Molecularly targeted therapies aim to obstruct cell autonomous programs required for tumor growth. We show that mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 4/6 inhibitors act ...in combination to suppress the proliferation of KRAS-mutant lung cancer cells while simultaneously provoking a natural killer (NK) cell surveillance program leading to tumor cell death. The drug combination, but neither agent alone, promotes retinoblastoma (RB) protein-mediated cellular senescence and activation of the immunomodulatory senescence-associated secretory phenotype (SASP). SASP components tumor necrosis factor-α and intercellular adhesion molecule-1 are required for NK cell surveillance of drug-treated tumor cells, which contributes to tumor regressions and prolonged survival in a KRAS-mutant lung cancer mouse model. Therefore, molecularly targeted agents capable of inducing senescence can produce tumor control through non-cell autonomous mechanisms involving NK cell surveillance.
Cuckoo search (CS) is a one of the most efficient evolutionary for global optimization and widely applied to solve diverse problems in the real world. Despite its efficiency and wide use, CS suffers ...from premature convergence and poor balance between exploitation and exploration. To cope with these issues, a new cuckoo search algorithm extension based on self-adaptive knowledge learning (I-PKL-CS) is proposed. In this study, learning model with individual history knowledge and population knowledge is introduced into the CS algorithm. Individuals constantly adjust their position by using historical knowledge and communicate with each other by using their own knowledge in the optimization process. In order to reduce complexity of the I-PKL-CS algorithm, the optimal learning model is selected to exploit the potential of individual knowledge learning and population knowledge learning by adopting threshold statistics learning strategy, which provides a good trade-off between the exploration and exploitation. The accuracy and performance of the proposed approach are evaluated by eighteen classic benchmark functions and CEC 2013 test suite. Statistical comparisons of the experimental results showed that the proposed I-PKL-CS algorithm made an appropriate trade-off between exploration and exploitation. Comparing the proposed I-PKL-CS with various CS algorithms, variants of differential evolution, and improved particle swarm optimization algorithms, the results demonstrate that I-PKL-CS is a competitive new type of algorithm.
The WC‐12%Cr3C2‐6%Ni coatings are prepared by high‐velocity oxygen‐fuel spraying technology on 42CrMo steel substrate, and then the sealing treatment is carried out by sol‐gel aluminum phosphate ...inorganic sealing agent. The composition, phase structure, morphologies, and porosities of the coatings are characterized by energy dispersive spectrometer (EDS), X‐ray diffraction, scanning electron microscope (SEM), and metallographic gray‐scale methods. Results show that the corrosion current density and corrosion rates of WC‐12%Cr3C2‐6%Ni coatings in different media are lessened by the aluminum phosphate sealing treatment, which can improve the corrosion resistance of the coating. The corrosion rates of unsealed and sealed coatings immersed in 3.5% Na2SO4 solution at 35℃ for 28 days are 0.99 and 0.38 g·m–2·h–1, and the porosity of the coatings is significantly decreased by the aluminum phosphate sealing treatment, which is lower than 2%. During the immersion corrosion, the sealed and unsealed coatings surface form oxide films with different compositions, which can slow down the corrosion along the normal direction of the coating surface in the process of continuous destruction and regeneration, and no obvious coating/substrate interface corrosion occurs.
The WC‐12%Cr3C2‐6%Ni coatings are prepared by HVOF spraying technology on 42CrMo steel substrate, and then the sealing treatment is carried out by sol‐gel aluminum phosphate inorganic sealing agent. The corrosion current density and corrosion rates of WC‐12%Cr3C2‐6%Ni coatings in different media are lessened by the aluminum phosphate sealing treatment which can decrease the residual cracks and porosities, and the porosities of sealed and unsealed coatings is lower than 2%.
Diamond‐like carbon (DLC) possesses brilliant and excellent properties, including excellent corrosion resistance as well as outstanding wear resistance. Ni and B co‐doped DLC films were deposited on ...AZ91D magnesium alloy by electrodeposition under mild conditions (300 V and 25°C). Uniform and dense morphology of co‐doped DLC films were observed, and Ni and B were uniformly incorporated into the carbon‐based films. Among all the electrodeposits, the appearance of D and G peaks near 1330 and 1570 cm−1 revealed that the as‐deposited films were typical DLC films. As the addition of Ni was increased to 0.05 g, the highest microindentation hardness, the lowest friction coefficient, and wear loss were achieved to be 164.5 HV, 0.3, and 0.6 × 10−5 kg/m, respectively. The amorphous carbon films fabricated at 0.05 g Ni had the lowest corrosion current density and the most positive corrosion potential, which was mainly due to the small and dense granular structure effectively hindering the penetration of corrosion media.
The B, Ni co‐doped diamond‐like carbon films prepared by low‐temperature liquid‐phase electrophoretic deposition on AZ91D magnesium alloys have better wear and corrosion resistance. In 3.5 wt% NaCl solution, the self‐corrosion potentials of the magnesium alloys‐coated diamond‐like carbon composite films were more positive than that of the bare magnesium alloy. Especially, the corrosion resistance was optimal when the Ni doping amount was 0.05 g/350 ml.
