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Dynamic regulation of histone methylation represents a fundamental epigenetic mechanism underlying eukaryotic gene regulation, yet little is known about how the catalytic activities of histone demethylases are regulated. Here, we identify and characterize NPAC/GLYR1 as an LSD2/KDM1b-specific cofactor that stimulates H3K4me1 and H3K4me2 demethylation. We determine the crystal structures of LSD2 alone and LSD2 in complex with the NPAC linker region in the absence or presence of histone H3 peptide, at resolutions of 2.9, 2.0, and 2.25 Å, respectively. These crystal structures and further biochemical characterization define a dodecapeptide of NPAC (residues 214-225) as the minimal functional unit for its cofactor activity and provide structural determinants and a molecular mechanism underlying the intrinsic cofactor activity of NPAC in stimulating LSD2-catalyzed H3K4 demethylation. Thus, these findings establish a model for how a cofactor directly regulates histone demethylation and will have a significant impact on our understanding of catalytic-activity-based epigenetic regulation.
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Oxidorreductasas de Alcohol/metabolismo , Coenzimas/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Modelos Moleculares , Oxidorreductasas N-Desmetilantes/química , Oxidorreductasas N-Desmetilantes/metabolismo , Oxidorreductasas de Alcohol/química , Secuencia de Aminoácidos , Cristalografía por Rayos X , Estabilidad de Enzimas , Células HeLa , Histonas/química , Humanos , Metilación , Datos de Secuencia Molecular , Péptidos/química , Unión Proteica , Especificidad por SustratoRESUMEN
While monolithic giant earth observation satellites still have obvious advantages in regularity and accuracy, distributed satellite systems are providing increased flexibility, enhanced robustness, and improved responsiveness to structural and environmental changes. Due to increased system size and more complex applications, traditional centralized methods have difficulty in integrated management and rapid response needs of distributed systems. Aiming to efficient missions scheduling in distributed earth observation satellite systems, this paper addresses the problem through a networked game model based on a game-negotiation mechanism. In this model, each satellite is viewed as a "rational" player who continuously updates its own "action" through cooperation with neighbors until a Nash Equilibria is reached. To handle static and dynamic scheduling problems while cooperating with a distributed mission scheduling algorithm, we present an adaptive particle swarm optimization algorithm and adaptive tabu-search algorithm, respectively. Experimental results show that the proposed method can flexibly handle situations of different scales in static scheduling, and the performance of the algorithm will not decrease significantly as the problem scale increases; dynamic scheduling can be well accomplished with high observation payoff while maintaining the stability of the initial plan, which demonstrates the advantages of the proposed methods.
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The Yes-associated protein (YAP) transcriptional coactivator is a key regulator of organ size and a candidate human oncogene inhibited by the Hippo tumor suppressor pathway. The TEAD family of transcription factors binds directly to and mediates YAP-induced gene expression. Here we report the three-dimensional structure of the YAP (residues 50-171)-TEAD1 (residues 194-411) complex, in which YAP wraps around the globular structure of TEAD1 and forms extensive interactions via three highly conserved interfaces. Interface 3, including YAP residues 86-100, is most critical for complex formation. Our study reveals the biochemical nature of the YAP-TEAD interaction, and provides a basis for pharmacological intervention of YAP-TEAD hyperactivation in human diseases.
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Proteínas Adaptadoras Transductoras de Señales/química , Proteínas de Unión al ADN/química , Proteínas Nucleares/química , Fosfoproteínas/química , Transactivadores/química , Factores de Transcripción/química , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Proteínas de Unión al ADN/metabolismo , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Conformación Proteica , Alineación de Secuencia , Factores de Transcripción de Dominio TEA , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAPRESUMEN
The fitness function value is a kind of important information in the search process, which can be more targeted according to the guidance of the fitness function value. Most existing meta-heuristic algorithms only use the fitness function value as an indicator to compare the current variables as good or bad but do not use the fitness function value in the search process. To address this problem, the mathematical idea of the fitting is introduced into the meta-heuristic algorithm, and a symmetric projection optimizer (SPO) is proposed to solve numerical optimization and engineering problems more efficiently. The SPO algorithm mainly utilizes a new search mechanism, the symmetric projection search (SP) method. The SP method quickly completes the fitting of the projection plane, which is located through the symmetry of the two points and finds the minima in the projection plane according to the fitting result. Fitting by using the fitness function values allows the SP to find regions where extreme values may exist more quickly. Based on the SP method, exploration and exploitation strategies are constructed, respectively. The exploration strategy is used to find better regions, and the exploitation strategy is used to optimize the discovered regions continuously. The timing of the use of the two strategies is designed so that the SPO algorithm can converge faster while avoiding falling into local optima. The effectiveness of the SPO algorithm is extensively evaluated using seven test suites, including CEC2017, CEC2019, CEC2020, and CEC2022. It is also compared with two sets of 19 recent competitive algorithms. Statistical analyses are performed using five metrics such as the Wilcoxon test, the Friedman test, and variance. Finally, the practicality of the SPO algorithm is verified by four typical engineering problems and a real spacecraft trajectory optimization problem. The results show that the SPO algorithm can find superior results in 94.6% of the comparison tests and is a promising alternative for solving real-world problems.
