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The human epigenetic cell-cycle regulator HCF-1 undergoes an unusual proteolytic maturation process resulting in stably associated HCF-1(N) and HCF-1(C) subunits that regulate different aspects of the cell cycle. Proteolysis occurs at six centrally located HCF-1(PRO)-repeat sequences and is important for activation of HCF-1(C)-subunit functions in M phase progression. We show here that the HCF-1(PRO) repeat is recognized by O-linked ß-N-acetylglucosamine transferase (OGT), which both O-GlcNAcylates the HCF-1(N) subunit and directly cleaves the HCF-1(PRO) repeat. Replacement of the HCF-1(PRO) repeats by a heterologous proteolytic cleavage signal promotes HCF-1 proteolysis but fails to activate HCF-1(C)-subunit M phase functions. These results reveal an unexpected role of OGT in HCF-1 proteolytic maturation and an unforeseen nexus between OGT-directed O-GlcNAcylation and proteolytic maturation in HCF-1 cell-cycle regulation.
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Factor C1 de la Célula Huésped/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Procesamiento Proteico-Postraduccional , Secuencia de Aminoácidos , Ciclo Celular , Glicosilación , Factor C1 de la Célula Huésped/química , Factor C1 de la Célula Huésped/genética , Humanos , Datos de Secuencia Molecular , Mutación , Subunidades de Proteína/metabolismo , Alineación de SecuenciaRESUMEN
Primordial black holes (PBHs) and the violation of the null energy condition (NEC) have significant implications for our understanding of the very early Universe. We present a novel approach to generate PBHs via the NEC violation in a single-field inflationary scenario. In our scenario, the Universe transitions from a first slow-roll inflation stage with a Hubble parameter H=H_{inf1} to a second slow-roll inflation stage with H=H_{inf2}â«H_{inf1}, passing through an intermediate stage of NEC violation. The NEC violation naturally enhances the primordial scalar power spectrum at a certain wavelength, leading to the production of PBHs with masses and abundances of observational interest. We also investigate the phenomenological signatures of scalar-induced gravitational waves resulting from the enhanced density perturbations. Our work highlights the potential of utilizing a combination of PBHs, scalar-induced gravitational waves, and primordial gravitational waves as a valuable probe for studying NEC violation during inflation, opening up new avenues for exploring the early Universe.
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OBJECTIVE: This observational study examined the factors associated with the physical activity (PA) of children and adolescents outside of school within the framework of Problem Behavior Theory (PBT). METHODS: This cross-sectional study obtained data from 6528 children and adolescents aged 6-16 years recruited from ten schools in Shanghai, China. The questionnaire measured out-of-school PA and PBT-based correlates. A series of multiple linear regressions were used to explore the factors influencing children and adolescents' out-of-school PA separately. Structural equation modeling (SEM) was used to explore the association between the three systems of PBT and out-of-school PA. RESULTS: Higher intrinsic motivation is positively associated with increased PA for children (b = 1.038, 95%CI: 0.897-1.180) and adolescents (b = 1.207, 95%CI: 0.890-1.524). Greater frequency of parental involvement in PA correlates with elevated PA for both children (b = 2.859, 95%CI: 2.147-3.572) and adolescents (b = 2.147, 95%CI: 0.311-3.983). In children, increased use of community exercise areas or facilities (b = 1.705, 95%CI: 0.234-3.176) and higher recreational screen time (b = 9.732, 95%CI: 5.614-13.850) are associated with higher PA. The SEM showed that factors of the personality system had a significant direct effect on out-of-school PA among children and adolescents, and factors of the behavior system also had a significant effect on children. CONCLUSIONS: Our findings suggest that the personality system, particularly intrinsic motivation, is important in promoting out-of-school PA in children and adolescents. For children, modifiable health behaviors in the behavior system can similarly influence PA.