Accumulation of mutant proteins is a major cause of many diseases (collectively called proteopathies), and lowering the level of these proteins can be useful for treatment of these diseases. We ...hypothesized that compounds that interact with both the autophagosome protein microtubule-associated protein 1A/1B light chain 3 (LC3)
and the disease-causing protein may target the latter for autophagic clearance. Mutant huntingtin protein (mHTT) contains an expanded polyglutamine (polyQ) tract and causes Huntington's disease, an incurable neurodegenerative disorder
. Here, using small-molecule-microarray-based screening, we identified four compounds that interact with both LC3 and mHTT, but not with the wild-type HTT protein. Some of these compounds targeted mHTT to autophagosomes, reduced mHTT levels in an allele-selective manner, and rescued disease-relevant phenotypes in cells and in vivo in fly and mouse models of Huntington's disease. We further show that these compounds interact with the expanded polyQ stretch and could lower the level of mutant ataxin-3 (ATXN3), another disease-causing protein with an expanded polyQ tract
. This study presents candidate compounds for lowering mHTT and potentially other disease-causing proteins with polyQ expansions, demonstrating the concept of lowering levels of disease-causing proteins using autophagosome-tethering compounds.
Ni and B co-doped diamond-like carbon (Ni/B-DLC) films were synthesized on the surface of AZ91D magnesium alloy by electrodeposition under mild environment. The formation mechanism of Ni/B-DLC films ...was discussed. The microstructure of the films was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). Results conveyed that the Ni-DLC and Ni/B-DLC films were hydrogenated amorphous carbon films. With the co-doping of Ni and B, the protruding mulberry-like structure of carbon-based films gave way to the compact and uniform granular structure. The intensity ratio (ID/IG) of D and G lines was decreased from 0.75 to 0.71. XRD patterns revealed that the doping of boron favored the sp3 hybridization of carbon atoms. Simultaneously, the infrared spectra demonstrated that hydrogen for Ni/B-DLC films was preferentially bonded with sp2 carbon atom. In addition, Ni/B-DLC films had excellent wear resistance, which was mainly attributed to the homogeneous and dense structure and considerable micro-indentation hardness.
•Ni-DLC and Ni/B-DLC films were prepared by a simple electrodeposition route.•The formation mechanism of Ni/B-DLC films was explored.•With the doping of boron, the mulberry-like structure of the film was replaced by the dense and uniform granular structure.•Boron doping was beneficial to the sp3 hybridization of carbon atoms.•Hydrogen for Ni/B-DLC films was preferentially linked to sp2 site.
Abstract
Natural killer (NK) cells exert critical roles in anti-tumor immunity but how their functions are regulated by epitranscriptional modification (e.g., N
6
-methyladenosine (m
6
A) ...methylation) is unclear. Here we report decreased expression of the m
6
A “writer” METTL3 in tumor-infiltrating NK cells, and a positive correlation between protein expression levels of METTL3 and effector molecules in NK cells. Deletion of
Mettl3
in NK cells alters the homeostasis of NK cells and inhibits NK cell infiltration and function in the tumor microenvironment, leading to accelerated tumor development and shortened survival in mice. The gene encoding SHP-2 is m
6
A modified, and its protein expression is decreased in METTL3-deficient NK cells. Reduced SHP-2 activity renders NK cells hyporesponsive to IL-15, which is associated with suppressed activation of the AKT and MAPK signaling pathway in METTL3-deficient NK cells. These findings show that m
6
A methylation safeguards the homeostasis and tumor immunosurveillance function of NK cells.
Zhu Xi's thoughts, as one of the most influential ideological doctrines in China, have been translated and interpreted in the English-speaking world for more than two hundred years. However, previous ...studies of their English translations focused on just one given period or region, thus leaving the overall westward path unveiled. This paper examines the translation and interpretation of Zhu Xi's thoughts in the English-speaking world ever since the beginning of the early 19th century. The two hundred years is divided into four stages, namely, Missionary Translation, Interpretation in/for Western Philosophical Frames, Interpretation in terms of Zhu's Own Discourse, and Modern Interpretation. Then different purposes and features of translations at different stages are analyzed. In the end, some key features of Zhu's thoughts being interpreted in the west are summarized, which may provide a reference for more effective translation of Zhu Xi's thoughts in the future.
Despite the growing attention paid to the research of translation technology teaching (TTT), there is still a lack of studies on students' attitudes and the motivational factors in relation to it. To ...this end, the paper reports on a questionnaire-based study that describes students' attitudes towards translation technology (in the Chinese MTI context) and explores its structural relations with translation mindsets and future work self.
Data were collected from 108 grade 2021 MTI students of three selected Chinese universities and analyzed using descriptive statistics and structural equation modeling (SEM).
The results demonstrate that Chinese MTI students' overall attitudes towards translation technology are slightly positive. So far, they perceive translation technology to be slightly effective for translation and are slightly mindful of it. They are slightly influenced by teachers and still feel inhibited when learning and using it. Furthermore, the results also indicate that growth translation mindsets positively influence students' attitudes towards the effectiveness of translation technology, teacher influence, exhibition to translation technology, and mindfulness about translation technology, whereas fixed translation mindsets only negatively predict students' teacher influence. Likewise, future work self-salience positively associates with students' attitudes towards the effectiveness of translation technology and mindfulness about translation technology, while future work self-elaboration positively relates to students' exhibition to translation technology. Among them, growth translation mindsets are the strongest predictor for all attitudes components.
Theoretical and pedagogical implications are also discussed.
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