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Introduction: Tumor-associated calcium signal transducer 2 (Trop2) has been used as a transport gate for cytotoxic agents into cells in antibody–drug conjugate designs because of its expression in a wide range of solid tumors. However, the specific role of Trop2 itself in breast cancer progression remains unclear and small molecules targeting Trop2 have not yet been reported. Objectives: To screen small molecules targeting Trop2, and to reveal its pharmacological effects and the molecular mechanisms of action. Methods: Small molecule targeting Trop2 was identified by cell membrane chromatography, and validated by cellular thermal shift assay and point mutation analyses. We investigated the pharmacological effects of Trop2 inhibitor using RNA-seq, human foreskin fibroblast (HFF)-derived extracellular matrix (ECM), Matrigel drop invasion assays, colony-forming assay, xenograft tumor model, 4T1 orthotopic metastasis model and 4T1 experimental metastasis model. The molecular mechanism was determined using immunoprecipitation, mass spectrometry, immunofluorescence, immunohistochemistry and Western blotting. Results: Here we identified Bruceine D (BD) as the inhibitor of Trop2, and demonstrated anti-metastasis effects of BD in breast cancer. Notably, Lys307 and Glu310 residues of Trop2 acted as critical sites for BD binding. Mechanistically, BD suppressed Trop2-induced cancer metastasis by blocking the formation of Trop2/β-catenin positive loop, in which the Trop2/β-catenin complex prevented β-catenin from being degraded via the ubiquitin-proteosome pathway. Destabilized β-catenin caused by BD reduced nucleus translocation, leading to the reduction of transcription of Trop2, the reversal of epithelial-mesenchymal transition (EMT) process, and the inhibition of ECM remodeling, further inhibiting cancer metastasis. Additionally, the inhibitory effects of BD on lung metastatic colonization and the beneficial effects of BD on prolongation of survival were validated in 4T1 experimental metastasis model. Conclusions: These results support the tumor-promoting role of Trop2 in breast cancer by stabilizing β-catenin in Trop2/β-catenin positive loop, and suggest Bruceine D as a promising candidate for Trop2 inhibition.

Summary: Although autosomal-dominant inheritance is believed an important cause of familial clustering Alzheimer’s disease (FAD), it covers only a small proportion of FAD incidence, and so we investigated epigenetic memory as an alternative mechanism to contribute for intergenerational AD pathogenesis. Our data in vivo showed that mys-2 of Caenorhabditis elegans that encodes a putative MYST acetyltransferase responsible for H4K16 acetylation modulated AD occurrence. The phenotypic improvements in the parent generation caused by mys-2 disfunction were passed to their progeny due to epigenetic memory, which resulted in similar H4K16ac levels among the candidate target genes of MYS-2 and similar gene expression patterns of the AD-related pathways. Furthermore, the ROS/CDK-5/ATM pathway functioned as an upstream activator of MYS-2. Our study indicated that MYS-2/MOF could be inherited intergenerationally via epigenetic mechanisms in C. elegans and mammalian cell of AD model, providing a new insight into our understanding of the etiology and inheritance of FAD.

Background Vorinostat (SAHA) is a histone deacetylase inhibitor that has shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, only a subset of patients with CTCL (30–35%) respond to SAHA and the response is not always sustainable. Thus, understanding the mechanisms underlying evasive resistance in this cancer is an unmet medical need to improve the efficacy of current therapies.Purpose This study aims to identify factors contributing to resistance against SAHA in CTCL and ways to mitigate it.Methods and results In this study, we demonstrated that attenuated reactive oxygen species (ROS) induces the expression of interleukin (IL)-2Rα, one of the IL-2 receptors, which drives resistance to SAHA in CTCL. We also determined that cantharidin could overcome SAHA resistance to CTCL by blocking IL-2Rα-related signaling via ROS-dependent manner. Mechanistically, accelerated translation of IL-2Rα contributes to excessive IL-2Rα protein formation as a result of reduced ROS levels in SAHA-resistant CTCL. At the same time, amplified IL-2R signals are evidenced by strengthened interaction of IL-2Rβ with IL-2Rγ and Janus kinase/signal transducer and activator of transcription molecules, and by increased expression of protein kinase B (AKT)/mTOR and mitogen-activated protein kinase signaling. Moreover, cantharidin, an active constituent of Mylabris used in traditional Chinese medicine, markedly increased ROS levels, and thereby restrained IL-2Rα translation, resulting in suppression of downstream pathways in SAHA-resistant cells. Cantharidin is also found to synergize with SAHA and triggers SAHA-resistant cell death via IL-2R signaling both in vitro and in vivo.Conclusion Our study uncovers a novel molecular mechanism of acquired SAHA resistance and also suggests that using cantharidin is a potential approach to overcome CTCL therapy resistance. Our findings underlie the therapeutic potential of cantharidin in treating CTCL.