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Ejercicio Físico , Motivación , Humanos , Estudios Transversales , Masculino , Femenino , Ejercicio Físico/psicología , China , Adolescente , Niño , Encuestas y Cuestionarios , Instituciones Académicas , Problema de Conducta/psicología , Pueblos del Este de AsiaRESUMEN
The question of whether spatial attention can modulate initial afferent activity in area V1, as measured by the earliest visual event-related potential (ERP) component "C1", is still the subject of debate. Because attention always enhances behavioral performance, previous research has focused on finding evidence of attention-related enhancements in visual neural responses. However, recent psychophysical studies revealed a complex picture of attention's influence on visual perception: attention amplifies the perceived contrast of low-contrast stimuli while dampening the perceived contrast of high-contrast stimuli. This evidence suggests that attention may not invariably augment visual neural responses but could instead exert inhibitory effects under certain circumstances. Whether this bi-directional modulation of attention also manifests in C1 and whether the modulation of C1 underpins the attentional influence on contrast perception remain unknown. To address these questions, we conducted two experiments (N = 67 in total) by employing a combination of behavioral and ERP methodologies. Our results did not unveil a uniform attentional enhancement or attenuation effect of C1 across all subjects. However, an intriguing correlation between the attentional effects of C1 and contrast appearance for high-contrast stimuli did emerge, revealing an association between attentional modulation of C1 and the attentional modulation of contrast appearance. This finding offers new insights into the relationship between attention, perceptual experience, and early visual neural processing, suggesting that the attentional effect on subjective visual perception could be mediated by the attentional modulation of the earliest visual cortical response.
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Electroencefalografía , Corteza Visual , Humanos , Potenciales Evocados Visuales , Corteza Visual/fisiología , Mapeo Encefálico/métodos , Estimulación Luminosa/métodos , Percepción Visual/fisiología , Potenciales Evocados , Atención/fisiologíaRESUMEN
Hg(I) may control Hg redox kinetics; however, its metastable nature hinders analysis. Herein, the stability of Hg(I) during standard preparation and analysis was studied. Gravimetric analysis showed that Hg(I) was stable in its stock solution (1000 mg L-1), yet completely disproportionated when its dilute solution (10 µg L-1) was analyzed using liquid chromatography (LC)-ICPMS. The Hg(I) dimer can form through an energetically favorable comproportionation between Hg(0) and Hg(II), as supported by density functional theory calculation and traced by the rapid isotope exchange between 199Hg(0)aq and 202Hg(II). However, the separation of Hg(0) and Hg(II) (e.g., LC process) triggered its further disproportionation. Polypropylene container, increasing headspace, decreasing pH, and increasing dissolved oxygen significantly enhanced the disproportionation or redox transformations of Hg(I). Thus, using a glass container without headspace and maintaining a slightly alkaline solution are recommended for the dilute Hg(I) stabilization. Notably, we detected elevated concentrations of Hg(I) (4.4-6.1 µg L-1) in creek waters from a heavily Hg-polluted area, accounting for 54-70% of total dissolved Hg. We also verified the reductive formation of Hg(I) in Hg(II)-spiked environmental water samples, where Hg(I) can stably exist in aquatic environments for at least 24 h, especially in seawater. These findings provide mechanistic insights into the transformation of Hg(I), which are indicative of its further environmental identification.
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Mercurio , Contaminantes Químicos del Agua , Mercurio/análisis , Agua de Mar/análisis , Agua de Mar/química , Isótopos/análisis , Contaminantes Químicos del Agua/análisisRESUMEN
Complexes with low-molecular-weight thiols are crucial species of methylmercury (MeHg) excreted by anaerobic Hg-methylating microbes, notably, MeHg-cysteine (MeHg-Cys). As MeHg-Cys diffuses into surface water, it would undergo a ligand exchange process with dissolved organic matter (DOM) under nonsulfidic conditions, inevitably altering MeHg speciation and bioavailability to phytoplankton. In this study, we investigated the competitive binding kinetics between MeHg-Cys and Suwannee River natural organic matter, and their influence on the adsorption and uptake of MeHg by the cyanobacterium, Synechocystis sp. PCC6803. Liquid chromatography-inductively coupled plasma mass spectrometry was employed to monitor the kinetics processes involving competition of DOM with Cys for MeHg binding, which revealed that competitive binding kinetics were dictated by the abundance of thiol moieties in DOM. Thiol concentrations of 0.97 and 49.34 µmol of thiol (g C)-1 resulted in competitive binding rate constant (k values) of 0.30 and 3.47 h-1, respectively. Furthermore, the time-dependent competitive binding of DOM toward MeHg-Cys significantly inhibited MeHg adsorption and uptake by cyanobacteria, an effect that was amplified by an increased thiol abundance in DOM. These findings offer valuable insights into the kinetic characteristics of MeHg's fate and transport, as well as their impact on bioconcentration in aquatic organisms within natural aquatic ecosystems.
