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Many oil fields in the Bohai Oilfield are currently in the stage of high water cut and low recovery. Thus, it is urgent to conduct in-depth research on the potential of these oil fields to maintain stable production. After 20 years of directional well development, Bohai B Oilfield has developed a set of layers with combined production and strong injection, resulting in severe interlayer interference and difficulties in tapping the potential of the remaining oil. Owing to the limited resolution of existing seismic data, it is not possible to identify the reservoir structure inside the braided river composite sand body, including the vertical and horizontal distribution of the interlayer and thin sand body. Therefore, directional well development is currently mainly used. Here, the seismic signal harmonic frequency enhancement technology is proposed, which directly uses the fundamental component of seismic data to predict harmonic and subharmonic information, and then adds it to the original seismic data to expand the high-frequency and low-frequency seismic information, achieving the purpose of frequency enhancement. This method overcomes the limitations of traditional convolutional models, eliminating the need of well information and to estimate seismic wavelets and assume sparse stratigraphic reflection coefficients, thereby reducing the human subjective factors. The research results, verified through dynamic and static information, showed that the seismic signal harmonic frequency enhancement technology can effectively and finely identify the internal structure of braided river sand bodies, help to transform directional wells into horizontal wells for development, avoid interlayer interference, and promote efficient extraction of the remaining oil.

The tumor suppressor p53 is a transcription factor involved in a variety of crucial cellular functions, including cell cycle arrest, DNA repair and apoptosis. Still, a growing number of studies indicate that p53 plays multiple roles in spermatogenesis, as well as in the occurrence and development of male infertility. The representative functions of p53 in spermatogenesis include the proliferation of spermatogonial stem cells (SSCs), spermatogonial differentiation, spontaneous apoptosis, and DNA damage repair. p53 is involved in various male infertility-related diseases. Innovative therapeutic strategies targeting p53 have emerged in recent years. This review focuses on the role of p53 in spermatogenesis and male infertility and analyses the possible underlying mechanism involved. All these conclusions may provide a new perspective on drug intervention targeting p53 for male infertility treatment.

Automatic crop mapping is essential for various agricultural applications. Although fully convolutional networks (FCNs) have shown effectiveness in crop mapping, they rely on labor-intensive pixel-level annotations. Weakly supervised semantic segmentation (WSSS) methods offer a solution by enabling pixel-level segmentation with less costly annotations, such as point, bounding box (bbox), and image-level annotations. However, these weak annotations often lack complete object information, leading to reduced accuracy. Moreover, there is limited exploration of WSSS methods in medium-resolution satellite imagery, such as Sentinel-2. Therefore, this study proposes SAMWS, a WSSS method based on the Segment Anything Model (SAM) for crop mapping using Sentinel-2 time series images. Leveraging SAM, our method can generate high-quality pseudo labels and accommodate various weak annotations without extensive adjustments. SAMWS comprises three stages: 1) finetuning SAM with adapters; 2) generating pseudo labels using weak annotations and finetuned SAM; and 3) training a segmentation network using pseudo labels for crop mapping. Experiments conducted on PASTIS and Munich datasets demonstrate the superiority of our approach. After SAM was finetuned with adapters, the F1-scores for parcel segmentation using point and bbox prompts increased by 75.0 % and 14.4 %, respectively, reaching 0.880 and 0.931. Additionally, our method achieves classification results closest to fully supervised learning when using point, bbox, and image-level annotations, with F1-scores of 0.810, 0.817, and 0.779, respectively. Our approach offers valuable insights into leveraging foundation models in the remote sensing domain and contains significant potential for crop monitoring. The relevant code will be made publicly available at https://github.com/Nick0317Sun/SAMWS.

Binderless tungsten carbide possesses superior wear/oxidation/corrosion resistance, high-temperature performance and polishing characteristics in comparison with traditional WC-Co cemented carbide. However, the poor sinterability coupled with intrinsic brittleness has become the twin problem restricting the development of binderless tungsten carbide especially for application specifically at the harsh conditions. Herein, we systemically investigated the effects of hybrid carbide and oxide ceramic binder, SiC whisker and graphene on the densification, microstructure evolution and mechanical properties of tungsten carbide prepared through two-step spark plasma sintering. These results demonstrate that ceramic binder together with SiC whisker performed effectively on improving the densification of WC, while graphene was the optimum reinforcement for WC-SiCw based nanocomposites. Excellent mechanical properties were achieved for SG0.15 samples with a hardness of 23.21 GPa, a flexural strength of 1207.2 MPa as well as a SENB fracture toughness of 10.66 MPa m1/2. This study could provide reference to develop high-performance binderless tungsten carbide matrix composites, further advancing the application of binderless tungsten carbide.

Large-scale crop mapping not only requires high-quality remote sensing data, but also has high requirements for multisource data organization and interpretation. How to make full use of multisource remote sensing data and combine it with artificial intelligence algorithms has become a key solution for current crop mapping. To solve the above problems, this study proposed a spatiotemporal data cubes approach, which could organize multisource remote sensing data in a unified manner and inherit the deep learning methods. Based on the spatiotemporal data cubes, an innovative sample expansion mechanism was designed, which will effectively solve the problem of sample scarcity in ground surveys. The Attention-based Bidirectional Long Short-Term Memory network was used with a late-fusion strategy as a classifier on each cube cell to further enhance the incorporation of multisource information. In this study, experiments toward winter wheat and garlic were conducted in the Henan Province of China (approximately 167 000 km2). The approach was verified via comparing with random forest and early-fusion strategy, which demonstrated competitive performance, achieving a weighted-average F1 score of 0.888, with individual F1 scores of 0.919, 0.854, and 0.846 for winter wheat, garlic, and others classes, respectively. The analysis also examined the impact of data availability and found that the temporal distribution of observations was more important than the absolute quantity of available data. Overall, the spatiotemporal data cubes approach proposed in this article has the potential to be extended to a national, intercontinental, or even global scale, and can provide a reference for large-scale crop mapping.

Abstract Breast cancer is a major threat to safety and health of women. The breast cancer stem cells (BCSCs) have multi-drug resistance to chemotherapy drugs, which leads to chemotherapy failure. We proposed a strategy of delivery of tumor-killing drugs and a resistance reversal agent, to enhance inhibition of BCSCs. Here, schisandrin B (SchB)/AP NPs are constructed using acid-grafted-poly (β-amino ester) (ATRA-g-PBAE, AP) grafted polymer nanoparticle encapsulated SchB, with pH-sensitive release function. This drug delivery system has good pharmacological properties and can increase the SchB release with the decrease of pH. The NPs showed cytotoxic effects in reversing ATRA resistance to BCSCs. Lysosomal escape was achieved when the nanoparticles were taken up by BCSCs. In addition, we found that NPs may reverse MDR by inhibiting the expression of P-glycoprotein (P-gp) and affecting the energy supply of drug efflux. This study provides a nanodelivery therapy strategy that reverses BCSCs multidrug resistance (MDR) and demonstrates that it did so by interfering with cancer cell energy metabolism. Therefore, the co-delivery strategy of ATRA and SchB provides a new option for the treatment of breast cancer.