ObjectiveAs the complicated and changing environment on the water imposes uncertain interference on the control of unmanned surface vehicles (USVs), a heading and speed controller for USVs with a Type-2 fuzzy control algorithm is proposed. On this basis, an intelligent autonomous and robust control system is developed. MethodsFirst, a motion characteristic model for heading and speed is constructed. The recursive least square (RLS) method is then used to identify the parameters of the model. Finally, based on the identified model, a Type-2 fuzzy control algorithm and sliding mode control algorithm are designed and validated through actual ship experiments.ResultsAs the experimental results indicate, compared with the sliding mode control algorithm, the Type-2 fuzzy control algorithm demonstrates better robustness and ideal anti-interference ability in controlling USVs, but its real-time response is slightly longer. ConclusionThe results of this study can provide references for the motion control of USVs subjected to uncertain interference.

Identifying ships is essential for maritime situational awareness. Automatic identification system (AIS) data and remote sensing (RS) images provide information on ship movement and properties from different perspectives. This study develops an efficient spatiotemporal association approach that combines AIS data and RS images for point–track association. Ship detection and feature extraction from the RS images are performed using deep learning. The detected image characteristics and neighboring AIS data are compared using a multi-dimensional feature similarity model that considers similarities in space, time, course, and attributes. An efficient spatial–temporal association analysis of ships in RS images and AIS data is achieved using the interval type-2 fuzzy system (IT2FS) method. Finally, optical images with different resolutions and AIS records near the waters of Yokosuka Port and Kure are collected to test the proposed model. The results show that compared with the multi-factor fuzzy comprehensive decision-making method, the proposed method can achieve the best performance (F1 scores of 0.7302 and 0.9189, respectively, on GF1 and GF2 images) while maintaining a specific efficiency. This work can realize ship positioning and monitoring based on multi-source data and enhance maritime situational awareness.

An insightful understanding of the formation mechanism of process-inherent defects and deformation is increasingly important for the property evaluation and structural design of ceramic matrix composites (CMCs). For this purpose, a coupled thermal–diffusive–mechanical modeling approach was proposed by considering three important phenomena that occur during the pyrolysis process for manufacturing CMCs: variations of the physical and mechanical properties of the constituents, generation and diffusive of pyrolysis gas, and multiple thermal deformations. The synergistic effects of these three phenomena on the stress, damage development, microstructural morphology, and process deformation of SiC matrix composites were investigated using finite-element simulations. This new approach was validated by comparing the simulation and experimental results. Significant volume shrinkage of the matrix during the polymer-to-ceramic transformation resulted in large tensile stresses and subsequent highly fragmented microstructure in CMCs. The pyrolysis-gas-induced expansion on the matrix under a damage state may yield a positive process deformation of CMCs at the macroscale, overcoming the effects of the volume shrinkage of the bulk matrix at the microscale. The modeling approach is expected to guide high-quality manufacturing of CMCs and comprehensive studies of structure–processing–property relationships.

In this study, the effects of carbon content on the microstructural evolution as well as compression and electrochemical corrosion properties of CoFeNiMn multi-principal component alloys (MPCAs) were investigated. A series of (Co25Fe25Ni25Mn25)100−xCx (x = 4, 5, 6, 7, 8) alloys were prepared by vacuum arc melting. Increasing carbon content, the structure transits from a single face-centered-cubic (FCC) phase into a mixed structure containing FCC phase and M23C6 carbides. The yield strength and hardness of the (Co25Fe25Ni25Mn25)100−xCx alloys were enhanced by increasing carbon content, which in turn decreases the ductility. The alloys containing eutectic carbides had a good combination of high yield strength (880 MPa), high fracture strength (2773 MPa), and large fracture strain (47%). Electrochemical measurements indicated that carbon content evidently affects the corrosion resistance of (Co25Fe25Ni25Mn25)100−xCx alloys in 3.5 wt% NaCl solution. Their corrosion resistance initially increases and then decreases with increasing carbon content. The increase in M23C6 carbides can accelerate pitting corrosion and degenerate their corrosion resistance. These findings not only provide comprehensive understanding of the carbon-alloyed behavior in FCC-type MPCAs but also show their potential engineering application as high-performance structural materials.

