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The CsPbI3 perovskite is a promising candidate for photovoltaic applications, for which several critical phase transitions govern both its efficiency and stability. Large-scale molecular dynamics simulations are valuable in understanding the microscopic mechanisms of these transitions, in which the accuracy of the simulation heavily depends on the empirical potential. This study parameterizes two efficient and stable empirical potentials for the CsPbI3 perovskite. In these two empirical potentials, the short-ranged repulsive interaction is described by the Lennard-Jones model or the Buckingham model, while the long-ranged Coulomb interaction is summed by the damped shifted force method. Our molecular dynamics simulations show that these two empirical potentials accurately capture the γ â ß â α and δ â α phase transitions for the CsPbI3 perovskite. Furthermore, they are up to two orders of magnitude more efficient than previous empirical models, owing to the high efficiency of the damped shifted force truncation treatment for the Coulomb interaction.
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Histone methyltransferase KMT2D is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL) and has been identified as an important pathogenic factor and prognostic marker. However, the biological relevance of KMT2D mutations on tumor microenvironment remains to be determined. KMT2D mutations were assessed by whole-genome/exome sequencing (WGS/WES) in 334 patients and by targeted sequencing in 427 patients with newly diagnosed DLBCL. Among all 761 DLBCL patients, somatic mutations in KMT2D were observed in 143 (18.79%) patients and significantly associated with advanced Ann Arbor stage and MYC expression ≥ 40%, as well as inferior progression-free survival and overall survival. In B-lymphoma cells, the mutation or knockdown of KMT2D inhibited methylation of lysine 4 on histone H3 (H3K4), downregulated FBXW7 expression, activated NOTCH signaling pathway and downstream MYC/TGF-ß1, resulting in alterations of tumor-induced regulatory T cell trafficking. In B-lymphoma murine models established with subcutaneous injection of SU-DHL-4 cells, xenografted tumors bearing KMT2D mutation presented lower H3K4 methylation, higher regulatory T cell recruitment, thereby provoking rapid tumor growth compared with wild-type KMT2D via FBXW7-NOTCH-MYC/TGF-ß1 axis.
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Proteína 7 que Contiene Repeticiones F-Box-WD , Linfoma de Células B Grandes Difuso , Mutación , Proteínas Proto-Oncogénicas c-myc , Linfocitos T Reguladores , Humanos , Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Animales , Ratones , Femenino , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Masculino , Linfocitos T Reguladores/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Receptores Notch/metabolismo , Persona de Mediana Edad , Línea Celular Tumoral , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Transducción de Señal , Adulto , Progresión de la Enfermedad , AncianoRESUMEN
BACKGROUND: Liver cirrhosis (LC) is the highest risk factor for hepatocellular carcinoma (HCC) development worldwide. The efficacy of the guideline-recommended surveillance methods for patients with LC remains unpromising. METHODS: A total of 4367 LCs not previously known to have HCC and 510 HCCs from 16 hospitals across 11 provinces of China were recruited in this multi-center, large-scale, cross-sectional study. Participants were divided into Stage â cohort (510 HCCs and 2074 LCs) and Stage â ¡ cohort (2293 LCs) according to their enrollment time and underwent Tri-phasic CT/enhanced MRI, US, AFP, and cell-free DNA (cfDNA). A screening model called PreCar Score was established based on five features of cfDNA using Stage â cohort. Surveillance performance of PreCar Score alone or in combination with US/AFP was evaluated in Stage â ¡ cohort. FINDINGS: PreCar Score showed a significantly higher sensitivity for the detection of early/very early HCC (Barcelona stage A/0) in contrast to US (sensitivity of 51.32% [95% CI: 39.66%-62.84%] at 95.53% [95% CI: 94.62%-96.38%] specificity for PreCar Score; sensitivity of 23.68% [95% CI: 14.99%-35.07%] at 99.37% [95% CI: 98.91%-99.64%] specificity for US) (P < 0.01, Fisher's exact test). PreCar Score plus US further achieved a higher sensitivity of 60.53% at 95.08% specificity for early/very early HCC screening. INTERPRETATION: Our study developed and validated a cfDNA-based screening tool (PreCar Score) for HCC in cohorts at high risk. The combination of PreCar Score and US can serve as a promising and practical strategy for routine HCC care. FUNDING: A full list of funding bodies that contributed to this study can be found in Acknowledgments section.