Taraxaci herba, as a traditional Chinese medicine, is the name of the Taraxacum genus in the Asteraceae family. Documented in the Tang Herbal Medicine (Tang Dynasty, AD 657–659), its medicinal properties cover a wide range of applications such as acute mastitis, lung abscess, conjunctival congestion, sore throat, damp-heat jaundice, and vision improvement. In the Chinese Pharmacopoeia (Edition 2020), more than 40 kinds of China-patented drugs containing Taraxaci herba were recorded. This review explores the evolving scientific understanding of Taraxaci herba, covering facets of ethnopharmacology, botany, phytochemistry, pharmacology, artificial cultivation, and quality control. In particular, the chemical constituents and pharmacological research are reviewed. Taraxaci herba has been certified as a traditional medicine plant, and its flavonoids, phenolic acids, and terpenoids have been identified and separated, which include Chicoric acid, taraxasterol, Taraxasteryl acetate, Chlorogenic acid, isorhamnetin, and luteolin; they are responsible for anti-inflammatory, antioxidant, antibacterial, anti-tumor, and anti-cancer activities. These findings validate the traditional uses of Taraxaci herba and lay the groundwork for further scientific exploration. The sources used in this study include Web of Science, Pubmed, the CNKI site, classic monographs, the Chinese Pharmacopoeia, the Chinese Medicine Dictionary, and doctoral and master’s theses.

Sorafenib is an important treatment strategy for advanced hepatocellular carcinoma (HCC). Unfortunately, drug resistance has become a major obstacle in sorafenib application. In this study, whole transcriptome sequencing (WTS) was conducted to compare the paired differences between non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and mRNAs, in sorafenib-resistant and parental cells. The overlap of differentially expressed ncRNAs (DENs) between the SMMC7721/S and Huh7/S cells and their parental cells was determined. 2 upregulated and 3 downregulated lncRNAs, 2 upregulated and 1 downregulated circRNAs, as well as 10 upregulated and 2 downregulated miRNAs, in both SMMC7721/S and Huh7/S cells, attracted more attention. The target genes of these DENs were then identified as the overlaps between the differentially expressed mRNAs achieved using the WTS analysis and the predicted genes of DENs obtained using the “co-localization” or “co-expression,” miRanda, and RNAhybrid analysis. Consequently, the potential regulatory network between overlapping DENs and their target genes in both SMMC7721/S and Huh7/S cells was explored. The “lncRNA-miRNA-mRNA” and “circRNA-miRNA-mRNA” networks were constructed based on the competitive endogenous RNA (ceRNA) theory using the Cytoscape software. In particular, lncRNA MED17-203-miRNA (miR-193a-5p, miR-197-3p, miR-27a-5p, miR-320b, miR-767-3p, miR-767-5p, miR-92a-3p, let-7c-5p)-mRNA,” “circ_0002874-miR-27a-5p-mRNA” and “circ_0078607-miR-320b-mRNA” networks were first introduced in sorafenib-resistant HCC. Furthermore, these networks were most probably connected to the process of metabolic reprogramming, where the activation of the PPAR, HIF-1, Hippo, and TGF-β signaling pathways is governed. Alternatively, the network “circ_0002874-miR-27a-5p-mRNA” was also involved in the regulation of the activation of TGF-β signaling pathways, thus advancing Epithelial-mesenchymal transition (EMT). These findings provide a theoretical basis for exploring the mechanisms underlying sorafenib resistance mediated by metabolic reprogramming and EMT in HCC.

Abstract Cancer has always posed a significant threat to human health, prompting extensive research into new treatment strategies due to the limitations of traditional therapies. Starvation therapy (ST) has garnered considerable attention by targeting the primary energy source, glucose, utilized by cancer cells for proliferation. Glucose oxidase (GOx), a catalyst facilitating glucose consumption, has emerged as a critical therapeutic agent for ST. However, mono ST alone struggles to completely suppress tumor growth, necessitating the development of synergistic therapy approaches. Metal catalysts possess enzyme-like functions and can serve as carriers, capable of combining with GOx to achieve diverse tumor treatments. However, ensuring enzyme activity preservation in normal tissue and activation specifically within tumors presents a crucial challenge. Nanodelivery systems offer the potential to enhance therapy effectiveness by improving the stability of therapeutic agents and enabling controlled release. This review primarily focuses on recent advances in the mechanism of GOx combined with metal catalysts for synergistic tumor therapy. Furthermore, it discusses various nanoparticles (NPs) constructs designed for synergistic therapy in different carrier categories. Finally, this review provides a summary of GOx-metal catalyst-based NPs (G-M) and offers insights into the challenges associated with G-M therapy, delivery design, and oxygen (O2) supply.

The current study applies towards investigate the sintering behavior, microstructure as well as mechanical properties of SiC whisker (SiCw) and multi-layer graphene (MLG) reinforced cemented TiB2 nano-composites fabricated through two-step sintering (TSS), highlighting the critical roles of SiCw and MLG as exceptional strengthening/toughening phases. The sinterability of TiB2–TiC–Ni was somewhat improved as a function of MLG or SiCw incorporation. The addition of SiCw resulted in the grain growth of matrix grains, whereas MLG addition significantly impeded the grain growth of TiB2. TSS is effective in suppressing the grain growth coupled with improving the densification in comparison with conventional sintering (CS). The major toughening mechanisms for SiCw/TiB2–TiC–Ni are SiCw bridging, crack deflection and branching. The major toughening mechanisms for MLG/TiB2–TiC–Ni are MLG bridging/pullout as well as crack deflection/branching/arresting. MLG is a superior reinforcement in comparison with SiCw.

Acanthopanax senticosus (Rupr. et Maxim.) Harms is a perennial shrub of the Acanthopanax genus in the Araliaceae family and has a high medicinal value. The application of zinc fertilizer can improve the yield and quality of medicinal materials. However, there are limited reports on approaches to increase the content of medicinal components in A. senticosus, hindering the improvement of its medicinal quality. In this study, A. senticosus was treated with 0.1% (LZn) and 0.4% (HZn) zinc sprayed on the leaf surface. The effects of zinc treatment on the medicinal components in the roots of A. senticosus were analyzed by comprehensive metabolomics and transcriptomics analyses. A total of 316 metabolites were detected, with a prevailing occurrence of terpenoids and phenylpropanoids. We identified metabolites related to the medicinal components that were upregulated after Zn treatment, including 43 terpenoids, 19 phenylpropanoids, eight phenols, and three flavonoids. Combining differential gene expression and K-means analysis, we found 95, 65, and 25 upregulated genes related to phenylpropanoid biosynthesis, terpenoid biosynthesis, and flavonoid biosynthesis, respectively. Under different concentrations of Zn treatment, the upregulated metabolite biosynthesis-related genes and differentially expressed transcription factors varied. Pearson correlation network analysis revealed significant correlations among terpenoids, phenylpropanoids, flavonoids biosynthetic genes, and several transcription factors (ERFs, WRKYs, bHLHs, NACs, and MYBs). This study lays the foundation for understanding the metabolic processes in response to varying levels of zinc foliar spray and provides a theoretical basis for enhancing the efficiency of zinc fertilizer utilization in A. senticosus.

