correlated positively with PAI-1 and pleural fibrosis area. In carbon black/bleomycin-treated mice, knockdown of protease-activated receptor-1 (PAR-1) markedly downregulated α-smooth muscle actin (α-SMA) and fibronectin, and attenuated pleural fibrosis. In pleural mesothelial cells (PMCs), thrombin concentration-dependently increased PAI-1, α-SMA, and collagen I expression. Specifically, Mycobacterium tuberculosis H37Ra (MTBRa) induced thrombin production by PMCs via upregulating tissue factor and prothrombin, and PAR-1 silencing considerably abrogated MTBRa-stimulated PAI-1 expression and MMT. Consistently, prothrombin/PAR-1 expression was evident in the pleural mesothelium of TBPE patients. Conclusively, thrombin upregulates PAI-1 and MMT and may contribute to tuberculous pleural fibrosis. Thrombin/PAR-1 inhibition may confer potential therapy for pleural fibrosis.
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Inhibidor 1 de Activador Plasminogénico/metabolismo , Pleura/patología , Receptor PAR-1/metabolismo , Trombina/metabolismo , Tuberculosis/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Modelos Animales de Enfermedad , Exudados y Transudados/metabolismo , Femenino , Fibrosis , Estudios de Seguimiento , Humanos , Masculino , Mesodermo/efectos de los fármacos , Mesodermo/crecimiento & desarrollo , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Mycobacterium tuberculosis/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Derrame Pleural/metabolismo , Derrame Pleural/patología , Transducción de Señal , Tuberculosis/patología , Adulto JovenRESUMEN
The mixed lineage leukemia protein-1 (MLL1), as a lysine methyltransferase, predominantly regulates the methylation of histone H3 lysine 4 (H3K4) and functions in hematopoietic stem cell (HSC) self-renewal. MLL1 gene fuses with partner genes that results in the generation of MLL1 fusion proteins (MLL1-FPs), which are frequently detected in acute leukemia. In the progress of leukemogenesis, a great deal of proteins cooperate with MLL1 to form multiprotein complexes serving for the dysregulation of H3K4 methylation, the overexpression of homeobox (HOX) cluster genes, and the consequent generation of leukemia. Hence, disrupting the interactions between MLL1 and the reciprocal proteins has been considered to be a new treatment strategy for leukemia. Here, we reviewed potential protein-protein interactions (PPIs) between MLL1 and its reciprocal proteins, and summarized the inhibitors to target MLL1 PPIs. The druggability of MLL1 PPIs for leukemia were also discussed.
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N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Leucemia/tratamiento farmacológico , Proteína de la Leucemia Mieloide-Linfoide/antagonistas & inhibidores , Proteínas de Neoplasias/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , N-Metiltransferasa de Histona-Lisina/química , Humanos , Leucemia/genética , Estructura Molecular , Proteína de la Leucemia Mieloide-Linfoide/química , Proteínas de Neoplasias/química , Unión Proteica/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
WDR5, a subunit of the SET/MLL complex, plays critical roles in various biological progresses and are abnormally expressed in many cancers. Here we report the design, synthesis, and biochemical characterization of a new chemical tool to capture WDR5 protein. The probe is a biotinylated version of compound 30 that is a potent WDR5 inhibitor we previously reported. Importantly, the probe displayed high affinity to WDR5 protein in vitro binding potency and showed the ability in specifically and real time monitoring WDR5 protein. Further, the biotinylated tag of the probe enabled selectively "chemoprecipitation" of WDR5 from whole cell lysates of MV4-11. This probe provided a new approach to identify the overexpressed WDR5 protein in different cancer cells and applications to proteomic analysis of WDR5 and WDR5-binding partners.