ObjectivesIn order to create a simulation test platform to effectively test the key technologies of intelligent ships such as guidance, navigation and control technology, this study uses system identification technology to identify the parameters of the Nomoto motion model of an intelligent ship with high precision.MethodsA hybrid parameter identification method is proposed by fully combining the advantages of the extended state observer (ESO) and the robust weighted least square support vector regression algorithm (RW-LSSVR), our previously well-evaluated identification method. The ESO-based state estimator is applied to calculate immeasurable states using measurable states and the second-order linear Nomoto model. To evaluate the proposed approach, models of two vessels with predefined parameter values are employed for simulation tests.ResultsThe proposed approach not only estimates immeasurable states with high accuracy, but also ensures good performance in steering model parameter identification, with values very close to the nominal values.ConclusionsThe proposed ESO-based identification method shows good generalizability and can effectively provide satisfactory estimates of immeasurable states, making it highly applicable to parameter identification.

Objectives: Bloodstream infections (BSIs) caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) have become a worldwide public health threat, and beta-lactam/beta-lactamase inhibitor combinations (BLBLIs) are considered as one reliable carbapenem-sparing antibiotic. However, it is still controversial whether BLBLIs are truly noninferior to carbapenems. Therefore, we conducted this meta-analysis to compare the efficacy of BLBLIs with carbapenems for ESBL-PE BSIs. Methods: A systematic search of PubMed, Cochrane Library, and Embase was conducted until December 2021 to enroll studies comparing BLBLIs with carbapenems for ESBL-PE BSIs. A subgroup analysis was performed based on the choice of therapy (empirical, definitive, and mixed therapy). The protocol was registered in the International Prospective Register of Systematic Reviews (#CRD42022316011). Results: A total of 2786 patients from one randomized clinical trial and 25 cohorts were included. There was no statistically significant difference between BLBLIs and carbapenems groups in therapeutical response (odds ratio [OR] = 1.19, P = 0.45) and mortality (OR = 1.06, P = 0.68). Furthermore, although the statistical difference was also not found in the subgroup analysis, BLBLIs performed better in definitive therapy than empirical therapy than carbapenems, with a numerically higher therapeutical response (OR = 1.42 vs 0.89) and a mildly lower mortality (OR = 0.85 vs 1.14). Conclusion: BLBLIs were noninferior to carbapenems for ESBL-PE BSIs, especially in definitive therapy. BLBLIs may be a valid alternative to spare the use of carbapenems.

The oncogenic role of ephrin type‐B receptor 4 (EPHB4) has been reported in many types of tumors, including chronic myeloid leukemia (CML). Here, we found that CML patients have a higher EPHB4 expression level than healthy subjects. EPHB4 knockdown inhibited growth of K562 cells (a human immortalized myelogenous leukemia cell line). In addition, transient transfection of EPHB4 siRNA led to sensitization to imatinib. These growth defects could be fully rescued by EPHB4 transfection. To identify an EPHB4‐specific inhibitor with the potential of rapid translation into the clinic, a pool of clinical compounds was screened and vandetanib was found to be most sensitive to K562 cells, which express a high level of EPHB4. Vandetanib mainly acts on the intracellular tyrosine kinase domain and interacts stably with a hydrophobic pocket. Furthermore, vandetanib downregulated EPHB4 protein via the ubiquitin‐proteasome pathway and inhibited PI3K/AKT and MAPK/ERK signaling pathways in K562 cells. Vandetanib alone significantly inhibited tumor growth in a K562 xenograft model. Furthermore, the combination of vandetanib and imatinib exhibited enhanced and synergistic growth inhibition against imatinib‐resistant K562 cells in vitro and in vivo. These findings suggest that vandetanib drives growth arrest and overcomes the resistance to imatinib in CML via targeting EPHB4.

Abstract At present, radiotherapy (RT) still acquires limited success in clinical due to the lessened DNA damage under hypoxia and acquired immune tolerance owing to the amplified programmed death ligand‐1 (PD‐L1) expression. Incredibly, intracellular PD‐L1 expression depression is proven to better sensitize RT by inhibiting DNA damage repair. However, the disability of the clinically used antibodies in disrupting the extracellular PD‐L1function still limits the effectiveness of radio‐immunotherapy. Therefore, better PD‐L1 regulation strategies are still urgently needed to better sensitize radio‐immunotherapy. Hence, for this purpose, TPP‐LND is synthesized by linking mitochondrial‐targeted triphenylphosphine cations (TPP+) to the antineoplastic agent lonidamine (LND), which significantly reduces the dose needed for LND to induce effective oxidative phosphorylation inhibition (2 vs 300 µM). Then, TPP‐LND is wrapped with liposomes to form TPP‐LND@Lip nanoparticles. By doing this, TPP‐LND@Lip nanoparticles can sensitize RT by reversing the hypoxic microenvironment of tumors to generate more DNA damage and reducing the expression of PD‐L1 via enhancing the adenosine 5′‐monophosphate‐activated protein kinase activation. As expected, these well‐designed economical TPP‐LND@Lip nanoparticles are more effective than conventional anti‐PD‐L1 antibodies to some extent.