Mycoplasma synoviae is a significant cause of respiratory disease and synovitis among chickens, and has an adverse economic impact on broiler breeding efforts. The present study was designed to develop a systematic understanding of the role that M. synoviae lipid-associated membrane proteins (LAMPs) may play in the virulence of this pathogen. Bioinformatics tools were used to identify 146 predicted membrane proteins and lipoproteins in the M. synoviae proteome. Then, Triton X-114 was used to extract LAMPs that were subsequently identified via LC–MS/MS. This approach enabled the detection of potential LAMPs, and the top 200 most abundant proteins detected using this strategy were subject to further analysis. M. synoviae cells (100 MOI) were exposed to chicken fibroblasts (DF-1) and macrophages (HD-11) in a 1:1 mixed culture. Analysis of LAMP transcripts identified 72 up-regulated LAMP genes which were analyzed in depth by bioinformatics. GO analysis revealed these genes to be enriched in the nucleotide binding, sulfur amino acid transmembrane transporter activity, tRNA binding, rRNA modification, and transition metal ion transport pathways. Moreover, KEGG enrichment analysis suggested that these genes were enriched in the biosynthesis of secondary metabolites, carbon metabolism, glycolysis/gluconeogenesis, and nitrogen metabolism pathways.

Hepatocellular carcinoma (HCC), the sixth most common cancer worldwide, is associated with a high degree of malignancy and poor prognosis. Patients with early HCC may benefit from surgical resection to remove tumor tissue and a margin of healthy tissue surrounding it. Unfortunately, most patients with HCC are diagnosed at an advanced or distant stage, at which point resection is not feasible. Systemic therapy is now routinely prescribed to patients with advanced HCC; however, drug resistance has become a major obstacle to the treatment of HCC and exploring purported mechanisms promoting drug resistance remains a challenge. Here, we focus on the determinants of drug resistance from the perspective of non-coding RNAs (ncRNAs), liver cancer stem cells (LCSCs), autophagy, epithelial-mesenchymal transition (EMT), exosomes, ferroptosis, and the tumor microenvironment (TME), with the aim to provide new insights into HCC treatment.

There has been growing interest in the high-entropy ceramic (HEC) recently owing to its tailorable compositions and microstructures, versatile properties, together with promising structural and functional applications. However, inferior fracture toughness (KIC) and damage tolerance restricted many practical applications of the HEC. Herein, we addressed this challenge by incorporating a three-dimensional graphene–carbon nanotube (3D G–CNT) as toughening agent in (Hf0.2Nb0.2Ta0.2Ti0.2Zr0.2)C. The resulting enhanced 3D G–CNT/(Hf0.2Nb0.2Ta0.2Ti0.2Zr0.2)C featured an outstanding toughness of 8.23 MPa·m1/2, while remaining superior strength (763 MPa) and hardness (24.7 GPa). An ultralow friction coefficient (0.15) coupled with an ultralow wear rate (w, 2.6×10−7 mm3/(N·m)) in the 3D G–CNT/(Hf0.2Nb0.2Ta0.2Ti0.2Zr0.2)C was obtained primarily as a function of lubricating scrolls, in which two-dimensional (2D) graphene acted as a tribolayer, and one-dimensional (1D) carbon nanotubes acted as nano ball bearings embedded inside. Strikingly, the 3D G–CNT/(Hf0.2Nb0.2Ta0.2Ti0.2Zr0.2)C exhibited rather low thermal conductivity (κ) yet excellent electrical conductivity (σ, 1.3×106 S/m) in comparison with the pure (Hf0.2Nb0.2Ta0.2Ti0.2Zr0.2)C. This study provided great potential for maximizing the physical and functional properties of the HEC for various applications.

Crop mapping using satellite imagery is crucial for agriculture applications. However, a fundamental challenge that hinders crop mapping progress is the scarcity of samples. The latest foundation model, Segment Anything Model (SAM), provides an opportunity to address this issue, yet few studies have been conducted in this area. This study investigated the parcel segmentation performance of SAM on commonly used medium-resolution satellite imagery (i.e., Sentinel-2 and Landsat-8) and proposed a novel automated sample generation framework based on SAM. The framework comprises three steps. First, an image optimization automatically selects high-quality images as the inputs for SAM. Then, potential samples are generated based on the masks produced by SAM. Finally, the potential samples are subsequently subjected to a sample cleaning procedure to acquire the most reliable samples. Experiments were conducted in Henan Province, China, and southern Ontario, Canada, using six proven effective classifiers. The effectiveness of our method is demonstrated through the combination of field-survey-collected samples and differently proportioned generated samples. Our results indicated that directly using SAM for parcel segmentation remains challenging, unless the parcels are large, regular in shape, and have distinct color differences from surroundings. Additionally, the proposed approach significantly improved the performance of classifiers and alleviated the sample scarcity problem. Compared to classifiers trained only by field-survey-collected samples, our method resulted in an average improvement of 16% and 78.5% in Henan and Ontario, respectively. The random forest achieved relatively good performance, with weighted-average F1 of 0.97 and 0.996 obtained using Sentinel-2 imagery in the two study areas, respectively. Our study contributes insights into solutions for sample scarcity in crop mapping and highlights the promising application of foundation models like SAM.

Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes (T2DM). Decreased mitochondrial abundance and function were found in white adipose tissue (WAT) of T2DM patients. Therefore, promoting WAT mitochondrial biogenesis and improving adipocyte metabolism may be strategies to prevent and reverse T2DM. Salvianolic acid A (SAA) has been found to exert anti-diabetic and lipid disorder-improving effects. However whether SAA benefits mitochondrial biogenesis and function in adipose tissue is unclear. Here, we evaluated SAA’s effect on mitochondrial biogenesis and function in 3T3-L1 adipocytes and investigated its potential regulatory mechanism. Results showed that SAA treatment significantly promoted the transcription and expression of peroxisome proliferator-activated receptor γ coactivator- 1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Meanwhile, SAA treatment significantly promoted mitochondrial biogenesis by increasing mitochondrial DNA (mtDNA) quantity, mitochondrial mass, and expression of mitochondrial respiratory chain enzyme complexes III and complex IV. These enhancements were accompanied by enhanced phosphorylation of AMPK and ACC and were suppressed by Compound C, a specific AMPK inhibitor. Furthermore, SAA treatment improved adipocytes mitochondrial respiration and stimulated ATP generation. These findings indicate that SAA exerts a potential therapeutic capacity against adipocytes mitochondrial dysfunction in diabetes by activating the AMPK-PGC-1α pathway.