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Carcinoma Hepatocelular , Ácidos Nucleicos Libres de Células , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/epidemiología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/epidemiología , alfa-Fetoproteínas , Estudios Transversales , Detección Precoz del Cáncer/métodos , Ultrasonografía/métodos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/complicaciones , Biomarcadores de TumorRESUMEN
Small-molecule phenolic substances widely exist in animals and plants, and have some shared biological activities. The metabolism of phenylalanine and tyrosine in the human body, and especially the metabolism of catecholamine neurotransmitters, produces endogenous small-molecule phenols. Endogenous small-molecule phenolic substances are functionally related to the important physiological processes and the occurrence of mental diseases in humans and some animals, which are systematically sorts and summarized in this review. Integrating the previous experimental research and literature analysis on natural small-molecule phenols by our research group, the understanding of the hypothesis that "small-molecule phenol are pharmacological signal carriers" was deepened. Based on above, the concept of "phenolomics" was further proposed, analyzed the research direction and research content which can bring into the knowledge framework of phenolomics. The induction of phenolomics will provide wider perspectives on explaining the pharmacological mechanism of drugs, discovering new drug targets, and finding biomarkers of mental diseases.
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Schistosomiasis, a parasite infectious disease caused by Schistosoma japonicum, often leads to egg granuloma and fibrosis due to the inflammatory reaction triggered by egg antigens released in the host liver. This study focuses on the role of the egg antigens CP1412 protein of S. japonicum (SjCP1412) with RNase activity in promoting liver fibrosis. In this study, the recombinant egg ribonuclease SjCP1412, which had RNase activity, was successfully prepared. By analysing the serum of the population, it has been proven that the anti-SjCP1412 IgG in the serum of patients with advanced schistosomiasis was moderately correlated with liver fibrosis, and SjCP1412 may be an important antigen associated with liver fibrosis in schistosomiasis. In vitro, the rSjCP1412 protein induced the human liver cancer cell line Hep G2 and liver sinusoidal endothelial cells apoptosis and necrosis and the release of proinflammatory damage-associated molecular patterns (DAMPs). In mice infected with schistosomes, rSjCP1412 immunization or antibody neutralization of SjCP1412 activity significantly reduced cell apoptosis and necroptosis in liver tissue, thereby reducing inflammation and liver fibrosis. In summary, the SjCP1412 protein plays a crucial role in promoting liver fibrosis during schistosomiasis through mediating the liver cells apoptosis and necroptosis to release DAMPs inducing an inflammatory reaction. Blocking SjCP1412 activity could inhibit its proapoptotic and necrotic effects and alleviate hepatic fibrosis. These findings suggest that SjCP1412 may be served as a promising drug target for managing liver fibrosis in schistosomiasis japonica.
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Schistosoma japonicum , Esquistosomiasis Japónica , Humanos , Ratones , Animales , Esquistosomiasis Japónica/complicaciones , Esquistosomiasis Japónica/parasitología , Ribonucleasas/metabolismo , Ribonucleasas/farmacología , Células Endoteliales , Cirrosis Hepática/parasitología , Cirrosis Hepática/patología , Hígado/patología , Inflamación/patologíaRESUMEN
The initiation, development and resolution of hepatic fibrosis are influenced by various cytokines, chemokines, damage-associated molecular patterns (DAMPs) and signaling pathways. A significant number of studies in recent years have indicated that the progression of hepatic fibrosis is closely linked to programmed cell death processes such as apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, cuproptosis, and PANoptosis. Inducement of hepatic stellate cells (HSCs) death or preventing death in other liver cells can delay or even reverse hepatic fibrosis. Nevertheless, the roles of programmed cell death in hepatic fibrosis have not been reviewed. Therefore, this review summarizes the characteristics of various of hepatic fibrosis and programmed cell death, focuses on the latest progress of programmed cell death in the promotion and regression of hepatic fibrosis, and highlights the different roles of the programmed cell death of HSCs and other liver cells in hepatic fibrosis. In the end, the possible therapeutic approaches targeting programmed cell death for treating hepatic fibrosis are discussed and prospected.