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Anilidas/farmacología , Benzamidas/farmacología , Biotina/análogos & derivados , Biotina/farmacología , N-Metiltransferasa de Histona-Lisina/metabolismo , Sondas Moleculares/farmacología , Anilidas/síntesis química , Benzamidas/síntesis química , Biotina/síntesis química , Línea Celular Tumoral , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Humanos , Péptidos y Proteínas de Señalización Intracelular , Simulación del Acoplamiento Molecular , Sondas Moleculares/síntesis química , Unión ProteicaRESUMEN
BACKGROUND AND OBJECTIVE: Parapneumonic effusion (PPE) is commonly caused by Gram-positive bacteria (GPB) and often presents with pleural loculation, which is characterized by overproduction of plasminogen activator inhibitor (PAI)-1. Lipoteichoic acid (LTA), a surface adhesion molecule of GPB, binds to the pleural mesothelium and triggers inflammation. However, the effects of LTA on PAI-1 expression in PPE and underlying mechanisms remain unclear. METHODS: Thirty consecutive patients with PPE were enrolled, including uncomplicated culture negative (CN, n = 11), Gram-negative bacteria (GNB, n = 7) and GPB (n = 12) groups stratified by pleural fluid characteristics and bacteriology, and the effusion PAI-1 levels were measured. In addition, human pleural mesothelial cells (PMC) were treated with LTA and the expression of PAI-1 and activation of signalling pathways were assayed. RESULTS: The median levels of PAI-1 were significantly higher in GPB (160.5 ng/mL) and GNB (117.0 ng/mL) groups than in the uncomplicated CN (58.0 ng/mL) group. In human PMC, LTA markedly upregulated PAI-1 mRNA and protein expression and enhanced elaboration of Toll-like receptor 2 (TLR2). Furthermore, LTA increased c-Jun N-terminal kinase (JNK) phosphorylation, induced activating transcription factor 2 (ATF2)/c-Jun nuclear translocation and activated PAI-1 promoter activity. Pretreatment with TLR2 siRNA significantly inhibited LTA-induced JNK phosphorylation and PAI-1 protein expression. CONCLUSION: Culture-positive PPE, especially that caused by GPB, has a significantly higher level of PAI-1 than uncomplicated CN PPE. LTA upregulates PAI-1 expression through activation of TLR2/JNK/activator protein 1 (AP-1) pathway in human PMC. Better understanding of the modulation of PAI-1 synthesis by LTA in PPE may provide potential therapies for infected pleural effusions.
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Células Epiteliales/metabolismo , Lipopolisacáridos/farmacología , Inhibidor 1 de Activador Plasminogénico/metabolismo , Derrame Pleural/metabolismo , Ácidos Teicoicos/farmacología , Factor de Transcripción Activador 2/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Técnicas de Cultivo de Célula , Femenino , Bacterias Gramnegativas , Bacterias Grampositivas , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Inhibidor 1 de Activador Plasminogénico/genética , Pleura/citología , Derrame Pleural/microbiología , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Factor de Transcripción AP-1/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The activity coefficient of a chemical in a mixture is important in understanding the thermodynamic properties and non-ideality of the mixture. The COSMO-SAC model based on the result of quantum mechanical implicit solvation calculations has been shown to provide reliable predictions of activity coefficients for mixed fluids. However, it is found that the prediction accuracy is in general inferior for associating fluids. Existing methods for describing the hydrogen-bonding interaction consider the strength of the interaction based only on the polarity of the screening charges, neglecting the fact that the formation of hydrogen bonds requires a specific orientation between the donor and acceptor pairs. In this work, we propose a new approach that takes into account the spatial orientational constraints in hydrogen bonds. Based on the Valence Shell Electron Pair Repulsion (VSEPR) theory, the molecular surfaces associated with the formation of hydrogen bonds are limited to those in the projection of the lone pair electrons of hydrogen bond acceptors, in addition to the polarity of the surface screening charges. Our results show that this new directional hydrogen bond approach, denoted as the COSMO-SAC(DHB) model, requires fewer universal parameters and is significantly more accurate and reliable compared to previous models for a variety of properties, including vapor-liquid equilibria (VLE), infinite dilution activity coefficient (IDAC) and water-octanol partition coefficient (Kow).
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In light of the serious challenge of severe global energy shortages, p-type dye-sensitized solar cells (p-DSSCs) have attracted increasing levels of interest. The potential of three Keggin-type transition metal-substituted polyoxometalates, TBA8 Na2 [SiW9 O37 {Co(H2 O)3 }]â 11 H2 O (SiW9 Co3 ), TBA4 [(SiO4 )W10 MnIII2 O36 H6 ]â 1.5 CH3 CNâ 2 H2 O (SiW10 MnIII2 ), and TBA3.5 H5.5 [(SiO4 )W10 MnIII/IV2 O36 ]â 10 H2 Oâ 0.5 CH3 CN (SiW10 MnIII/IV2 ) has been explored as pure inorganic dye photosensitizers for p-DSSCs (TBA=(n-C4 H9 )4 N+ ). The three dyes show overall conversion efficiencies of 0.038, 0.029, and 0.027 %, respectively, all of which are higher than that of coumarin 343 (0.017 %). These polyoxometalates are the first three pure inorganic dyes reported for use with p-DSSCs and therefore demonstrate a new strategy for designing efficient dyes, especially pure inorganic dyes. Moreover, they broaden the range of applications for polyoxometalates.