Mycoplasma synoviae infection rates in chickens are increasing worldwide. Genomic studies have considerably improved our understanding of M. synoviae biology and virulence. However, approximately 20% of the predicted proteins have unknown functions. In particular, the M. synoviae ATCC 25204 genome has 663 encoding DNA sequences, among which 155 are considered encoding hypothetical proteins (HPs). Several of these genes may encode unknown virulence factors. This study aims to reannotate all 155 proteins in M. synoviae ATCC 25204 to predict new potential virulence factors using currently available databases and bioinformatics tools. Finally, 125 proteins were reannotated, including enzymes (39%), lipoproteins (10%), DNA-binding proteins (6%), phase-variable hemagglutinin (19%), and other protein types (26%). Among 155 proteins, 28 proteins associated with virulence were detected, five of which were reannotated. Furthermore, HP expression was compared before and after the M. synoviae infection of cells to identify potential virulence-related proteins. The expression of 14 HP genes was upregulated, including that of five virulence-related genes. Our study improved the functional annotation of M. synoviae ATCC 25204 from 76% to 95% and enabled the discovery of potential virulence factors in the genome. Moreover, 14 proteins that may be involved in M. synoviae infection were identified, providing candidate proteins and facilitating the exploration of the infection mechanism of M. synoviae.

Mycoplasma bovis is a global concern for the cattle industry owing to its high rates of infection and resulting morbidity, but its pathogenesis remains poorly understood. Metabolic pathways and characteristics of M. bovis clinical strain were elucidated by comparing the differential expression of metabolites between M. bovis clinical strain NX114 and M. bovis international reference strain PG45. Metabolites of M. bovis in the logarithmic stage were analyzed based on the non-targeted metabolomic technology of ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS). We found 596 metabolites with variable expression, of which, 190 had substantial differences. Differential metabolite analysis of M. bovis NX114 showed organic acids and their derivatives, nucleosides, and nucleotide analogs as important components. We found O-Phospho-L-serine (SEP) as a potential signature metabolite and indicator of pathogenicity. The difference in nucleic acid metabolites reflects the difference in growth phenotypes between both strains of M. bovis. According to KEGG enrichment analysis, the ABC transporter synthesis route had the most differential metabolites of the first 15 differential enrichment pathways. This study reflects the species-specific differences between two strains of M. bovis and further enriches our understanding of its metabolism, paving the way for further research into its pathogenesis.

This paper describes the preparation route and formation mechanism of a Al2O3–Ti2O3 composite. During the fabrication of a ferro-titanium alloy from titanium concentrate via a thermite method, CaO is generally added to reduce the viscosity of the liquid and promote the separation of the ferro-titanium alloy and Al2O3–CaO–TiO2 slag. The latter represents a multi-oxide system mainly composed of CaAl12O19, CaAl4O7, and CaTiO3 species with poor high-temperature performance, which considerably limits its practical application. The performance optimization and high value-added application of this slag involve the elimination of the CaO phase and replacement of TiO2 with Ti2O3 particles to prevent the formation of a multi-oxide system due to the low solubility of Ti2O3 in Al2O3. The Al2O3–Ti2O3 composite material was successfully prepared via industrial experiments, and its synthesis mechanism and corresponding reaction model are established.

The purpose of the present research was to examine the ability of Tremella polysaccharide (TP) to stabilize zein nanoparticles (zein NPs) and appraise the performance of zein/Tremella polysaccharide nanoparticles (zein/TP NPs) in terms of encapsulating and delivering curcumin. In this study, the zein/TP NPs were fabricated based on the anti-solvent precipitation method, which were used to protect and deliver curcumin. The results suggested that TP could be deposited on the surface of zein NPs by virtue of electrostatic interaction, so as to improve the hydrophilicity of zein, provide better protection for curcumin and assemble more stable nanoparticles. Compared with zein NPs (54.73%), the zein/TP NPs exhibited higher encapsulation efficiency of curcumin (93.34%) and excellent re-dispersibility. Furthermore, the retention rate of curcumin encapsulated in zein/TP NPs reached 80.78% and 90.74% after UV irradiation and 80 °C heat treatment for 2 h, respectively, which proved that the addition of TP significantly improved the stability of curcumin. Meanwhile, in vitro digestion study demonstrated that the bioaccessibility of curcumin encapsulated in zein/TP NPs increased by 37.36% compared with in zein NPs. Therefore, the zein/TP NPs may be served as an effective and potential carrier for the delivery of nutraceuticals.

Summary: Mutations in the MECP2 gene underlie a spectrum of neurodevelopmental disorders, most commonly Rett syndrome (RTT). We ask whether MECP2 mutations interfere with human astrocyte developmental maturation, thereby affecting their ability to support neurons. Using human-based models, we show that RTT-causing MECP2 mutations greatly impact the key role of astrocytes in regulating overall brain bioenergetics and that these metabolic aberrations are likely mediated by dysfunctional mitochondria. During post-natal maturation, astrocytes rely on neurons to induce their complex stellate morphology and transcriptional changes. While MECP2 mutations cause cell-intrinsic aberrations in the astrocyte transcriptional landscape, surprisingly, they do not affect the neuron-induced astrocyte gene expression. Notably, however, astrocytes are unable to develop complex mature morphology due to cell- and non-cell-autonomous aberrations caused by MECP2 mutations. Thus, MECP2 mutations critically impact key cellular and molecular features of human astrocytes and, hence, their ability to interact and support the structural and functional maturation of neurons.

Abstract Rational design of low‐cost and high‐efficiency non‐precious metal‐based catalysts toward the hydrogen evolution reaction (HER) is of paramount significance for the sustainable development of the hydrogen economy. Interfacial manipulation‐induced electronic modulation represents a sophisticated strategy to enhance the intrinsic activity of a non‐precious electrocatalyst. Herein, we demonstrate the straightforward construction of Co/MoS2 hetero‐nanoparticles anchored on inverse opal‐structured N,S‐doped carbon hollow nanospheres with an ordered macroporous framework (denoted as Co/MoS2@N,S–CHNSs hereafter) via a template‐assisted method. Systematic experimental evidence and theoretical calculations reveal that the formation of Co/MoS2 heterojunctions can effectively modulate the electronic configuration of active sites and optimize the reaction pathways, remarkably boosting the intrinsic activity. Moreover, the inverse opal‐structured carbon substrate with an ordered porous framework is favorable to enlarge the accessible surface area and provide multidimensional mass transport channels, dramatically expediting the reaction kinetics. Thanks to the compositional synergy and structural superiority, the fabricated Co/MoS2@N,S–CHNSs exhibit excellent HER activity with a low overpotential of 105 mV to afford a current density of 10 mA/cm2. The rationale of interface manipulation and architectural design herein is anticipated to be inspirable for the future development of efficient and earth‐abundant electrocatalysts for a variety of energy conversion systems.

Engineering structures such as pipelines usually operate under stressing conditions. When corrosion occurs on the structures in service environments, the stress and corrosion reactions synergistically result in a so-called mechano-electrochemical (M-E) interaction, adversely affecting the structural integrity. This work reviewed the fundamentals of the M-E interaction for pipeline corrosion, where both corrosion thermodynamics and kinetics were derived by incorporating the effect of stress and strain applied on the pipelines. Under an elastic deformation, the M-E interaction for pipeline corrosion is usually negligible, while a dynamic elastic stress can degrade the integrity of corrosion scale on the steel and slightly accelerates the steel corrosion. However, plastic deformation results in an appreciable M-E interaction, remarkably changing both corrosion potential and corrosion rate of pipeline steels. Based on the M-E interaction theory, a multi-physics field coupling model with finite element analysis was developed to assess corrosion defects on pipelines for failure prediction. Perspectives of the M-E interaction in pipeline corrosion research and preventive management were analyzed.