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Compuestos de Metilmercurio , Compuestos de Sulfhidrilo , Compuestos de Metilmercurio/metabolismo , Compuestos de Metilmercurio/química , Adsorción , Cinética , Compuestos de Sulfhidrilo/metabolismo , Compuestos de Sulfhidrilo/química , Cisteína/metabolismo , Cisteína/química , Contaminantes Químicos del Agua/metabolismo , Contaminantes Químicos del Agua/químicaRESUMEN
Algae are an entry point for mercury (Hg) into the food web. Bioconcentration of Hg by algae is crucial for its biogeochemical cycling and environmental risk. Herein, considering the cell heterogeneity, we investigated the bioconcentration of coexisting isotope-labeled inorganic (199IHg) and methyl Hg (201MeHg) by six typical freshwater and marine algae using dual-mass single-cell inductively coupled plasma mass spectrometry (scICP-MS). First, a universal pretreatment procedure for the scICP-MS analysis of algae was developed. Using the proposed method, the intra- and interspecies heterogeneities and the kinetics of Hg bioconcentration by algae were revealed at the single-cell level. The heterogeneity in the cellular Hg contents is largely related to cell size. The bioconcentration process reached a dynamic equilibrium involving influx/adsorption and efflux/desorption within hours. Algal density is a key factor affecting the distribution of Hg between algae and ambient water. Cellular Hg contents were negatively correlated with algal density, whereas the volume concentration factors almost remained constant. Accordingly, we developed a model based on single-cell analysis that well describes the density-driven effects of Hg bioconcentration by algae. From a novel single-cell perspective, the findings improve our understanding of algal bioconcentration governed by various biological and environmental factors.
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Mercurio , Mercurio/metabolismo , Espectrometría de Masas , Compuestos de Metilmercurio/metabolismo , Contaminantes Químicos del Agua/metabolismo , Cadena Alimentaria , Análisis de la Célula IndividualRESUMEN
OBJECTIVE: To investigate any connections between urinary organophosphorus pesticide (OPP) metabolites and adiposity measures. METHODS: In this study, data from the National Health and Nutrition Examination Survey (NHANES) projects from 2003 to 2008, 2011 to 2012, and 2015 to 2018 were analysed. Obesity was defined as a body mass index (BMI) of 30 kg/m² or higher. Abdominal obesity was defined as a waist circumference (WC) over 102 cm for men and 88 cm for women. Four urinary OPP metabolites (dimethyl phosphate [DMP], diethyl phosphate [DEP], dimethyl phosphorothioate [DMTP], and diethyl phosphorothioate [DETP]) and adiposity measures were examined using multiple linear regression and logistic regression analyses. The correlations between a variety of urinary OPP metabolites and the prevalence of obesity were investigated using weighted quantile sum regression and quantile g-computation regression. RESULTS: In this analysis, a total of 9,505 adults were taken into account. There were 49.81% of male participants, and the average age was 46.00 years old. The median BMI and WC of the subjects were 27.70 kg/m2 and 97.10 cm, respectively. Moreover, 35.60% of the participants were obese, and 54.42% had abdominal obesity. DMP, DMTP, and DETP were discovered to have a negative correlation with WC and BMI in the adjusted models. DMP (OR = 0.93 [95% CI: 0.89-0.98]), DEP (OR = 0.94 [95% CI: 0.90-0.99]), DMTP (OR = 0.91 [95% CI: 0.86-0.95]), and DETP (OR = 0.85 [95% CI: 0.80-0.90]) exhibited negative associations with obesity prevalence. Similar correlations between the prevalence of abdominal obesity and the urine OPP metabolites were discovered. Moreover, the mixture of urinary OPP metabolites showed negative associations with adiposity measures, with DMTP and DETP showing the most significant effects. CONCLUSION: Together, higher levels of urinary OPP metabolites in the urine were linked to a decline in the prevalence of obesity.