Carbon fibre smart concrete is not only a promising type of structural materials, but also has prospective applications in fields that have special functional requirements. Here, the carbon fibre smart concrete was prepared by the extrusion moulding technique, and the resistivity, pressure-sensitive and temperature-sensitive characteristics were discussed as well as the freezing-thawing properties. The results show that the total porosity of the smart concrete decreases when the carbon fibre was added into a cement matrix, which is 15.72% in the case when carbon fibre content is 1.0 wt.%. The resistivity of the smart concrete decreases quickly with the addition of carbon fibre, which gradually decreases with an increasing temperature and then gradually increases, and the critical transition temperature zone is in the range of 100-130 °C. The compressive and flexural strengths of the smart concrete are the highest when the carbon fibre content is 0.6 wt.%. The rate of change of the resistivity shows an obvious linear response under cyclic loading effects. The freeze-thaw resistance ability of the smart concrete with the addition of carbon fibres is better than that without carbon fibres, and the compressive strength reaches the highest level when the carbon fibre mass fraction is 0.6 wt.%, which indicates that a suitable amount of carbon fibres can effectively restrict the damage to smart concrete induced by temperature stress.

Abstract Backgrounds Cartilaginous endplate (CEP) plays an essential role in intervertebral disc (IVD) health and disease. The aim was to compare the CEP structure of lumbar IVD and to reveal the detailed pattern of integration between the CEP and bony endplate (BEP) from different species. Methods A total of 34 IVDs (5 human, 5 goat, 8 pig, 8 rabbit, and 8 rat IVDs) were collected, fixed and midsagittally cut; in each IVD, one‐half was used for histological staining to observe the CEP morphology, and the other half was used for scanning electron microscopy (SEM) analysis to measure the diameters and distributions of collagen fibers in the central and peripheral CEP areas and to observe the pattern of CEP‐BEP integration from different species. Results The human, pig, goat, and rabbit IVDs had the typical BEP‐CEP structure, but the rat CEP was directly connected with the growth plate. Human CEP was the thickest (896.95 ± 87.71 μm) among these species, followed by pig, goat, rat, and rabbit CEPs. Additionally, the mean cellular density of the rabbit CEP was the highest, which was 930 ± 202 per mm2, followed by the rat, goat, pig, and human CEPs. In all the species, the collagen fiber diameter in the peripheral area was much bigger than that in the central area. The collagen fiber diameters of CEP from the human, pig, goat, and rat were distributed between 35 nm and 65 nm. The BEP and CEP were connected by the collagen from the CEP, aggregating into bundles or cross links with each other to form a network, and anchored to BEP. Conclusions Significant differences in the thickness, cellular density, and collagen characterization of CEPs from different species were demonstrated; the integration of BEP‐CEP in humans, pigs, goats, and rabbits was mainly achieved by the collagen bundles anchoring system, while the typical BEP‐CEP interface did not exist in rats.

