The exonuclease activity of Apurinic/apyrimidinic endonuclease 1 (APE1) is responsible for processing matched/mismatched terminus in various DNA repair pathways and for removing nucleoside analogs ...associated with drug resistance. To fill in the gap of structural basis for exonucleolytic cleavage, we determine the APE1-dsDNA complex structures displaying end-binding. As an exonuclease, APE1 does not show base preference but can distinguish dsDNAs with different structural features. Integration with assaying enzyme activity and binding affinity for a variety of substrates reveals for the first time that both endonucleolytic and exonucleolytic cleavage can be understood by an induced space-filling model. Binding dsDNA induces RM (Arg176 and Met269) bridge that defines a long and narrow product pocket for exquisite machinery of substrate selection. Our study paves the way to comprehend end-processing of dsDNA in the cell and the drug resistance relating to APE1.
The numerical hydroelastic method is used to study the structural response of a hexagon enclosed platform (HEP) of flexible module rigid connector (FMRC) structure that can provide life ...accommodation, ship berthing and marine supply for ships sailing in the deep ocean. Six trapezoidal floating structures constitute the HEP structure so that it is a symmetrical very large floating structure (VLFS). The HEP has the characteristics of large area and small depth, so its hydroelastic response is significant. Therefore, this paper studies the structural responses of a hexagon enclosed platform of FMRC structure in waves by means of a 3D potential-flow hydroelastic method based on modal superposition. Numerical models, including the hydrodynamic model, wet surface model and finite element method (FEM) model, are established, a rigid connection is simulated by many-point-contraction (MPC) and the number of wave cases is determined. The load and structural response of HEP are obtained and analyzed in all wave cases, and frequency-domain hydroelastic calculation and time-domain hydroelastic calculation are carried out. After obtaining a number of response amplitude operators (RAOs) for stress and time-domain stress histories, the mechanism of the HEP structure is compared and analyzed. This study is used to guide engineering design for enclosed-type ocean platforms.
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•3D integrated electrodes covered with vertically-aligned ternary Co-Ni-P nanowires.•Excellent hydrogen evolution activity in acidic solutions.•Outstanding long-term stability upon ...continuous galvanostatic electrolysis.
Self-supported electrodes comprising densely-packed, vertically-aligned Co-Ni-P ternary nanowire arrays supported on a nickel foam current collector (Co-Ni-P/NF) have been fabricated through hydrothermal growth of Co-Ni precursor nanowires on nickel foam, followed by a facile phosphorization treatment using low-cost red phosphorous. The morphology, crystal structure, microstructure and chemical composition of the as-fabricated Co-Ni-P nanowires are comprehensively investigated using scanning electron microscopy, X-ray diffraction, transmission electron microscopy and X-ray photoelectron spectroscopy. The as-obtained Co-Ni-P nanowires are porous and composed of polycrystalline solid solution, and Co, Ni and P are uniformly distributed over nanowires. Moreover, these nanowires are firmly adhered to the nickel foam with excellent structural robustness, forming an integrated electrode. The self-supported integrated electrode exhibits outstanding catalytic activity towards the hydrogen evolution reaction (HER), which can deliver current densities of −10, −20 and −100mAcm−2 at small overpotentials of 68, 94 and 134mV, respectively. Furthermore, it is able to sustain continuous galvanostatic electrolysis at −10mAcm−2 for 40h without obvious degradation, showing good long-term stability. The excellent electrocatalytic performance can be attributed, on the one hand, to the intrinsically high catalytic activity of Co-Ni-P ternary nanowires; on the other hand, to the unique porous nanowire morphology and monolithic electrode structure that not only offer appreciable electrocatalytically active sites, but also provide efficient conductive paths and facilitate mass transport of electrolyte and release of the generated gas bubbles.