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Encuestas Nutricionales , Obesidad , Compuestos Organofosforados , Plaguicidas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Obesidad/epidemiología , Compuestos Organofosforados/orina , Plaguicidas/orina , Estados Unidos/epidemiología , Contaminantes Ambientales/orina , Adulto Joven , Anciano , Índice de Masa Corporal , Prevalencia , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisisRESUMEN
Histone variants have been implicated in regulating chromatin dynamics and genome functions. Previously, we have shown that histone variant H3.3 actively marks enhancers and cooperates with H2A.Z at promoters to prime the genes into a poised state in mouse embryonic stem cells (mESCs). However, how these two important histone variants collaboratively function in this process still remains elusive. In this study, we found that depletion of different components of HIRA complex, a specific chaperone of H3.3, results in significant decreases of H2A.Z enrichment at genome scale. In addition, CUT&Tag data revealed a genomic colocalization between HIRA complex and SRCAP complex. In vivo and in vitro biochemical assays verified that HIRA complex could interact with SRCAP complex through the Hira subunit. Furthermore, our chromatin accessibility and transcription analyses demonstrated that HIRA complex contributed to preset a defined chromatin feature around TSS region for poising gene transcription. In summary, our results unveiled that while regulating the H3.3 incorporation in the regulatory regions, HIRA complex also collaborates with SRCAP to deposit H2A.Z onto the promoters, which cooperatively determines the transcriptional potential of the poised genes in mESCs.
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Proteínas de Ciclo Celular/metabolismo , Chaperonas de Histonas/metabolismo , Histonas/metabolismo , Células Madre Embrionarias de Ratones/metabolismo , Factores de Transcripción/metabolismo , Animales , Línea Celular , Ensamble y Desensamble de Cromatina , RatonesRESUMEN
AIM: To explore the potential role of microRNA miR-221-5p on the angiopoietin-1 (Ang-1)/Ang-2/Tie-2 signaling axis after subarachnoid hemorrhage (SAH) in a rat model. METHODS: Aspects of the rat's behavior were measured using the Kaoutzanis scoring system to test neurological responses. This included feeding behavior, body contraction, motor, and eye-opening responses. Brain sections were studied using transmission electron microscopy and Evans blue extravasation. Levels of Ang-1, Ang-2, and Tie-2 were determined by Western blot, while miR-221-5p was quantified using stem-loop real-time quantitative PCR (RT-qPCR). RESULTS: The SAH group responded worse to the neurological response test than the sham-operated group. The intercellular space was widened in the SAH group, but not in the sham-operated group. Evans blue dye leaked significantly more into brain tissue cells of the SAH group. Stem-loop qRT-PCR showed elevated miR-221-5p levels. Additionally, Ang-1 and Tie-2 were reduced but Ang-2 expression was increased after SAH. This led to a significant reduction of the Ang-1/Ang-2 ratio in the brain tissue, which was associated with the destruction of the blood-brain barrier. CONCLUSION: The data indicate that miR-221-5p might regulate blood-brain barrier dysfunction through the Ang-1/Ang-2/Tie-2 signaling axis, suggesting that it should be further investigated as a potential novel biomarker.