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This paper presents a facile hydrothermal route to synthesize monodispersive and single-crystalline BaHfO(3) hollow micro- and nanospheres in a concentrated basic environment. The hollow spheres were size tunable from submicrometer to nanoscale by simply adjusting the base concentration at a suitable temperature. The base concentration played the key role on forming BaHfO(3) hollow spheres. Detailed investigations on base concentration, reaction temperature, and duration indicated that the formation of BaHfO(3) hollow spheres was driven by Ostwald ripening process. Because of the abundance of defects, the as-prepared BaHfO(3) hollow nanospheres exhibited a blue light emission under UV-light excitation at room temperature. Calcination led to the photoluminescence declination due to the decrease of defects.
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Lithium-sulfur (Li-S) batteries have been widely considered as the next-generation energy storage system but hindered by the soluble polysulfide intermediate-induced shuttle effect. Doping heteroatoms was confirmed to enhance the affinity of polysulfide and the carbon host, release the shuttle effect, and improve the battery performance. To enhance the Lewis acidity and reinforce the interaction between polysulfide and the carbon skeleton, a novel covalent triazine framework (CTFO) was designed and fabricated by copolymerizing 2,4,6-triphenoxy-s-triazine and 2,4,6-trichloro-1,3,5-triazine through Friedel-Crafts alkylation. Polymerization led to triazine substitution on the para-position of the phenoxy groups of 2,4,6-triphenoxy-triazine and produced two-dimensional three-connected honeycomb nanosheets. These nanosheets were confirmed to exhibit packing in the AB style through the intralayer π-π interaction to form a three-dimensional layered network with micropores of 0.5 nm. The practical and simulated results manifested the enhanced polysulfide capture capability due to the abundant N and O heteroatoms in CTFO. The unique porous polar network endowed CTFO with improved Li-S battery performance with high Coulombic efficiency, rate capability, and cycling stability. The S@CTFO cathode delivered an initial discharge capacity of 791 mAh g-1 at 1C and retained a residual capacity of 512 mAh g-1 after 300 charge-discharge cycles with an attenuation rate of 0.117%. The present results confirmed that multiple heteroatom doping enhances the interaction between the porous polar CTF skeleton and polysulfide intermediates to improve the Li-S battery performance.
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Nosiheptide-resistance methyltransferase (NSR) methylates 23S rRNA at the nucleotide adenosine 1067 in Escherichia coli and thus contributes to resistance against nosiheptide, a sulfur-containing peptide antibiotic. Here, the expression, purification and crystallization of NSR from Streptomyces actuosus are reported. Diffracting crystals were grown by the hanging-drop vapour-diffusion method in reservoir solution consisting of 0.35 M ammonium chloride, 24%(w/v) PEG 3350, 0.1 M MES pH 5.7 at 293 K. Native data have been collected from the apo enzyme and a SAM complex, as well as apo SeMet SAD data. The diffraction patterns of the apo form of NSR, of NSR complexed with SAM and of SeMet-labelled NSR crystals extended to 1.90, 1.95 and 2.25 A resolution, respectively, using synchrotron radiation. All crystals belonged to space group P2(1), with approximate unit-cell parameters a = 64.6, b = 69.6, c = 64.9 A, beta = 117.8 degrees .
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Farmacorresistencia Bacteriana , Metiltransferasas/química , S-Adenosilmetionina/química , Streptomyces/enzimología , Cristalización , Cristalografía por Rayos X , Metiltransferasas/metabolismo , S-Adenosilmetionina/metabolismo , Streptomyces/efectos de los fármacos , Tiazoles/farmacologíaRESUMEN
Optical resonance formed inside a nanocavity resonator can trap light within the active region and hence enhance light absorption, effectively boosting device or material performance in applications of solar cells, photodetectors (PDs), and photocatalysts. Complementing conventional circular and spherical structures, a new type of multishelled spherical resonant strategy is presented. Due to the resonance-enhanced absorption by multiple convex shells, ZnO nanoshell PDs show improved optoelectronic performance and omnidirectional detection of light at different incidence angles and polarization. In addition, the response and recovery speeds of these devices are improved (0.8 and 0.7 ms, respectively) up to three orders of magnitude faster than in previous reports because of the existence of junction barriers between the nanoshells. The general design principles behind these hollow ZnO nanoshells pave a new way to improve the performance of sophisticated nanophotonic devices.