An active optical system with three segmented mirrors was proposed to verify the co-focus and co-phase progress. In this system, a kind of large-stroke and high-precision parallel positioning platform was specially developed to help support the mirrors and reduce the error between them, which can move in three degrees of freedom out of plane. The positioning platform was composed of three flexible legs and three capacitive displacement sensors. For the flexible leg, a kind of forward-type amplification mechanism was specially designed to amplify the displacement of the piezoelectric actuator. The output stroke of the flexible leg was no less than 220 μm and the step resolution was up to 10 nm. Further, a linear model was established to identify the amplification ratio between the actuator and the flexible leg, which can increase the precision of the positioning platform. Moreover, three capacitive displacement sensors with a resolution of 2.5 nm were symmetrically installed in the platform to accurately measure the position and attitude of the platform. To improve the stability and precision of the platform, particle swarm optimization algorithm was applied to identify the control matrix, which can help the platform achieve ultra-high precision positioning. The results showed that the theoretical matrix parameters had a maximum deviation of 5.67% from the experimental ones. Finally, abundant experiments verified the excellent and stable performance of the platform. The results proved that while bearing the heavy mirror, which is no more than 5 kg, the platform can realize a 220 μm translation stroke and 2.0 mrad deflection stroke, with a high step resolution of 20 nm and 0.19 μrad. These indicators can perfectly cater to the requirements of the proposed segmented mirror system’s co-focus and co-phase adjustment progress.

In this paper, (Al2OC)x(AlN)1-x whiskers are successfully synthesized in resin-bonded Al-Al2O3 composite at 1000–1300°C in flowing N2 by forming highly active AlN in the composite with Al2O(g) as a transition phase. The formation of highly active AlN reduces the formation temperature of (Al2OC)x(AlN)1-x, while the diffusion and mass transfer of Al2O(g) construct a highly active Al2O3-Al4C3-AlN ternary system in the composite, and thus make the (Al2OC)x(AlN)1-x grow into a whisker morphology. The formation mechanism of the Al2O(g) can be expressed as: The uniformly dispersed C produced by phenolic resin enlarges the reaction temperature range of Al by forming an Al2O3-AlN-Al4C3-C composite shell wrapping the Al particle, and the reaction between continuously exposed fresh liquid Al and trace O2(g) in high-purity nitrogen achieves the continuous generation of the Al2O(g).

1G, a novel derivative of curcumin, exhibits promising anticancer activities in various cancer cell lines. To support its further pharmacological studies, a liquid chromatography–tandem mass spectrometry method was developed and validated in accordance with FDA's Guidance. After extraction by protein precipitation, analytes were separated by a 4.5 min gradient elution (water/0.1% formic acid and methanol) on a reverse-phase C18 column at 40 °C. The multiple reaction monitoring mode was used for quantification on a triple quadrupole mass spectrometer with positive ionization. The assay was linear over the concentration range of 5–1000 ng/mL with a correlation coefficient (r) greater than 0.99. Values of intra- and inter-day precision and accuracy were satisfactory, i.e.

Abstract WC-Co alloys have enjoyed great practical significance owing to their excellent properties during the past decades. Despite the advantages, however, recently there have been concerns about the challenges associated with the use of Co, i.e. price instability, toxicity and properties degeneration, which necessitates the fabrication of binderless tungsten carbide (BTC). On the other hand, BTC or BTC composites, none of them, to date has been commercialized and produced on an industrial scale, but only used to a limited extent for specialized applications, such as mechanical seals undergoing high burthen as well as high temperature electrical contacts. There are two challenges in developing BTC: fully densifying the sintered body together with achieving a high toughness. Thus, this review applies towards comprehensively summarize the current knowledge of sintering behavior, microstructure, and mechanical properties of BTC, highlighting the densification improving strategies as well as toughening methods, so as to provide reference for those who would like to enhance the performance of BTC with better reliability advancing them to further wide applications and prepare the material in a way that is environment friendly, harmless to human health and low in production cost. This paper shows that the fabrication of highly dense and high-performance BTC is economically and technically feasible. The properties of BTC can be tailored by judiciously selecting the chemical composition coupled with taking into careful account the effects of processing techniques and parameters.

The polarisome is a dynamic protein complex that nucleates F-actin for polarized yeast growth, but its regulation is unclear. Here, the authors report that the polarisome protein Aip5 undergoes Spa2-mediated phase separation in physiological and stress conditions, potentially for regulating actin assembly.

pH-responsive and CD44 receptor-mediated targeted nanoparticles for eliminating cancer stem cells (CSCs) were developed based on complexes of PEG-poly(β-amino ester) (PEG-PBAE) micelles (PPM) coated with hyaluronic acid (HA) (HA-coated PPM complex, or HPPMc). Thioridazine (Thz) was loaded into HPPMc with a decent drug loading content. The release results of the drug in vitro showed that Thz was released from the HPPMc, which was stimulated by both the acidic pH and specific enzymes. Cytotoxicity studies on mammospheres (MS) revealed that the toxicity potential of Thz-loaded HPPMc (Thz–HPPMc) at pH 5.5 was better than drug solutions. Compared with that at pH 7.4, a higher cellular uptake of a coumarin-6 (C6)-labeled complex at pH 5.5 was observed, which demonstrated that complexes were efficiently taken up in MS. Meanwhile, free HA competitively inhibited the cellular uptake of HPPMc, which revealed that the uptake mechanism was CD44 receptor-mediated endocytosis. Within the acidic endolysosomal environment, the protonation of PBAE facilitated the escape of the complex from the lysosome and releases the drug. The results of in vivo distribution studies and tumor suppression experiments showed that HPMMc could stay in the tumor site of BALB/c nude mice for a longer period of time, and Thz–HPPMc could significantly improve the tumor-suppressing effect. All these results demonstrated the great potential of the multifunctional nanoparticle system for eliminating CSCs.

As an emerging diabetes diagnostic indicator and a dynamic change index, HbA1c can not only reflect the average blood glucose level over a period of time but can also well predict the incidence of related microvascular complications. It is important to develop a detection method that can dynamically characterize HbA1c. Silicon nanowire (SiNW) devices were mass-produced using top-down sputtering technology, and a microdialyzer was installed in a SiNW field effect tube biosensor detection system. Finally, the detection system was used to detect HbA1c levels quantitatively and dynamically in experimental rabbits. Various measurements showed that mass-produced SiNW devices have ideal dimensions, stable structures, and good performance. A series of microscopy results showed that the SiNW surface can be functionalized for intermolecular interactions. The addition of a dialysis device can effectively overcome Debye shielding, making the blood test similar to the pure standard test. Finally, the dynamic detection of HbA1c within 40 h was realized. SiNW biosensors are capable of the dynamic detection of biomolecules, and dynamic observation of the interaction between blood glucose and HbA1c provides new ideas for the diagnosis and treatment of patients with diabetes. Therefore, the SiNW biosensor can reflect the dynamic changes in HbA1c in a shorter time, which has a certain potential value in the clinical treatment of diabetes.