Many circular RNAs (circRNAs) are produced from back-splicing of exons of precursor mRNAs and are generally co-expressed with cognate linear RNAs. Methods for circRNA-specific knockout are lacking, ...largely due to sequence overlaps between forms. Here, we use base editors (BEs) for circRNA depletion. By targeting splice sites involved in both back-splicing and canonical splicing, BEs can repress circular and linear RNAs. Targeting sites predominantly for circRNA biogenesis, BEs could efficiently repress the production of circular but not linear RNAs. As hundreds of exons are predominantly back-spliced to produce circRNAs, this provides an efficient method to deplete circRNAs for functional study.
Endometriotic lesions are known to be hyperinnervated, especially in lesions of deep endometriosis (DE), which are frequently in close proximity to various nerve plexuses. DE lesions typically have ...higher fibromuscular content than that of ovarian endometriomas (OE) lesions, but the underlying reason remains elusive. Aside from their traditional role of pain transduction, however, whether or not sensory nerves play any role in the development of endometriosis is unclear. Here, we show that, thorough their respective receptors neurokinin receptor 1 (NK1R), calcitonin receptor like receptor (CRLR), and receptor activity modifying protein 1 (RAMP-1), neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP) induce epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT) and further turn stromal cells into smooth muscle cells (SMCs) in endometriotic lesions, resulting ultimately in fibrosis. We show that SP and CGRP, or the rat dorsal root ganglia (DRG) supernatant, through the induction of NK1R and CGRP/CRLR/RAMP-1 signaling pathways, promoted EMT, FMT and SMM in endometriosis, resulting in increased migratory and invasive propensity, cell contractility, production of collagen, and eventually to fibrosis. Neutralization of NK1R and/or CGRP/CRLR/RAMP-1 abrogated these processes. Extended exposure of endometriotic stromal cells to SP and/or CGRP or the DRG supernatant induced increased expression of α-SMA, desmin, oxytocin receptor, and smooth muscle myosin heavy-chain. Finally, we show that DE lesions had significantly higher nerve fiber density, increased staining levels of α-SMA, NK1R, CRLR, and RAMP-1, concomitant with higher lesional fibrotic content than that of OE lesions. The extent of lesional fibrosis correlated positively with the staining levels of NK1R, CRLR, and RAMP-1, as well as the nerve fiber density in lesions. Thus, this study provides another piece of evidence that sensory nerves play an important role in promoting the development and fibrogenesis of endometriosis. It explains as why DE frequently have higher fibromuscular content than that of OE, highlights the importance of lesional microenvironment in shaping the lesional fate, gives more credence to the idea that ectopic endometrium is fundamentally wounds that go through repeated tissue injury and repair, and should shed much needed light into the pathophysiology of endometriosis.
Sepsis is a life‐threatening organ dysfunction syndrome, and liver is a susceptible target organ in sepsis, because the activation of inflammatory pathways contributes to septic liver injury. ...Oxidative stress has been documented to participate in septic liver injury, because it not only directly induces oxidative genotoxicity, but also exacerbates inflammatory pathways to potentiate damage of liver. Therefore, to ameliorate oxidative stress is promising for protecting liver in sepsis. Wogonin is the compound extracted from the medicinal plant Scutellaria baicalensis Geogi and was found to exert therapeutic effects in multiple inflammatory diseases via alleviation of oxidative stress. However, whether wogonin is able to mitigate septic liver injury remains unknown. Herein, we firstly proved that wogonin treatment could improve survival of mice with lipopolysaccharide (LPS)‐ or caecal ligation and puncture (CLP)‐induced sepsis, together with restoration of reduced body temperature and respiratory rate, and suppression of several pro‐inflammatory cytokines in circulation. Then, we found that wogonin effectively alleviated liver injury via potentiation of the anti‐oxidative capacity. To be specific, wogonin activated Nrf2 thereby promoting expressions of anti‐oxidative enzymes including NQO‐1, GST, HO‐1, SOD1 and SOD2 in hepatocytes. Moreover, wogonin‐induced Nrf2 activation could suppress NF‐κB‐regulated up‐regulation of pro‐inflammatory cytokines. Ultimately, we provided in vivo evidence that wogonin activated Nrf2 signalling, potentiated anti‐oxidative enzymes and inhibited NF‐κB‐regulated pro‐inflammatory signalling. Taken together, this study demonstrates that wogonin can be the potential therapeutic agent for alleviating liver injury in sepsis by simultaneously ameliorating oxidative stress and inflammatory response through the activation of Nrf2.