Abstract Background Carnitine palmitoyl transferase 1A (CPT1A), the key regulator of fatty acid oxidation, contributes to tumor metastasis and therapeutic resistance. We aimed to identify its clinical significance as a biomarker for the diagnosis and prediction of breast cancer. Methods Western blot, ELISA and in silico analysis were used to confirm CPT1A levels in breast cancer cell lines, cell culture medium and breast cancer tissues. Four hundred thirty breast cancer patients, 200 patients with benign breast disease, and 400 healthy controls were enrolled and randomly divided into a training set and a test set with a 7:3 ratio. Training set was used to build diagnostic models and 10-fold cross validation was used to demonstrate the performance of the models. Then test set was aimed to validate the effectiveness of the diagnostic models. ELISA was conducted to detect individual serum CPT1A levels. Receiver operating characteristic (ROC) curves were generated, and binary logistic regression analyses were performed to evaluate the effectiveness of CPT1A as a biomarker in breast cancer diagnosis. CPT1A levels between post-operative and pre-operative samples were also compared. Results CPT1A was overexpressed in breast cancer tissues, cell lines and cell culture medium. Serum CPT1A levels were higher in breast cancer patients than in controls and were significantly associated with metastasis, TNM stage, histological grading and molecular subtype. CPT1A levels were decreased in post-operative samples compared with paired pre-operative samples. Moreover, CPT1A exhibited a higher efficacy in differentiating breast cancer patients from healthy controls (training set: area under the curve, AUC, 0.892, 95% CI, 0.872–0.920; test set, AUC, 0.904, 95% CI, 0.869–0.939) than did CA15–3, CEA, or CA125. Conclusion CPT1A is overexpressed in breast cancer and can be secreted out of breast cancer cell. Serum CPT1A is positively associated with breast cancer progression and could serve as an indicator for disease monitoring. Serum CPT1A displayed a remarkably high diagnostic efficiency for breast cancer and could be a novel biomarker for the diagnosis of breast cancer.

Abstract Background Unresectable lung or liver organ metastases of colorectal carcinoma (CRC) remain a major obstacle in clinical therapeutics. Epithelial to mesenchymal transition (EMT), a major cause of highly frequent metastasis in tumor, can be promoted by the Wnt/β‐catenin pathway that is aberrantly activated in approximately 90% of CRC. This research aimed to elucidate the antimetastatic potential of sanguinarine (SG) in CRC and the underlying molecular mechanism. Methods The in vitro anticancer effect of SG was determined via cell viability experiment and colony formation assay. Xenograft model of nude mice was used to confirm the antitumor effect of SG in vivo. The antimetastatic potential of SG was investigated by the metastasis model of nude mice, hematoxylin and eosin (H&E) staining, migration assay, and wound‐healing analysis. Immunoblotting analysis, immunofluorescence staining, and immunohistochemistry assay were conducted to elucidate the molecular mechanism. Results In this study, we reported that SG has a selective inhibitory effect on LoVo cells with metastatic characteristics. Furthermore, our results showed attenuation in the migration and metastatic ability of SG‐treated LoVo cells and also decreased metastatic nodules of liver and lung in mice metastasis model. This was also confirmed at the molecular level via H&E staining. Further study revealed that SG had negative impacts on the Wnt/β‐catenin pathway and EMT markers in LoVo cells both in vitro and in vivo. Conclusions Taken together, the antimetastatic potential of SG attributed to the suppression of the Wnt/β‐catenin signaling, which further prevented EMT progression. SG may be of value in a potential therapy for the management of metastasis CRC.

Bisphenol A (BPA) is a ubiquitous environmental pollutant that can specifically induce estrogen receptor β (ERβ) expression, and the latter plays a crucial role during wound healing. However, no study has investigated the association between BPA exposure and skin regeneration. This study aimed to explore the impacts of BPA on wound repair using mice models. C57BL/6 mice were administrated with BPA in two different ways during the process of wound healing—dietary intake (5 and 50 mg/kg) and wound application (1 and 100 nM). Mice primary fibroblasts were exposed to BPA to verify the role of BPA on the function of fibroblasts. We also applied BPA in diabetic mice to evaluate its therapy value. BPA showed dual effects on wound healing, which were dependent on the application routes. Dietary intake of BPA delayed wound healing by suppressing ovarian estrogen secretion, whereas wound application of BPA accelerated skin regeneration via up-regulating wound localized ERβ expression. Highly expressed ERβ enhanced the function of fibroblasts and promoted the transformation from fibroblasts to myofibroblasts. Impacts of BPA on wound healing were dismissed when ERβ was blocked. Moreover, wound application of BPA significantly accelerated wound repair in diabetic mice, but has no significant adverse effect on ovarian hormones levels. The current study indicates that although BPA disrupts the function of the endocrine system when administrated by diet, local application of BPA on wounds shows a superior role in promoting wound repair, and this may provide a novel approach for the therapy of pathologic wound healing.

An amendment to this paper has been published and can be accessed via the original article.