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Even though manganese is a bioelement essential for metabolism, excessive manganese levels in water can be detrimental to fish development and growth. Therefore, the aim of this study was to evaluate the effects of Mn2+ (0, 0.5,1, 2, and 4 mg·L-1) exposure for 30 d on the growth performance, growth hormone/insulin-like growth factor (GH/IGF) axis, hypothalamic-pituitary-thyroid (HPT) axis, and monoaminergic neurotransmitters of Epinephelus moaraâ×Epinephelus lanceolatusâ(Yunlong grouper). Compared with the control and low Mn2+concentration groups of (0.5 and 1 mg·L-1), the high concentration of Mn2+ (4 mg·L-1) significantly reduced body weight (BW), body length (BL), weight gain rate (WGR), and specific growth rate (SGR), increased the feed coefficient rate (FCR) and mortality of Yunlong groupers (P < 0.05). Further, the levels of GH and IGF, along with the expression of ghra and ghrb were significantly reduced after exposure to 2 and 4 mg·L-1 Mn2+for 30 d, whereas the expression of sst5 was significantly up-regulated after exposure to 2 and 4 mg·L-1 Mn2+for 20 and 30 days. Moreover, Mn2+exposure increased thyroid hormone (T3) and thyroid stimulating hormone (TSH) contents, accompanied by increased mRNA levels of dio1 and dio2, however, the T4 level was decreased. Finally, dopamine (DA) and serotonin (5-HT) levels significantly decreased after long-term exposure to higher concentrations of Mn2+, and the levels their metabolites changed as well, suggesting that the synthesis and metabolism of DA and 5-HT were affected. Accordingly, changes in the GH/IGF and HPT axes-related parameters may be the cause of growth inhibition in juvenile groupers under Mn2+ exposure, indicating that the relationship between endocrine disorder and growth inhibition should not be ignored.
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Lubina , Contaminantes Químicos del Agua , Animales , Lubina/fisiología , Manganeso , Serotonina , Contaminantes Químicos del Agua/toxicidad , Sistema EndocrinoRESUMEN
Although hepatocellular carcinoma (HCC) is rather frequent, little is known about the molecular pathways underlying its development, progression, and prognosis. In the current study, we comprehensively analyzed the deferentially expressed metabolism-related genes (MRGs) in HCC based on TCGA datasets attempting to discover the potentially prognostic genes in HCC. The up-regulated MRGs were further subjected to analyze their prognostic values and protein expressions. Twenty-seven genes were identified because their high expressions were significant in OS, PFS, DFS, DSS, and HCC tumor samples. They were then used for GO, KEGG, methylation, genetics changes, immune infiltration analyses. Moreover, we established a prognostic model in HCC using univariate assays and LASSO regression based on these MRGs. Additionally, we also found that SLC38A1, an amino acid metabolism closely related transporter, was a potential prognostic gene in HCC, and its function in HCC was further studied using experiments. We found that the knockdown of SLC38A1 notably suppressed the growth and migration of HCC cells. Further studies revealed that SLC38A1 modulated the development of HCC cells by regulating PI3K/AKT/mTOR signaling via glutamine mediated energy metabolism. In conclusion, this study identified the potentially prognostic MRGs in HCC and uncovered that SLC38A1 regulated HCC development and progression by regulating PI3K/AKT/mTOR signaling via glutamine mediated energy metabolism, which might provide a novel marker and potential therapeutic target in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Glutamina/metabolismo , Neoplasias Hepáticas/patología , Proliferación Celular/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Metabolismo Energético , Línea Celular Tumoral , Sistema de Transporte de Aminoácidos A/metabolismoRESUMEN
