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Chronic obstructive pulmonary disease (COPD) is an intractable disease involving as tickym ucus layer and nanoagents with mucus-penetrating capability offer anew way to deliver drugs.H owever,d rug release from nanovehicles requires optimization to enhance the therapeutic effects of COPD therapy. Herein, black phosphorus quantum dots (BPQDs) are combined with PEGylated chitosan nanospheres containing the antibiotic amikacin (termed PEG@CS/BPQDs-AM NPs). As ad rug-delivery system, the hydrophilicity of PEG and positive charge of CS facilitate the penetration of nanovehicles through the mucus layer.T he nanovehicles then adhere to the mucous membrane.F urthermore,t he BPQDs degrade rapidly into nontoxicP O 4 3À and acidic H + ,t hereby promoting the dissociation of PEGylated CS nanospheres, accelerating the release of AM, decreasing the vitality of biofilms for ease of eradication. Our results reveal that drug delivery mediated by BPQDs is af easible and desirable strategy for precision medicine and promising for the clinical therapyo fCOPD.

Abstract. The ability to debug programs composed using aspect-oriented programming (AOP) techniques is critical to the adoption of AOP. Nevertheless, many AOP systems lack adequate support for debugging, making it difficult to diagnose faults and understand the program's composition and control flow. We present an AOP debug model that characterizes AOP-specific program composition techniques and AOP-specific program behaviors, and relates them to the AOP-specific faults they induce. We specify debugging criteria that we feel all AOP systems should support and compare how several AOP systems measure up to this ideal.We explain why AOP composition techniques, particularly dynamic and binary weaving, hinder source-level debugging, and how results from related research on debugging optimized code help solve the problem. We also present Wicca, the first dynamic AOP system to support full source-level debugging. We demonstrate how Wicca's powerful interactive debugging features allow a programmer to quickly diagnose faults in the base program behavior or AOPspecific behavior.

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Aberrant histone acetylation plays an essential role in the neoplastic process via the epigenetic silencing of tumour suppressor genes (TSGs); therefore, the inhibition of histone deacetylases (HDAC) has become a promising target in cancer therapeutics. To investigate the correlation of histone acetylation with clinicopathological features and TSG expression, we examined the expression of acetylated H3 (AcH3), RARβ2, E-cadherin, and β-catenin by immunohistochemistry in 65 cervical squamous cell carcinoma patients. The results revealed that the absence of AcH3 was directly associated with poor histological differentiation and nodal metastasis as well as reduced/negative expression of RARβ2, E-cadherin, and β-catenin in clinical tumour samples. We further demonstrated that the clinically available HDAC inhibitors valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA), in combination with all-trans retinoic acid (ATRA), can overcome the epigenetic barriers to transcription of RARβ2 in human cervical cancer cells. Chromatin immunoprecipitation analysis showed that the combination treatment increased the enrichment of acetylated histone in the RARβ2-RARE promoter region. In view of these findings, we evaluated the antitumor effects induced by combined VPA and ATRA treatment in a xenograft model implanted with poorly differentiated human squamous cell carcinoma. Notably, VPA restored RARβ2 expression via epigenetic modulation. Additive antitumour effects were produced in tumour xenografts by combining VPA with ATRA treatment. Mechanistically, the combination treatment reactivated the expression of TSGs RARβ2, E-cadherin, P21CIP1, and P53 and reduced the level of p-Stat3. Sequentially, upregulation of involucrin and loricrin, which indicate terminal differentiation, strongly contributed to tumour growth inhibition along with partial apoptosis. In conclusion, targeted therapy with HDAC inhibitors and RARβ2 agonists may represent a novel therapeutic approach for patients with cervical squamous cell carcinoma.

The aerospace industry is widely employing strain-life methodologies for structural fatigue predictions. Under spectrum loading, overloads significantly affect the fatigue, therefore it is very important to accurately account for the cyclic transient deformation phenomena. Describing these phenomena requires advanced plasticity models that involve a set of material parameters. Even for the well-known Chaboche model, there is lack of understanding of each parameter's sensitivity