The prediction of ship location has become an increasingly popular research hotspot in the field of maritime transportation engineering, which benefits maritime safety supervision and security. Existing methods of ship location prediction based on motion characteristics have a large uncertainty and cannot guarantee trajectory prediction accuracy of the target ship. An improved method of location prediction using k-nearest neighbor (KNN) is proposed in this paper. An expanded circle area of the latest point of the target ship is first generated to find the reference points with similar movement characteristics in the constraints of distance and time intervals. Then, the top k-nearest neighbors are determined based on the degree of similarity. Relationships between the reference point of each neighbor and the latest points of the target ship are calculated. The predicted location of the target ship can then be determined by a weighted calculation of the locations of all neighbors at the predicted time and their relationships with the target ship. Experiments of ship location prediction in 10 min, 20 min, and 30 min were conducted. The correlation coefficient of the location prediction error for the three experiments was 0.992, 0.99, and 0.9875, respectively. The results show that ship location prediction with reference to multiple nearest neighbors with similar movements can provide better accuracy.

Abstract Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Overexpression of pleomorphic adenoma gene like‐2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti‐HCC drugs that target PLAGL2. Drug repositioning may facilitate the development of PLAGL2‐targeted drug candidates. Methods The expression of PLAGL2 in HCC clinical tissue samples and HCC cell lines was analyzed by western blotting. The constructed HCC cell models were used to confirm the underlying function of PLAGL2 as a therapeutic target. Multiple in vitro and in vivo assays were conducted to determine the anti‐proliferative and apoptosis‐inducing effects of selenium sulfide (SeS2), which is clinically used for the treatment of seborrheic dermatitis and tinea versicolor. Results PLAGL2 expression was higher in HCC tumor tissues than in normal adjacent tissues. Its overexpression promoted the resistance of HCC cells of mitochondrial apoptosis through the regulation of the downstream C‐MET/STAT3 signaling axis. SeS2 exerted significant anti‐proliferative and apoptosis‐inducing effects on HCC cells in a PLAGL2‐dependent manner. Mechanistically, SeS2 suppressed C‐MET/STAT3, AKT/mTOR, and MAPK signaling and triggered Bcl‐2/Cyto C/Caspase‐mediated intrinsic mitochondrial apoptosis both in vitro and in vivo. Conclusions Our data reveal an important role of PLAGL2 in apoptosis resistance in HCC and highlight the potential of using SeS2 as a PLAGL2 inhibitor in patients with HCC.

Background: LncRNAs play an essential role in a variety of diseases. Zinc finger antisense 1 (ZFAS1), a newly identified lncRNA, is a transcript antisense to the 5ʹ end of the gene Znfx1. The purpose of this study was to aim to compare the levels of ZFAS1 between ischemic stroke (IS) and healthy control subjects and explore its potential role as a noninvasive biomarker in the diagnosis of IS. Methods: A total of 176 patients and 111 healthy controls were included in the study. RT-qPCR was performed to detect the expression of ZFAS1. Results: The results showed that level of ZFAS1 in IS patients was significantly lower than controls (P = 0.0002). Furthermore, we found that the ZFAS1 levels in large-artery atherosclerosis (LAA) strokes were significantly downregulated than those in non-LAA strokes and controls. Meanwhile, ZFAS1 levels in the small vessel occlusion (SVO) group were lower than those in cardioembolism (CE) (P = 0.0197) and controls (P = 0.0041). Multinomial logistic regression analyses showed that the expression of ZFAS1 was not associated with the CE (P = 0.185) and SVO (P = 0.268) stroke groups, while lower ZFAS1 levels (P

This study contributes to developing a novel hybrid identification method based on intelligent algorithms, i.e. the least support vector regression algorithm (LS-SVR) and the artificial bee colony algorithm (ABC), to deal with the identification of the simplified ship dynamic model while the outliers exist in the measurements. The ship dynamic model is directly derived from our previous work which has been well verified and validated. The outliers are detected by introducing the robust estimation method namely the $3\sigma $ principle and then deleted from the training data. The weighted version of LS-SVR (WLS-SVR) with spareness and robustness ability is used as the fundamental identification approach. To improve the performance of the WLS-SVR, the structural parameters involved in it are optimized by utilizing the artificial bee colony algorithm (ABC), and the weights of it are adaptively set with the use of the adaptive weight method. Two case studies including the simulation study on a container ship and the experimental study on an Unmanned Surface Vessel (USV) are carried out to test the proposed hybrid intelligent identification method. The simulation study demonstrates the effectiveness and the acceptable time complexity in terms of the engineering application of the proposed identification method through the comparison with the cross-validation method and particle swarm optimization algorithm optimized LS-SVR. In the experimental study, ABC-LSSVR, ABC-LSSVR with the $3\sigma $ principle (D-ABC-LSSVR), ABC-LSSVR with the adaptive weight (ABC-AWLSSVR), and ABC-LSSVR with both the $3\sigma $ principle and the adaptive weight (D-ABC-AWLSSVR) are applied to identify the steering model for the USV. The results indicate that the influence of the outliers on model identification is effectively diminished by the robust $3\sigma $ principle and the adaptive weight method and that the D-ABC-AWLSSVR outperforms over the other three identification methods in terms of the mean squared error (MSE) of the model predictions.