EZH2, a subunit of the polycomb repressive complex 2 (PRC2) catalyzing trimethylation of histone H3 lysine 27 (H3K27), induces epithelial-mesenchymal transition (EMT) in cancers. However, whether ...EZH2 regulates EMT in endometriosis is unclear. Here, we show that EZH2 expression, along with its associated PRC2 proteins, is significantly elevated in ectopic and eutopic endometrium from women with endometriosis as compared with control endometrium. EZH2 knockdown or inhibition restored the epithelial phenotypes of endometriotic epithelial cells, concomitant with the upregulation of E-cadherin and downregulation of vimentin and transcription factors (Snail and Slug) as well as reduced cellular migratory and invasive propensity. Conversely, overexpression of EZH2 induced the expression of Snail, Slug and vimentin and suppresses E-cadherin expression. In vivo administration of 3-Deazaneplanocin A (DZNep), an EZH2 inhibitor, significantly inhibited the growth of endometriotic lesions and improved generalized hyperalgesia, along with attenuated EMT and reduced fibrosis in endometriosis. Notably, platelets induced EZH2 upregulation and increased H3K27 and H3K9 trimethylation levels in endometriotic epithelial cells. These data identify EZH2 as a novel driver of EMT in endometriosis, implicates the link between wound healing and epigenetic changes in the context of endometriosis, and underscore the role of platelets in the development of endometriosis.
Integration of cancer diagnosis and treatment, namely theranostics, is an important issue in the biomedical field. Benefiting from an excellent photothermal effect, ROS generation ability, and the ...desired mesoporous structure of the TiO2–x matrix, we strategically designed and fabricated a TiO2–x based theranostic system for realizing fluorescence/photoacoustic tomography (PAT) bimodal imaging guided triple therapy for photothemal/photodynamic/chemotherapy in this work. Nonstoichiometric TiO2–x nanospheres are excellent near-infrared absorptive material, which takes on both photosensitizer and photothermal agent roles in implementing PDT/PTT combination therapy and PAT imaging. Moreover, the mesoporous structure of TiO2–x also allowed drug loading, and the polydopamine sealing layer enabled it to induce NIR/pH-triggered drug controlled release. Resultantly, both the in vitro and in vivo experiment manifested the remarkable tumor inhibition and tumor imaging effects by the TiO2–x based theranostic system. The antitumor mechanism was attributable to a synergistic therapeutic effect (combination index = 0.318) of DOX-induced DNA damage, and PDT/PTT caused mitochondrial dysfunction and a change in the cell membrane permeability. Innovatively, the B-mode ultrasonography was adopted to monitor the rehabilitation process at the solid tumor site after treatment, which observed a liquefaction necrosis process.
A facile method based on microwave-assisted solvothermal process has been developed to synthesize flowerlike MgO precursors, which were then transformed to MgO by simple calcinations. All the ...chemicals used (magnesium nitrate, urea, and ethanol) were low cost and environmentally benign. The products were characterized by X-ray powder diffraction, scanning electron microscopy, transmission electron microscopy, high-resolution TEM, and N2 adsorption-desorption methods. These flowerlike MgO nanostructures had high surface area and showed superb adsorption properties for Pb(II) and Cd(II), with maximum capacities of 1980 mg/g and 1500 mg/g, respectively. All these values are significantly higher than those reported on other nanomaterials. A new adsorption mechanism involving solid–liquid interfacial cation exchange between magnesium and lead or cadmium cations was proposed and confirmed.
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