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MicroARNs , Hemorragia Subaracnoidea , Ratas , Animales , Barrera Hematoencefálica , Angiopoyetina 1/genética , Angiopoyetina 1/metabolismo , Azul de Evans/metabolismo , MicroARNs/metabolismoRESUMEN
OBJECTIVES: This study explored how race and socioeconomic status (SES) moderated the association between moderate-to-vigorous physical activity (MVPA) and depressive symptoms with compositional data. METHODS: Participants were 2803 US adults from the 2005-2006 cycle of the National Health and Nutrition Examination Survey. Accelerometers were used to measure MVPA, light-intensity physical activity (LPA) and sedentary behaviours (SB). Participants self-reported sleep duration and depressive symptoms. SES was derived by latent class analysis using household income level, education attainment and occupation. The association between the relative time of MVPA and depressive symptoms and the moderating effects of race and SES were investigated through compositional data analysis. Isotemporal substitution analysis was employed to estimate the association of time reallocation from other movement behaviours to MVPA with depressive symptoms. RESULTS: Increased time spent in MVPA relative to time spent in LPA, SB and sleep was inversely associated with depressive symptoms (OR (95% CI)=0.679 (0.538-0.855)). The relative time of MVPA significantly interacted with race and SES for depressive symptoms (P for interaction <0.05). Reallocating 10-30 min from sleep, SB or LPA to MVPA was associated with lower odds of depressive symptoms solely among non-Hispanic white individuals and those with higher SES. CONCLUSION: This study used compositional data to reveal a reverse association between MVPA and depressive symptoms among white individuals and those with higher SES. Our results provide evidence of how race and SES moderate the relationship between MVPA and depressive symptoms. Future research is needed to further explore these racial and socioeconomic differences.
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BACKGROUND: As the global aging process accelerates, the health challenges posed by sarcopenia among middle-aged and older adults are becoming increasingly prominent. However, the available evidence on the adverse effects of air pollution on sarcopenia is limited, particularly in the Western Pacific region. This study aimed to explore relationships of multiple air pollutants with sarcopenia and related biomarkers using the nationally representative database. METHODS: Totally, 6585 participants aged over 45 years were enrolled from the China Health and Retirement Longitudinal Study (CHARLS) in 2011 and 3443 of them were followed up until 2015. Air pollutants were estimated from high-resolution satellite-based spatial-temporal models. In the cross-sectional analysis, we used generalized linear regression, unconditional logistic regression analytical and restricted cubic spline (RCS) methods to assess the single-exposure and non-linear effects of multiple air pollutants on sarcopenia and related surrogate biomarkers (serum creatinine and cystatin C). Several popular mixture analysis techniques such as Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS) regression, and quantile-based g-computation (Qgcomp) were further used to examinate the combined effects of multiple air pollutants. Logistic regression was used to further analyze the longitudinal association between air pollution and sarcopenia. RESULTS: Each interquartile range increase in PM2.5, PM10 and NO2 was significantly associated with an increased risk of sarcopenia, with adjusted odds ratios (aORs) of 1.09 [95â¯% confidence interval (CI): 1.01, 1.20], 1.24 (95â¯% CI: 1.14, 1.35) and 1.18 (95â¯% CI: 1.08, 1.28), respectively. Our findings also showed that five air pollutants were significantly associated with the sarcopenia index. In addition, employing a mixture analysis approach, we confirmed significant combined effects of air pollution mixtures on sarcopenia risk and associated biomarkers, with PM10 and PM2.5 identified as major contributors to the combined effect. The results of the exposure-response (E-R) relationships, subgroup analysis, longitudinal analysis and sensitivity analysis all showed the unfavorable impact of air pollution on sarcopenia risk and related vulnerable populations. CONCLUSIONS: Single-exposure and co-exposure to multiple air pollutants were positively associated with sarcopenia among middle-aged and older adults in China. Our study provided new evidence that air pollution mixture was significantly associated with sarcopenia related biomarkers.