Identification of parameters involved in the linear response model with high precision is a highly cost-effective, as well as a challenging task, in developing a suitable model for the verification and validation (V+V) of some key techniques for autonomous vessels in the virtual testbed, e.g., guidance, navigation, and control (GNC). In order to deal with this identification problem, a novel identification framework is proposed in this paper by introducing the extended state observer (ESO), and the well-evaluated robust weighted least square support vector regression algorithm (RW-LSSVR). A second-order linear response model is investigated in this study due to its wide use in controller designs. Considering the highly possible situation that only limited states could be measured directly, the required but immeasurable states in identifying parameters contained in the response model are approximately estimated by the ESO. Theoretical analysis of the stability is given to show and improve the applicability of the ESO. Simulation studies based on linear response models with predefined parameter values of a cargo vessel and a patrol vessel maneuvering in an open water area are carried out, respectively. Results show that the proposed approach not only estimates immeasurable states with high accuracy but also ensures good performance on the parameter identification of the response model with very close values to the nominal ones. The proven identified approach is economic because it only requires limited kinds of low-cost sensors.

In this study, the microstructure evolution and mechanical properties of CoFeNiMnMox high-entropy alloy after adding Mo were investigated. With the increase in Mo content, Mo atoms occupied lattice sites and the microstructure changed from hypoeutectic of primary FCC-phase to Laves phase particles of FCC-phase, and Vickers microhardness increased steadily from 193 to 357. The yield strength increased from 187 MPa when the Mo content was 0.25 to 537 MPa when the Mo content was 1.0. The microstructure formation can be explained by atomic size difference δ and parameter ΔχA. δ ≥ 3.87% and ΔχA ≥ 5.24% criterion is proposed to better predict the microstructure formation of the coexistence of (FCC + Laves) phases.

Fe-based metallic glass has wide industrial application due to its unique mechanical behavior and magnetic properties. In the present work, the non-isothermal crystallization kinetics in Fe68Nb6B23Mo3 glassy alloys were investigated by differential scanning calorimeter (DSC). The results indicate that both the glass transformation and crystallization process display an obvious kinetic effect. The activation energy is calculated using Kissinger’s method and Ozawar’s method. The activation energy for Tg (glass transition temperatures), Tx (crystallization initiation temperatures) and Tp (crystallization peak temperatures) calculated from Kissinger equation, is 308 ± 4, 342 ± 5 and 310 ± 7 kJ mol−1, respectively. The activation energy for Tg, Tx and Tp calculated from Ozawa equation is 322 ± 3, 356 ± 5 and 325 ± 7 kJ mol−1, respectively. With the increase of the crystallization volume fraction x, the Avrami exponent n(x) first decreases and then increases. At the preliminary step, 0 < x < 0.25, 2.5 < n(x) < 4.0 stands for the growth from a small size with an increasing nucleation rate. When 0.25 < x < 0.71, n(x) decreases from 2.5 to 1.5, indicating that this stage is controlled by the growth of small particles with a decreasing nucleation rate.

Cohesive zone models rely on the formulation of a cohesive constitutive law. The latter describes the relation between displacement and traction in a cohesive element at an integration point. Cohesive constitutive laws in the presence of opening and shearing modes are less studied in comparison with those formulated for a single mode, particularly when the mode mixity changes. The mode mixity at an integration point is determined by the load history at the point. In this study, a formulation of the cohesive constitutive law is proposed for a mixed mode loading condition with the ability to deal with the variation in mode mixity. The proposed law is constructed incrementally and takes into account the load history. The validation is performed by simulating delamination in carbon fiber/epoxy composites in the mixed-mode bending test that is commonly used to characterize the inter-laminar fracture toughness. Although the mode mixity is fixed in this test at the specimen level, it varies locally at the element level. Cohesive constitutive laws proposed in the literature predict macroscopic delamination behavior that is dependent on the strength of the interface, while, according to the analysis of linear elastic fracture mechanics, the dependence is expected to be only on the fracture toughness. Predictions with the current formulation, where the cohesive law is updated incrementally, show low sensitivity to the interface strength. The structural response simulated with it had a good agreement with the analytical solution of linear elastic fracture mechanics.