BACKGROUND: As digital medicine has exerted profound influences upon diagnosis and treatment of hepatobiliary diseases, our study aims to investigate the accuracy of three-dimensional visualization and evaluation (3DVE) system in assessing the resectability of hilar cholangiocarcinoma (hCCA), and explores its potential clinical value. MATERIALS AND METHODS: The discovery cohort, containing 111 patients from April 2013 to December 2019, was retrospectively included to determine resectability according to revised criteria for unresectability of hCCA. 3D visualization models were reconstructed to evaluate resectability parameters including biliary infiltration, vascular involvement, hepatic atrophy and metastasis. Evaluation accuracy were compared between contrast-enhanced CT and 3DVE. Logistic analysis was performed to identify independent risk factors of R0 resection. A new comprehensive 3DVE classification of hCCA based on factors influencing resectability was proposed to investigate its role in predicting R0 resection and prognosis. The main outcomes were also analyzed in cohort validation, including 34 patients from January 2020 to August 2022. RESULTS: 3DVE showed an accuracy rate of 91% (95%CI 83.6-95.4%) in preoperatively evaluating hCCA resectability, significantly higher than 81% (95%CI 72.8-87.7%) of that of CT (p = 0.03). By multivariable analysis, hepatic artery involvement in 3DVE was identified an independent risk factor for R1 or R2 resection (OR = 3.5, 95%CI 1.4,8.8, P < 0.01). New 3DVE hCCA classification was valuable in predicting patients' R0 resection rate (p < 0.001) and prognosis (p < 0.0001). The main outcomes were internally validated. CONCLUSIONS: 3DVE exhibited a better efficacy in evaluating hCCA resectability, compared with contrast-enhanced CT. Preoperative 3DVE demonstrated hepatic artery involvement was an independent risk factor for the absence of R0 margin. 3DVE classification of hCCA was valuable in clinical practice.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Tumor de Klatskin , Humanos , Tumor de Klatskin/diagnóstico por imagen , Tumor de Klatskin/cirugía , Tumor de Klatskin/patología , Colangiocarcinoma/diagnóstico por imagen , Colangiocarcinoma/cirugía , Colangiocarcinoma/patología , Imagenología Tridimensional , Estudios Retrospectivos , Neoplasias de los Conductos Biliares/diagnóstico por imagen , Neoplasias de los Conductos Biliares/cirugía , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/diagnóstico por imagen , Conductos Biliares Intrahepáticos/cirugía , Conductos Biliares Intrahepáticos/patologíaRESUMEN
The ecological environment of Poyang Lake basin is an important part of the construction of ecological civilizations in the south of China. Based on the Landsat satellite remote sensing images, using the principal component analysis (PCA) method to construct the remote sensing ecological index (RSEI) as an evaluation index of ecological environment quality, introducing the Geodetector model to quantitatively detect the explanatory power of different influencing factors on the spatial divergence of the ecological environment, and exploring the changes in ecological environment quality in the Poyang Lake basin from 1990 to 2020 and the impact of different driving factors. The results of the study showed that there were obvious regional differences in the ecological environment quality in the basin. The areas with bad and poor ecological quality were mainly distributed in the central and northern plains; the areas with high and good quality grades were mainly distributed in the hilly and mountainous region of the southwestern part of the basin; the overall ecological environment of the Poyang Lake basin has been improving over the past 30 years; and the improved areas were mainly distributed in low-altitude areas. Geodetector results showed that population density was the factor with the highest explanatory power for the spatial divergence of ecological environment quality in the Poyang Lake basin. Among different natural factors, topographic factors (slope, aspect) had a higher driving force than meteorological factors (temperature, precipitation). The night light index factor showed an increasing yearly trend, indicating that the ecological environment quality of the Poyang Lake basin was gradually increased due to the influence of urbanization development. The construction of the RSEI model based on Google Earth Engine could not only effectively ensure the accuracy of ecological environment quality evaluation in different years but could also quickly realize image preprocessing and index calculations, which greatly improved the efficiency of ecological environment evaluation. These research results can provide a theoretical basis and scientific data support for the ecological environment protection work in the Poyang Lake basin.