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Contaminantes Atmosféricos , Contaminación del Aire , Biomarcadores , Material Particulado , Sarcopenia , Humanos , Sarcopenia/inducido químicamente , China/epidemiología , Masculino , Anciano , Contaminantes Atmosféricos/análisis , Persona de Mediana Edad , Femenino , Estudios Transversales , Material Particulado/análisis , Estudios Longitudinales , Contaminación del Aire/efectos adversos , Contaminación del Aire/estadística & datos numéricos , Biomarcadores/sangre , Exposición a Riesgos Ambientales/efectos adversos , Creatinina/sangre , Cistatina C/sangreRESUMEN
To analyse the clinical features, imaging manifestation, pathological typing and genetic testing results of patients undergoing surgery for ground-glass opacity (GGO) nodules, and explore the reasonable diagnosis and treatment program for GGO patients as to provide the basis for the establishment of GGO treatment process. This study is an exploratory study. 465 cases with GGO confirmed by HRCT, undergoing surgery and approved by pathologic diagnosis in Shanghai pulmonary hospital were enrolled in this study. All the patients with GGO were cases with single lesion. The relationship between the clinical, imaging, pathological and molecular biological data of single GGO were statistically studied. (1) Among 465 cases, the median age was 58 years and females were 315 (67.7%); there were 397 (85.4%) non-smoking, and 354 cases (76.1%) had no clinical symptoms. There were 33 cases of benign and 432 cases of malignant GGO. Significant differences were observed on the size, vacuole sign, pleural indentation and blood vessel sign of GGO between two groups (p < 0.05). Of 230 mGGO, there were no AAH, 13 cases of AIS, 25 cases of MIA and 173 cases of invasive adenocarcinoma. The probability of solid nodules in invasive adenocarcinoma was higher than that in micro invasive carcinoma, and the difference was statistically significant (p < 0.05). 360 cases were followed up with the average follow-up time of 6.05 months, and GGO of 34 cases (9.4%) increased. (2) In 428 adenocarcinoma samples approved by pathologic diagnosis, there were 262 (61.2%) lesions of EGFR mutation, 14 (3.3%) lesions of KRAS mutation, 1 (0.2%) lesion of Braf mutation, 9 (2.1%) lesions of EML4-ALK gene fusion and 2 (0.5%) lesions of ROS1 fusion. The detection rate of gene mutation in mGGO was higher than that of pGGO. During the follow-up period, genetic testing results of 32 GGO showed that EGFR mutation rate was 53.1%, ALK positive rate of 6.3%, KRAS mutation rate of 3.1% and no ros1 and BRAF gene mutation. No statistically significant difference was observed in comparison with unchanged GGO. (3) EGFR mutation rate of invasive adenocarcinoma was the highest (168/228, 73.7%), mainly in the 19Del and L858R point mutations. No KRAS mutation was found in atypical adenoma hyperplasia. No significant difference was observed on the mutation rate of KRAS between different types of GGO (p = 0.811). EML4-ALK fusion gene was mainly detected in invasive adenocarcinoma (7/9). GGO tends to occur in young, non-smoking women. The size of GGO is related to the degree of malignancy. Pleural depression sign, vacuole sign and vascular cluster sign are all characteristic images of malignant GGO. pGGO and mGGO reflect the pathological development of GGO. During the follow-up, it is found that GGO increases and solid components appear, which is the indication of surgical resection. The detection rate of EGFR mutations in mGGO and invasive adenocarcinoma is high. pGGO has heterogeneity in imaging, pathology and molecular biology. Heterogeneity research helps to formulate correct individualized diagnosis and treatment plans.
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Adenocarcinoma , Neoplasias Pulmonares , Humanos , Femenino , Persona de Mediana Edad , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas B-raf/genética , Tomografía Computarizada por Rayos X/métodos , China , Adenocarcinoma/genética , Genotipo , Receptores ErbB/genética , Proteínas Tirosina Quinasas Receptoras/genética , Estudios RetrospectivosRESUMEN
In drug discovery, one of the most important tasks is to find novel and biologically active molecules. Given that only a tip of iceberg of drugs was founded in nearly one-century's experimental exploration, it shows great significance to use in silico methods to expand chemical database and profile drug-target linkages. In this study, a web server named ChemGenerator was proposed to generate novel activates for specific targets based on users' input. The ChemGenerator relies on an autoencoder-based algorithm of Recurrent Neural Networks with Long Short-Term Memory by training of 7 million of molecular Simplified Molecular-Input Line-Entry System as the basic model, and further develops target guided generation by transfer learning. As results, ChemGenerator gains lower loss (<0.01) than existing reference model (0.2~0.4) and shows good performance in the case of Epidermal Growth Factor Receptor. Meanwhile, ChemGenerator is now freely accessible to the public by http://smiles.tcmobile.org. In proportion to endless molecular enumeration and time-consuming expensive experiments, this work demonstrates an efficient alternative way for the first virtual screening in drug discovery.