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PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.
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Carcinoma de Células Renales/metabolismo , Proteínas HMGB/metabolismo , Neoplasias Renales/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Animales , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Proteínas de Unión al ADN , Regulación hacia Abajo/genética , Eliminación de Gen , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Proteínas HMGB/deficiencia , Humanos , Hidronefrosis/genética , Hidronefrosis/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Integrasas/metabolismo , Riñón/metabolismo , Riñón/patología , Neoplasias Renales/genética , Neoplasias Renales/patología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Fosforilación Oxidativa , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Transcripción GenéticaRESUMEN
BACKGROUND AND OBJECTIVE: The covalently closed circular DNA (cccDNA), as the template of HBV transcription, plays a key role in the virus infection. The present study aimed to compare the effect of pegylated interferon (IFN)-α-2a with that of conventional IFN-α-2a on intrahepatic covalently closed circular (ccc)DNA in patients with chronic hepatitis B. METHODS: Seventy-six HBeAg-positive chronic hepatitis B patients were randomly divided into two groups (n=38): group A was treated with interferon alpha-2a (IFN-α-2a) and group B was treated with peginterferon alpha-2a (peg IFN-α-2a). The intrahepatic level of cccDNA and its detection rate, levels of hepatitis B virus (HBV) DNA in liver and serum, histologic inflammation and some biochemistry parameters (alanine aminotransferase, aspartate aminotransferase and total bilirubin levels) were measured. RESULTS: The outcome of 48 weeks therapy showed that the mean level of intrahepatic HBV cccDNA level and its detection rate, the levels of HBV DNA and the histology and biochemistry parameters were significantly decreased following therapy in two groups (P<0.05). While, the reductions in the group treated with peg IFN-α-2a were greater (P<0.05). CONCLUSIONS: It may be concluded that the ability of the peg IFN-α-2a to clear and suppress cccDNA and HBV DNA was superior compared with that of conventional IFN-α-2a. Furthermore, the effects of peg IFN-α-2a on histology and biochemistry parameters were also more obvious than conventional IFN-α-2a.
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Antivirales/uso terapéutico , ADN Circular/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Adulto , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , ADN Viral/análisis , Femenino , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéuticoRESUMEN
Quintuple-shelled SnO2 hollow microspheres are prepared by a hard-template method. DSSCs constructed with SnO2 multi-shell photoanodes show a record photoconversion efficiency of 7.18% due to enhanced light scattering. SnO2 hollow microspheres that are utilized as a scattering layer on top of P25 films increase the DSSC photoconversion efficiency from 7.29% to 9.53%.
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A series of multishelled ZnO hollow microspheres with controlled shell number and inter-shell spacing have been successfully prepared by a simple carbonaceous microsphere templating method, whose large surface area and complex multishelled hollow structure enable them load sufficient dyes and multi-reflect the light for enhancing light harvesting and realize a high conversion efficiency of up to 5.6% when used in dye-sensitized solar cells.
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Colorantes/química , Suministros de Energía Eléctrica , Microesferas , Microtecnología/métodos , Energía Solar , Óxido de Zinc/química , CalorRESUMEN
Based on the theory of sol-gel science, perovskite SrHfO(3) hollow cuboidal particles with tunable sizes were rationally synthesized by templateless hydrothermal reactions in KOH solutions. The concentrated KOH solution not only elevated the supersaturation of the reactants to promote the grain growth of SrHfO(3) but also controlled the aggregated particle sizes by compressing the electrical double layers of the primary particulates. The following Ostwald ripening process produced hollow particles with sizes ranging from submicrometer to hundred nanometre. The HRTEM image and SAED pattern revealed the single crystal nature of each hollow cuboidal nanoshell. The KOH concentration and reaction time related experiments confirmed that the formation of SrHfO(3) hollow cuboidal nanoshell was driven by the Ostwald ripening process and followed our assumption. The particles experienced solid, core-shell and hollow morphologies as the reaction proceeded. Also, the formation of SrHfO(3) hollow cuboidal nanoshells favored high reaction temperature which initiated and accelerated the ripening process. The as-prepared hollow cuboidal nanoshells displayed blue light emission under UV laser excitation at room temperature. After calcination, the photoluminescence intensity declined due to the improvement of crystallinity.