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BACKGROUND: Hepatocellular carcinoma (HCC) generally arises from a background of liver cirrhosis (LC). Patients with cirrhosis and suspected HCC are recommended to undergo serum biomarker tests and imaging diagnostic evaluation. However, the performance of routine diagnostic methods in detecting early HCC remains unpromising. METHODS: Here, we conducted a large-scale, multicenter study of 1675 participants including 490 healthy controls, 577 LC patients, and 608 HCC patients from nine clinical centers across nine provinces of China, profiled gene mutation signatures of cell-free DNA (cfDNA) using Circulating Single-Molecule Amplification and Resequencing Technology (cSMART) through detecting 931 mutation sites across 21 genes. RESULTS: An integrated diagnostic model called "Combined method" was developed by combining three mutation sites and three serum biomarkers. Combined method outperformed AFP in the diagnosis of HCC, especially early HCC, with sensitivities of 81.25% for all stages and 66.67% for early HCC, respectively. Importantly, the integrated model exhibited high accuracy in differentiating AFP-negative, AFP-L3-negative, and PIVKA-II-negative HCCs from LCs.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , alfa-Fetoproteínas , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Cirrosis Hepática/diagnóstico , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genéticaRESUMEN
Objective To investigate the effect of recombinant Schistosoma japonicum egg ribonuclease SjCP1412 (rSjCP1412) on proliferation, cell cycle, apoptosis and activation of human hepatic stellate cells LX-2 in vitro, and explore the underlying mechanisms. Methods The rSjCP1412 protein was expressed in Escherichia coli BL21 by prokaryotic expression, and the highly purified soluble rSjCP1412 protein was prepared by Ni NTA affinity chromatography and urea gradient refolding dialysis. Yeast RNA was digested using 12.5, 25.0, 50.0 µg rSjCP1412 proteins at 37 °C for 2, 3, 4 h, and the enzymatic products were electrophoresed on 1.5% agarose gel to observe the RNAase activity of rSjCP1412 protein. The proliferation of LX-2 cells stimulated by different doses of rSjCP1412 protein for 48 hours was measured using CCK-8 assay, and the apoptosis of LX-2 cells stimulated by different doses of rSjCP1412 protein for 48 hours was detected using the Annexin V-FITC/PI double staining, while the percentage of LX-2 cells at G0/G1, S and G2/M phases of cell cycle following stimulation with different doses of rSjCP1412 protein for 48 h was detected by DAPI staining. The type I collagen, type III collagen and α-smooth muscle actin (α-SMA) mRNA expression was quantified using quantitative florescent real-time PCR (qPCR) assay and Western blotting at transcriptional and translational levels in LX-2 cells following stimulation with different doses of rSjCP1412 protein for 48 h, while soluble egg antigen (SEA) served a positive control and PBS without rSjCP1412 protein as a normal control in the above experiments. The expression of collagen I, α-SMA and Smad4 protein was determined using Western blotting in LX-2 cells following stimulation with rSjCP1412 protein, transforming growth factor-β1 (TGF-β1) alone or in combination, to examine the signaling for the effect of rSjCP1412 protein on LX-2 cells. Results The rSjCP1412 protein was successfully expressed and the highly purified soluble rSjCP1412 protein was prepared, which had a RNase activity. Compared with the normal group, the survival rates of LX-2 cells significantly decreased post-treatment with 12.5, 25.0, 50.0 µg/mL rSjCP1412 protein and SEA for 48 h (F = 22.417 and 20.448, both P values < 0.05). The apoptotic rates of LX-2 cells significantly increased post-treatment with 12.5, 25.0, 50.0 µg/mL rSjCP1412 protein for 48 h (F = 11.350, P < 0.05), and treatment with 12.5, 25.0, 50.0 µg/mL rSjCP1412 protein for 48 h resulted in arrest of LX-2 cells in G0/G1 phase (F = 20.710, P < 0.05). Treatment with 12.5, 25.0, 50.0 µg/mL rSjCP1412 protein for 48 h caused a significant reduction in relative expression levels of collagen I (F = 11.340, P < 0.05), collagen III (F = 456.600, P < 0.05) and α-SMA mRNA (F = 23.100, P < 0.05) in LX-2 cells, and both rSjCP1412 protein and SEA treatment caused a significant reduction in collagen I (F = 1 302.000, P < 0.05), α-SMA (F = 49.750, P < 0.05) and Smad4 protein expression (F = 52.420, P < 0.05) in LX-2 cells. In addition, rSjCP1412 protein treatment inhibited collagen I (F = 66.290, P < 0.05), α-SMA (F = 31.300, P < 0.05) and Smad4 protein expression (F = 27.010, P < 0.05) in LX-2 cells activated by TGF-β1. Conclusion rSjCP1412 protein may induce apoptosis of LX-2 cells and inhibit proliferation, cell cycle and activation of LX-2 cells through down-regulating Smad4 signaling molecules.