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Bases de Datos de Compuestos Químicos , Descubrimiento de Drogas , Internet , Redes Neurales de la Computación , Programas Informáticos , LigandosRESUMEN
Recognizing aberrant cytoplasmic dsDNA and stimulating cGAS-STING-mediated innate immunity is essential for the host defense against viruses. Recent studies have reported that SARS-CoV-2 infection, responsible for the COVID-19 pandemic, triggers cGAS-STING activation. cGAS-STING activation can trigger IRF3-Type I interferon (IFN) and autophagy-mediated antiviral activity. Although viral evasion of STING-triggered IFN-mediated antiviral function has been well studied, studies concerning viral evasion of STING-triggered autophagy-mediated antiviral function are scarce. In the present study, we have discovered that SARS-CoV-2 ORF3a is a unique viral protein that can interact with STING and disrupt the STING-LC3 interaction, thus blocking cGAS-STING-induced autophagy but not IRF3-Type I IFN induction. This novel function of ORF3a, distinct from targeting autophagosome-lysosome fusion, is a selective inhibition of STING-triggered autophagy to facilitate viral replication. We have also found that activation of bat STING can induce autophagy and antiviral activity despite its defect in IFN induction. Furthermore, ORF3a from bat coronaviruses can block bat STING-triggered autophagy and antiviral function. Interestingly, the ability to inhibit STING-induced autophagy appears to be an acquired function of SARS-CoV-2 ORF3a, since SARS-CoV ORF3a lacks this function. Taken together, these discoveries identify ORF3a as a potential target for intervention against COVID-19.
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COVID-19 , Quirópteros , Interferón Tipo I , Animales , Humanos , Antivirales , Autofagia , Inmunidad Innata , Proteínas de la Membrana/genética , Nucleotidiltransferasas , Pandemias , SARS-CoV-2/metabolismoRESUMEN
GAS41, a member of the human YEATS domain family, plays a pivotal role in human cancer development. It serves as a highly promising epigenetic reader, facilitating precise regulation of cell growth and development by recognizing essential histone modifications, including histone acetylation, benzoylation, succinylation, and crotonylation. Functional readouts of these histone modifications often coincide with cancer progression. In addition, GAS41 functions as a novel oncogene, participating in numerous signaling pathways. Here, we summarize the epigenetic functions of GAS41 and its role in the carcinoma progression. Moving forward, elucidating the downstream target oncogenes regulated by GAS41 and the developing small molecule inhibitors based on the distinctive YEATS recognition properties will be pivotal in advancing this research field.
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Insomnia displays heterogeneous trajectories across adolescence, which may induce addictive behaviours, including internet gaming disorder and substance use. This study aimed to investigate the latent trajectory classes of insomnia symptoms over 2 years and to examine the associations between insomnia trajectories and these addictive behaviours. Participants were 910 adolescents from six middle schools in Shanghai, China (52.7% males; mean age = 13.17 years). The three-wave survey measured insomnia symptoms, internet gaming disorder, substance use, depressive symptoms, and sociodemographic characteristics from 7th to 9th grade. Latent class growth modelling was performed to identify the latent trajectory classes of insomnia symptoms. Then multivariable logistic regressions were conducted within the best-fitting latent class growth model to examine the associations of insomnia trajectories with internet gaming disorder and substance use. Two latent trajectory classes of insomnia symptoms were recognised: the non-insomnia group (71.8%) and the insomnia group (28.2%). In the multivariable analysis controlling for baseline demographic variables and depressive symptoms, the insomnia group had a higher risk of developing internet gaming disorder (OR = 2.203 [95% CI: 1.258-3.858]) and substance use (OR = 2.215 [95% CI: 1.324-3.705]) compared with the non-insomnia group. These findings add to a growing body of research on heterogeneous trajectories of insomnia symptoms during adolescence, suggesting that intervention strategies are needed to target the characteristics or developmental patterns of different insomnia subgroups. The ultimate goal is to mitigate the impact of insomnia symptoms on adolescent addictive behaviours.