Reactive oxygen species (ROS) play an important role in cellular metabolism. Many chemotherapeutic drugs are known to promote apoptosis through the production of ROS. In the present study, the novel curcumin derivative, 1g, was found to inhibit tumor growth in colon cancer cells both in vitro and in vivo. Bioinformatics was used to analyze the differentially expressed mRNAs. The mechanism of this effect was a change in mitochondrial membrane potential caused by 1g that increased its pro-apoptotic activity. In addition, 1g produced ROS, induced G1 checkpoint blockade, and enhanced endoplasmic reticulum (ER)-stress in colon cancer cells. Conversely, pretreatment with the ROS scavenging agent N-acetyl-l-cysteine (NAC) inhibited the mitochondrial dysfunction caused by 1g and reversed ER-stress, cell cycle stagnation, and apoptosis. Additionally, pretreatment with the p-PERK inhibitor GSK2606414 significantly reduced ER-stress and reversed the apoptosis induced by colon cancer cells. In summary, the production of ROS plays an important role in the destruction of colon cancer cells by 1g and demonstrates that targeted strategies based on ROS represent a promising approach to inhibit colon cancer proliferation. These findings reveal that the novel curcumin derivative 1g represents a potential candidate therapeutics for the treatment of colon cancer cells, via apoptosis caused by mitochondrial dysfunction and endoplasmic reticulum stress.

Context: 1 D is a novel derivative of curcumin and shows very promising antitumor activities in various cancer cell lines. Objective: To characterize its preclinical pharmacokinetic profiles, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of 1 D in rat plasma. Materials and methods: An aliquot of 50 μL plasma sample was processed by protein precipitation with methanol. Chromatographic separation was accomplished on a Zorbax Eclipse Plus C18 column (2.1 mm × 50 mm, 1.8 μm) with a gradient elution system (water/0.1% formic acid and methanol). Detection was performed by multiple reaction monitoring (MRM) mode using electrospray ionization in the positive ion mode. The optimized fragmentation transition for 1 D was m/z 491.2 → 361.2. Results: The method was linear over the concentration range of 5–1000 ng/mL. The intra- and inter-day precisions were less than 9.8% and the accuracy was within ± 14.5%. The mean recovery of 1 D ranged from 102.5 to 105.9%. No matrix effects and significant sample loss during sample processing were observed. The validated method has been successfully applied to a pharmacokinetic study in rats after intravenous administration of 1 D. Non-compartmental pharmacokinetic parameters, including half-life (t1/2), apparent volume of distribution (Vz), clearance (CLz), and area under the concentration-time curve (AUC(0–t)) were 4.92 h, 46.56 L/kg, 6.33 L/h/kg, and 806.70 μg/L/h, respectively. Discussion and conclusions: Results demonstrated that 1 D displayed favourable pharmacokinetic properties for further in vivo pharmacologic evaluation, which could be facilitated by the validated LC-MS/MS method.

Abstract Background Based on previous findings, we hypothesized that Vasohibin 2 (VASH2) protein may induce epithelial‐mesenchymal transition (EMT) of pancreatic cancer (PC) cells by promoting the malignant behaviors of these cells. The present study aimed to test this hypothesis and explore the possible mechanisms involved. Methods The expression of VASH2 in PC tissues and cell lines was detected by quantitative real‐time PCR and Western blot. PC cells with overexpression or knockdown of VASH2 were used to examine the involvement of VASH2 in EMT by detecting the expression of epithelial (E‐cadherin) and mesenchymal (vimentin) markers and EMT‐related transcription factor ZEB1/2, in gemcitabine resistance and tumor cell invasion by apoptosis and invasion assays, and in cancer stem cell‐like phenotypes by detecting the proportion of CD24+CD44+ and side population (SP) cells in PC cells with flow cytometry. The impact of VASH2 overexpression and knockdown on components of the Hedgehog signaling pathway was also assessed. Results We found that VASH2 was highly expressed in PC tissues and cells. It promoted the EMT of PC cells by altering ZEB1/2 expression. VASH2 also stimulated invasion and chemotherapeutic resistance of PC cells and increased the proportion of cancer stem‐like cells in PC cells. VASH2 did so by upregulating the expression of multiple molecules in the Hedgehog signaling pathway of PC cells. Conclusion VASH2 promotes malignant behaviors of PC cells by inducing EMT via activation of the Hedgehog signaling pathway.

The sensitivity of cotton to salt stress depends on the genotypes and salt types. Understanding the mechanism of ion homeostasis under different salt stresses is necessary to improve cotton performance under saline conditions. A pot experiment using three salt stresses saline stress (NaCl+Na2SO4), alkaline stress (Na2CO3+NaHCO3), and saline-alkaline stress (NaCl+Na2SO4+Na2CO3+NaHCO3) and two cotton varieties (salt-tolerant variety L24 and salt-sensitive variety G1) was conducted. The growth, ion concentrations, and Na+ transport-related gene expression in the cotton varieties were determined. The inhibitory effects of saline-alkaline stress on cotton growth were greater than that of either saline stress or alkaline stress alone. The root/shoot ratio under alkaline stress was significantly lower than that under saline stress. The salt-tolerant cotton variety had lower Na and higher K concentrations in the leaves, stems and roots than the salt-sensitive variety under different salt stresses. For the salt-sensitive cotton variety, saline stress significantly inhibited the absorption of P and the transport of P, K, and Mg, while alkaline stress and saline-alkaline stress significantly inhibited the uptake and transport of P, K, Ca, Mg, and Zn. Most of the elements in the salt-tolerant variety accumulated in the leaves and stems under different salt stresses. This indicated that the salt-tolerant variety had a stronger ion transport capacity than the salt-sensitive variety under saline conditions. Under alkaline stress and salt-alkaline stress, the relative expression levels of the genes GhSOS1, GhNHX1 and GhAKT1 in the salt-tolerant variety were significantly higher than that in the salt-sensitive variety. These results suggest that this salt-tolerant variety of cotton has an internal mechanism to maintain ionic homeostasis.

While the track irregularity in turnout areas has a significant impact on wheel-rail contact, driving safety, and stability, the impact of track irregularity in front of the incoming turnout on vehicles is often overlooked. This paper fills the gaps in the study. As a result, a rigid-flexible coupled dynamic model of the vehicle and turnout is developed. The effect of various irregularities in front of the turnout on the dynamic performance of a vehicle at high speeds has been investigated based on a random sampling method. The results show that different types of track irregularities in front of the turnout have different effects on the dynamic responses of vehicles. The vehicle dynamic performance is most sensitive to short-wavelength (3 m) irregularities in front of the turnout. The alignment irregularity with long-wavelength (40 m) has a significant effect on the wheelset lateral force and lateral acceleration of the vehicle body, caused by two-point contact between the wheel and rail. The frequency range of the effect of the irregularities on the wheel-rail force, safety indicators, and accelerations of the vehicle is mainly below 200 Hz, 50 Hz, and 20 Hz. In this study, a comprehensive assessment of different irregularities is conducted, as well as a quantitative reflection on the effect of the irregularity on the dynamic indicators, providing a reference for maintenance.