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Fournier's gangrene (FG) is a life-threatening and special form of necrotizing fasciitis, characterized by occult onset, rapid progress and high mortality, occurring mainly in men over 50 years of age. Risk factors of FG include diabetes, HIV infection, chronic alcoholism and other immunosuppressive state. FG was previously considered as an idiopathic disease, but in fact, three quarters of the infections originated from the skin, urethra and gastrointestinal tract. Initial symptoms of FG are often inconsistent with severity and can progress promptly to fatal infection. Although the treatment measures of FG have been improved in recent years, the mortality does not seem to have decreased significantly and remains at 20% - 30%. The time to identify FG and the waiting period before surgical debridement are directly related to the prognosis. Therefore, in addition to the combination of intensive fluid resuscitation and broad-spectrum antibiotics, treatment of FG should particularly emphasize the importance of early surgical debridement assisted with fecal diversion and skin reconstruction when necessary. This paper is to briefly summarize the progress in the definition, epidemiology, clinical manifestations, diagnosis, treatment and prognosis of Fournier's gangrene in recent years, more importantly, illustrates the importance of multidisciplinary cooperation in the management of FG.
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Uncontrolled lithium dendrites seriously hinder the commercialization of lithium metal batteries in comparison to the durable lithium-ion batteries. Herein, inspired by squashy pomegranate structure, a novel loading strategy of metallic lithium (Li) is introduced to construct dendrite-free Li metal anodes through porous reduced graphene oxide/Au (PRGO/Au) composite microrods (MRs) as unique storage parcels. The abundant internal voids and robust host structure are capable of achieving high mass loading of Li metal and effectively alleviating the conceivable volume change during cycling, accompanied by the preferential selective plating/stripping of Li inside the graphene-based MRs with the embedded Au nanonuclei. As a result, the obtained PRGO/Au-Li anodes deliver a long-lifespan stable cycling up to 600 h with a high specific capacity of ≈2140 mA h g-1 and voltage hysteresis as low as 20 mV in the absence of dendrites. The assembled full cells exhibit excellent rate capability and cycling stability. This work provides an alternative strategy to construct advanced high-energy-density lithium batteries via the unique 1D bioinspired graphene-based packaging strategy.
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Adhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an essential membrane receptor for maintaining male fertility, in complex with a Gs trimer. Whereas the formations of two kinks were determinants of the active state, identification of a potential ligand-binding pocket in ADGRG2 facilitated the screening and identification of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate and deoxycorticosterone as potential ligands of ADGRG2. The cryo-EM structures of DHEA-ADGRG2-Gs provided interaction details for DHEA within the seven transmembrane domains of ADGRG2. Collectively, our data provide a structural basis for the activation and signaling of ADGRG2, as well as characterization of steroid hormones as ADGRG2 ligands, which might be used as useful tools for further functional studies of the orphan ADGRG2.