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Conducta Adictiva , Trastornos del Inicio y del Mantenimiento del Sueño , Masculino , Humanos , Adolescente , Femenino , Estudios Longitudinales , China/epidemiología , Trastornos del Inicio y del Mantenimiento del Sueño/complicaciones , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , Encuestas y Cuestionarios , Conducta Adictiva/complicaciones , Conducta Adictiva/epidemiología , Conducta Adictiva/diagnóstico , InternetRESUMEN
One effective strategy for treating atherosclerosis is to inhibit the injury of vascular endothelial cells (VECs) induced by oxidized low-density lipoprotein (oxLDL) and high glucose (HG). This study synthesized and evaluated a series of novel Nrf2 activators derived from the marine natural product phidianidine for their ability to protect human umbilical VECs against oxLDL- and HG-induced injury. The results of in vitro bioassays demonstrated that compound D-36 was the most promising Nrf2 activator, effectively inhibiting the apoptosis of HUVECs induced by oxLDL and HG. Furthermore, Nrf2 knockdown experiments confirmed that compound D-36 protected against oxLDL- and HG-induced apoptosis in HUVECs by activating the Nrf2 pathway. These findings provide important insights into a new chemotype of marine-derived Nrf2 activators that could potentially be optimized to develop effective anti-atherosclerosis agents.
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The Information-Motivation-Behavioral skills (IMB) model of antiretroviral therapy (ART) adherence was applied in people living with HIV/AIDS in Shanghai, China to understand how adherence-related information, motivation and behavioral skills would affect ART adherence. The LifeWindows Information-Motivation-Behavioral Skills ART Adherence Questionnaire (LW-IMB-AAQ) was translated into Chinese and used. The IMB model was then implemented by testing standardized path estimates with standard model fitness indices in the participants. 426 participants from 11 community centres in Putuo district of Shanghai were recruited, of which 95.3% reported a high level of adherence (>95% adherence). The fitness indices of the final adjusted model were χ2 = 6.110, df = 7, p = 0.527(>0.05), CFI = 1.000(>0.9) and RMSEA = 0.000 (<0.08). In the model, information, which was separated into two sections (the perceived effect of ART on health and knowledge about ART medication), had an indirect effect on the ART adherence through behavioral skills, while motivation did not have such an effect. Neither information nor motivation had a direct effect on ART adherence. In addition, motivation was related to the two sections of information. The feasibility of the IMB model of ART adherence is verified by its application to predictive of adherence-related behaviors among HIV+ patients in this study.
Asunto(s)
Infecciones por VIH , Motivación , Humanos , Infecciones por VIH/tratamiento farmacológico , China/epidemiología , Cooperación del Paciente , Antirretrovirales/uso terapéutico , Cumplimiento de la MedicaciónRESUMEN
Tin-based gas sensors have been developed for many years owing to their advantages of low price, high response and stability. However, selectivity remains a significant issue. Herein, Ag-SnO2nanofibers are synthesized using AgCl as the doping reagent. The 3%Ag-SnO2nanofibers sensors show a high response of 68 toward 1 ppm H2S at 90 °C. Besides, the sensor with 3% AgCl possesses the shortest response time about 136 s at 150 °C which is only 30% value of the sensor without AgCl doping. It is also demonstrated that the nanofibers show a high selectivity towards H2S. According to theex situx-ray photoelectron spectrum and x-ray diffraction results, AgCl was transferred to Ag2S after Ag-SnO2was exposed to H2S, and reversible transformation between Ag2SO4and Ag2S was the main mechanism for H2S detection. Compared with pure SnO2nanofiber sensors, the presence of Ag2S with high conductivity greatly affects the resistance to H2S, resulting in high selectivity and response. This mechanism differs from that of the transformation between Ag2O and Ag2SO4. This study may provide a new strategy for the design and investigation of sensors with high selectivity.