Phosphorus (P) deficiency affects plant yield and quality, yet at the same time, excessive phosphorus application does not necessarily promote the growth of plants. How to maintain a balance between biomass accumulation and phosphorus application is a problem. Therefore, the purpose of this research was to explore the relationship between yield and quality of Bupleurum and phosphorus fertilization, based on three phosphorus fertilization levels (20 kg∙ha−1; 10 kg∙ha−1; and 0 kg∙ha−1). We adopted gas chromatography-mass spectrometry to assess the response of primary metabolites of different plant tissues (flowers, main shoots, lateral shoots and roots) to phosphorus fertilization. At the same time, high-performance liquid chromatography was used to quantify saikosaponin A and saikosaponin D, the main active ingredients of Bupleurum. Our research showed that low phosphorus level application has a positive impact on the yield and quality of Bupleurum, especially the above-ground parts increasing the fresh weight of flowers and lateral shoots and the length of main shoots, and moreover, increasing the saikosaponins content in all above-ground parts while decreasing the content in roots which show no significance increase in fresh weight and length. However, high phosphorus level showed a negative impact as it decreases the saikosaponins content significantly in flowers and roots. Furthermore, phosphorus application changed the proportion of saikosaponins, promoting the content of saikosaponin A and inhibiting the content of saikosaponin D in most organs of Bupleurum. Therefore, we can say that high phosphorus application is not preferable to the yield and quality of Bupleurum. To identify the metabolic pathways and special key metabolites, a total of 73 metabolites were discovered, and four differential metabolites—ether, glycerol, chlorogenic and L-rhamnose—were considered to be the key metabolites of Bupleurum’s response to phosphorus fertilization. Furthermore, Bupleurum’s response to phosphorus fertilization was mainly related to metabolic pathways, such as starch and sucrose metabolism and galactose metabolism. Under the phosphorus level, the content of sugars, organic acids and their derivatives, polyols and their derivatives and alkyl were upregulated in flowers. Furthermore, the contents of compounds in the main shoot and lateral shoots showed the same upward trend, except glycosides and polyols and their derivatives.

Material design was performed to solve the twin problems of densification together with brittleness of binderless TiC (BTC). Novel binderless TiC composites reinforced by multilayer graphene (MLG) were fabricated through two-step sintering (TSS) with the auxiliary of nano-sized TiC and WC as sintering aids. The synergistic effects of multilayer graphene and two-step sintering on densification behavior as well as mechanical properties has been investigated. The results demonstrated that excellent mechanical properties were achieved for 0.45 wt% MLG addition with a hardness of 24.36 GPa, a flexural strength of 708.9 MPa as well as a fracture toughness of 7.28 MPa·mm1/2. MLG exerted multifaceted influence on the hybrid TiC-based materials: 1) enhancing the densification and suppressing the grain growth simultaneously; 2) improving the uniform distribution of nano TiC and WC particles throughout the micro TiC matrix; 3) facilitating the load transferring from the matrix to MLG by introducing multi-phase and multi-scale strong-weak hybrid interfaces; 4) inducing efficient toughening mechanisms. Keywords: Multilayer graphene, Binderless TiC, Densification behavior, Toughening mechanisms, Mechanical properties

A hybrid antenna consisting of a patch cavity and a metal grating is designed in this work. This antenna can effectively localize and enhance the intensity of the electric field inside a quantum well photodetector (QWP). The optical properties of the designed antenna are theoretically investigated, and it is found that the electric field can be increased by a factor of ∼104 in the infrared region (6–10 μm) and ∼105 in the terahertz (THz) region (100 μm). These enhancements can greatly improve the performance of QWPs. In the THz region, it is theoretically estimated that the hybrid antenna can increase the working temperature of the detector to 195 K, and the noise equivalent power is theoretically estimated to be as low as ∼10−18 W/Hz0.5 at T = 4 K and ∼10−15 W/Hz0.5 at room temperature, T = 300 K. These results are of great significance for applications of QWPs.

Context: Salvianolic acid A (Sal A) is a hydrophilic bioactive compound isolated from Salvia miltiorrhiza Bunge (Lamiaceae). It exerts beneficial effects after oral administration on diabetic complications. Objective: To systematically study the absorption, distribution and excretion of Sal A after single-dose oral administration. Materials and methods: Animal experiments were conducted in Sprague-Dawley rats. Plasma was sampled at designated times after oral doses of 5, 10 and 20 mg/kg, and an intravenous dose of 50 μg/kg. Tissues were harvested at 10, 60 and 120 min postdosing. Bile, urine and feces were collected at specified intervals before and after dosing. Absorption and distribution characteristics were analyzed by LC–MS, and excretion characteristics were analyzed by UPLC–MS/MS. The Caco-2 cell model was applied to investigate potential mechanisms. Results: The Cmax (5 mg/kg: 31.53 μg/L; 10 mg/kg: 57.39 μg/L; 20 mg/kg: 111.91 μg/L) of Sal A increased linearly with doses (r> 0.99). The calculated absolute bioavailability was 0.39–0.52%. Transport experiment showed poor permeability and the ratio of PB–A to PA–B was 3.13–3.97. The highest concentration of Sal A was achieved in stomach followed by small intestine and liver, and it could also be detected in brain homogenate. Approximately 0.775% of its administered dose was excreted via feces, followed by bile (0.00373%) and urine (0.00252%). Discussion and conclusions: These results support the future development of Sal A as an oral drug for the treatment of diabetic complications. Future research should be conducted to investigate the reason for its poor bioavailability and improve this situation.

Bupleurum (Apiaceae) is widely used in traditional Chinese medicine to treat inflammatory and infectious diseases. Although roots are the only used parts in China, other countries use the whole plant. The yield and quality of Bupleurum depend mainly on fertilizers, especially nitrogen. The current study aimed to assess the relationship between the nitrogen fertilization level and the quality and metabolomic response of different parts (flowers, main shoots, lateral shoots and roots) of Bupleurum to three nitrogen fertilization levels (control group: 0 kg·ha−1; low-nitrogen group: 55 kg·ha−1; high-nitrogen group: 110 kg·ha−1). The results showed that a high nitrogen level increases Bupleurum yield and quality parameters only in aerial parts, especially flowers, but has no significant effect on roots. The HPLC method was exploited for simultaneous quantification of three saikosaponins (A, C and D), which are the main bioactive components in the plant. It was found that the total content of saikosaponins decreased with high nitrogen fertilization in roots but significantly increased in flowers. Moreover, nitrogen fertilizer promoted the content of saikosaponin A but inhibited saikosaponins C and saikosaponins D in most parts of the plant. To study the response of primary metabolites, we adopted gas chromatography–mass spectrometry (GC−MS) analysis; 84 metabolites were identified that were mostly up-regulated with a high nitrogen level in flowers but down-regulated in roots. Four differential metabolites—D-fructose, lactose, ether and glycerol—were recognized as key metabolites in Bupleurum under nitrogen fertilization. Meanwhile, The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results explained that the impact of nitrogen fertilization on Bupleurum was attributed to the C-metabolism, N-metabolism, and lipids metabolism. This research put forward new insights into potential mechanisms and the relationship between the quality and yield of Bupleurum and nitrogen fertilization.