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Receptores Acoplados a Proteínas G , Transducción de Señal , Humanos , Masculino , Microscopía por Crioelectrón , Sulfato de Deshidroepiandrosterona , Desoxicorticosterona , Ligandos , Receptores Acoplados a Proteínas G/químicaRESUMEN
The gas permeation through nanoscale membranes like graphene has been extensively studied by experiments and empirical models. In contrast to planar membranes, the single-walled carbon nanotube has a natural confined hollow structure, which shall affect the gas permeation process. We perform molecular dynamics simulations to investigate the effect of the nanotube diameter on the gas permeation process. It is found that the permeance constant increases with the increase of the nanotube diameter, which can not be explained by existing empirical models. We generalize the three-state model to describe the diameter dependence for the permeance constant, which discloses a distinctive confinement-induced adsorption phenomenon for the gas molecule on the nanotube's inner surface. This adsorption phenomenon effectively reduces the pressure of the bulk gas, leading to the decrease of the permeance constant. These results illustrate the importance of the adsorption within the confined space on the gas permeation process.
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MicroRNAs (miRNAs) are involved in lymphoma progression by regulating the tumor microenvironment. Serum miR130b is overexpressed in diffuse large B-cell lymphoma (DLBCL), inducing Th17 cell alterations. To further illustrate its biological significance and therapeutic rationale, miR130b was detected by quantitative real-time PCR in the serum samples of 532 newly diagnosed DLBCL patients. The mechanism of miR130b on lymphoma progression and the tumor microenvironment was investigated both in vitro and in vivo. Therapeutic targeting miR130b was also evaluated, including OX40 agonistic antibody and lipid nanoparticles (LNPs)-miR130b antagomir. The results showed that serum miR130b significantly correlated with tumor miR130b and serum interleukin-17, indicating lymphoma relapse and inferior survival of DLBCL patients. MiR130b overexpression altered tumor microenvironment signaling pathways and increased Th17 cell activity. As mechanism of action, miR130b downregulated tumor OX40L expression by directly targeting IFNAR1/p-STAT1 axis, recruiting Th17 cells via OX40/OX40L interaction, thereby promoting immunosuppressive function of Th17 cells. In co-culture systems of B-lymphoma cells with immune cells, miR130b inhibited lymphoma cell autophagy, which could be counteracted by OX40 agonistic antibody and LNPs-miR130b antagomir. In murine xenograft model established with subcutaneous injection of A20 cells, both OX40 agonistic antibody and LNPs-miR130b antagomir remarkably inhibited Th17 cells and retarded miR130b-overexpressing tumor growth. In conclusion, as an oncogenic biomarker of DLBCL, miR130b was related to lymphoma progression through modulating OX40/OX40L-mediated lymphoma cell interaction with Th17 cells, attributing to B-cell lymphoma sensitivity towards OX40 agonistic antibody. Targeting miR130b using LNPs-miR130b antagomir could also be a potential immunotherapeutic strategy in treating OX40-altered lymphoid malignancies.
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Linfoma de Células B Grandes Difuso , MicroARNs , Animales , Humanos , Liposomas , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Nanopartículas , Células Th17/metabolismo , Células Th17/patología , Microambiente Tumoral/genéticaRESUMEN
Speciation plays a central role in evolutionary studies, and particularly how reproductive isolation (RI) evolves. The origins and persistence of RI are distinct processes that require separate evaluations. Treating them separately clarifies the drivers of speciation and then it is possible to link the processes to understand large-scale patterns of diversity. Recent genomic studies have focused predominantly on how species or RI originate. However, we know little about how species persist in face of gene flow. Here, we evaluate a contact zone of two closely related toad-headed lizards (Phrynocephalus) using a chromosome-level genome assembly and population genomics. To some extent, recent asymmetric introgression from Phrynocephalus putjatai to P. vlangalii reduces their genomic differences. However, their highly divergent regions (HDRs) have heterogeneous distributions across the genomes. Functional gene annotation indicates that many genes within HDRs are involved in reproduction and RI. Compared with allopatric populations, contact areas exhibit recent divergent selection on the HDRs and a lower population recombination rate. Taken together, this implies that divergent selection and low genetic recombination help maintain RI. This study provides insights into the genomic mechanisms that drive RI and two species persistence in the face of gene flow during the late stage of speciation.