PEG-poly(β-amino ester) (PEG-PBAE), which is an effective pH-responsive copolymer, was mainly synthesized by Michael step polymerization. Thioridazine (Thz), which was reported to selectively eliminate cancer stem cells (CSCs), was loaded into PEG-PBAE micelles (PPM) prepared by self-assembly at low concentrations. The critical micelle concentrations (CMC) of PPM in water were 2.49 μg/mL. The pH-responsive PBAE segment was soluble due to protonated tertiary amine groups when the pH decreased below pH 6.8, but it was insoluble at pH 7.4. The Thz-loaded PEG-PBAE micelle (Thz/PPM) exhibited a spherical shape, and the drug loading was 15.5%. In vitro release of Thz/PPM showed that this pH-sensitivity triggered the rapid release of encapsulated Thz in a weakly acidic environment. The in vitro cytotoxicity and cellular uptake of various formulations at pH 7.4 and 5.5 were evaluated on the mammospheres (MS), which were sorted by MCF-7 human breast cancer cell lines and identified to be a CD44+/CD24− phenotype. The results of the cytotoxicity assay showed that blank micelles were nontoxic and Thz/PPM exhibited a similar anti-CSC effect on MS compared to Thz solution. Stronger fluorescence signal of Coumarin-6 (C6) was observed in MS treated by C6-loaded PPM (C6/PPM) at pH 5.5. The tumor inhibition rate and tumor weight of the free DOX and Thz/PPM groups were significantly different from those of the other groups, which free DOX and Thz/PPM effectively suppressed breast tumor growth in vivo. The above experimental results showed that Thz/PPM is an ideal and effective pH-responsive drug delivery carrier to a targeted therapy of CSCs.

A sensitive, specific and rapid LC-MS method was developed and validated for the determination of salvianolic acid D (SalD) in rat plasma. This method used a single quadrupole mass spectrometer with an electrospray ionization (ESI) source. A single ion monitoring scanning (SIM) mode was employed. It showed good linearity over the concentration range from 3.3 to 666.7 ng/mL for the determination of SalD. The R.S.D.% of intra-day and inter-day precision values were no more than 7.69%, and the accuracy was within 91%−104% at all quality control levels. This LC-MS method was applied to the pharmacokinetic study of SalD in rats. A two-compartmental model analysis was employed. The plasma concentrations at 2 min (C2min) were 5756.06±719.61, 11,073.01±1783.46 and 21,077.58±5581.97 μg/L for 0.25, 0.5 and 1 mg/kg intravenous injection, respectively. The peak plasma concentration (Cmax) was 333.08±61.21 μg/L for 4 mg/kg oral administration. The area under curve (AUC0−t) was 14,384.379±8443.184, 22,813.369±11,860.823, 46,406.122±27,592.645 and 8201.740±4711.961 μg/L·h for intravenous injection (0.25, 0.5 and 1 mg/kg) and oral administration (4 mg/kg), respectively. The bioavailability of SalD was calculated to be 4.159%±0.517%.

‘Biased’ ligands of G protein-coupled receptors (GPCRs) represent a type of promising analgesic with reduced on-target side effects. PZM21, a potent μ-opioid-receptor (μOR)-biased agonist with a new chemical scaffold compared to classic opioids, has been identified as a therapeutic lead molecule for treating pain. In the current study, novel PZM21 analogues were synthesized and evaluated for their in vitro and in vivo efficacy. Novel compound 7a and PZM21 demonstrated undetectable β-arrestin-2 recruitment, however, their analgesic effects need to be further confirmed. Compounds 7b, 7d, and 7g were stronger analgesics than PZM21 in both the mouse formalin injection assay and the writhing test. Compound 7d was the most potent analogue, requiring a dose that was 1/16th to 1/4th of that of PZM21 for its analgesic activity in the two assays, respectively. Therefore, compound 7d could serve as a lead to develop new biased μOR agonists for treating pain.

Little attention has been paid to the effect of Rho-kinase inhibitor on the vascular dysfunction of nitric oxide-deficient hypertension. We aimed to investigate whether the Rho-kinase inhibitor fasudil showed beneficial effect on the vascular dysfunction of the NG-nitro-l-arginine methyl ester (l-NAME) treated rat, as well as to compare the differential effects of fasudil and angiotensin II receptor antagonist valsartan on vascular function. In the present study, both valsartan and fasudil exerted antihypertensive action on the l-NAME-treated rats, while only valsartan attenuated the cardiac hypertrophy. Treatment with valsartan showed improvement on vascular reactivity to norepinephrine, KCl and CaCl2, whereas fasudil therapy showed little effect on vasoconstriction. Endothelium-dependent vasodilation to acetylcholine was reduced in the NO-deficient group but was normalized by the fasudil therapy. The increased expression of RhoA and Rho-kinase (ROCK) in the vasculature was corrected well to normal level by either valsartan or fasudil administration, which seemed to be at least partially responsible for the beneficial effect of the drug infusion. These findings suggest that the angiotensin II receptor antagonist interferes more with the contractile response than Rho-kinase inhibitor, whereas inhibition of Rho-kinase activity exhibits a better improvement on vasorelaxation than blockade of angiotensin II receptor.

Successful immune-mediated regression of solid tumors is difficult because of the small number of cytotoxic T lymphocytes (CTLs) that were traffic to the tumor site. Here, the targeting of tumor-specific infiltrating CTLs was dependent on a fusion protein consisting of human epidermal growth factor (EGF) and staphylococcal enterotoxin A (SEA) with the D227A mutation. EGF-SEA strongly restrained the growth of murine solid sarcoma 180 (S180) tumors (control versus EGF-SEA, mean tumor weight: 1.013 versus 0.197 g, difference = 0.816 g). In mice treated with EGF-SEA, CD4+, CD8+ and SEA-reactive T lymphocytes were enriched around the EGFR expressing tumor cells. The EGF receptors were potentially phosphorylated by EGF-SEA stimulation and the fusion protein promoted T cells to release the tumoricidal cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Intratumoral CTLs secreted cytolytic pore-forming perforins and granzyme B proteins near the surface of carcinomas, causing the death of many tumor cells. We additionally show that labeled EGF-SEA was directly targeted to the tumor tissue after intravenous (i.v.) injection. The findings demonstrate that antibody-like EGF-SEA plays an important role in arresting CTLs in the solid tumor site and has therapeutic potential as a tumor-targeting agent.