Objective To study the effect of augmented renal clearance (ARC) on vancomycin therapeutic drug monitoring in patients undergoing neurosurgery. Methods A retrospective observational analysis was conducted in a neurosurgery department from January 2019 to June 2019. Patients undergoing vancomycin therapeutic drug monitoring were assigned to the normal renal function or ARC group. The baseline characteristics, vancomycin therapeutic drug monitoring data, and prognosis were compared and analyzed. Results In total, 104 patients were enrolled, including 78 and 26 patients in the normal renal function and ARC groups, respectively. There were significant differences in age, weight, creatinine clearance, the vancomycin treatment duration, the total dose, the trough concentration, and the trough concentration achievement rate between the two groups. Prognosis did not differ between the two groups. The trough concentration achievement rate in the ARC group was only 19.23%. Conclusion For young, obese, or otherwise healthy patients undergoing neurosurgery, attention should be paid to the possibility of ARC and the need for individualized dose adjustment based on the results of therapeutic drug monitoring.

Citrus fruits: The proteins of elaioplasts A study of the proteins in bodies called elaioplasts in citrus fruit cells will help to clarify elaioplast formation and functions. Plant cells contain several types of membrane-bound bodies called plastids, with elaioplasts being an incompletely characterized type. They are known to store oils in the cells, especially molecules called terpenes that influence the fragrances and flavors of citrus fruits. Researchers in China, led by Yunliu Zeng at Huazhong Agricultural University, analyzed the protein molecules in elaioplasts of kumquat peel to investigate possible roles for elaioplasts other than oil storage. They identified more than 600 proteins and assigned likely functions to many. The results suggest the proteins are involved in chemical energy transactions and the manufacture of various categories of biomolecules. This will guide research to fully characterize the activities and significance of elaioplasts.

Memory-augmented recurrent neural networks (M-RNNs) have demonstrated empirically that they are very attractive for many applications, but a good theoretical understanding of their behaviors is unclear yet. In this paper, three analytical indicators named duration, addressability, and capacity of general forms of the additional memory in M-RNNs are formalized. The analysis results of the interactions among these indicators reveal that it is hard for an M-RNN to simultaneously provide good performance on more than two out of three of indicators. Meanwhile, the duration, addressability, and capacity are applied to analyze and compare two M-RNNs: long short term memory and neural turing machine for different cases. The comparison results show that none of the models has better performance on one indicator than the other model all the time. Moreover, it is found that separating memory system into sub-memories can bring the increasing duration and addressability and the decreasing capacity for the whole memory system.

The polymorphism of lipoprotein lipase (LPL) gene Ser447Ter (S447X) has long been linked to hypertension and blood pressure variation, but the established data remained controversial. To better elucidate this inconsistency, a meta-analysis was conducted. We comprehensively searched electronic databases, including Pubmed, EMBASE, China National Knowledge Infrastructure (CNKI), Web of Science, for all literatures with the last update on February 2016. The strength of association was calculated by using odds ratios (ORs) and weighted mean differences (WMDs) with corresponding 95% confidence intervals (CIs). Further stratified analyses, cumulative meta-analysis analysis, and sensitivity analyses were performed. A total of 14 studies (3592 cases and 4643 controls) for hypertension and 14 studies (n = 9254) for blood pressure were included. Overall, significant associations were revealed between S447X polymorphism and hypertension risk using allelic comparison (OR = 0.86, 95%CI 0.77 to 0.96), heterozygote comparison (OR = 0.85, 95%CI 0.75 to 0.96), and the dominant model (OR = 0.85, 95%CI 0.75 to 0.96), especially in Asians. Furthermore, in subgroup analyses restricted to the population-based controls studies, the high-quality studies, and the large sample size studies, these significant associations were still observed. As for blood pressure association, significant reductions of systolic blood pressure (WMD = −1.25 mmHg, 95%CI −2.25 to −0.25 mmHg) and diastolic blood pressure (WMD = −1.91 mmHg, 95%CI −3.25 to −0.56 mmHg) levels were found using dominant model. No publication bias was observed in any comparison model. Therefore, current meta-analysis suggested that the LPL S447X polymorphism is likely to be a protective factor in the development of hypertension.

Determination of ship maneuvering models is a tough task of ship maneuverability prediction. Among several prime approaches of estimating ship maneuvering models, system identification combined with the full-scale or free- running model test is preferred. In this contribution, real-time system identification programs using recursive identification method, such as the recursive least square method (RLS), are exerted for on-line identification of ship maneuvering models. However, this method seriously depends on the objects of study and initial values of identified parameters. To overcome this, an intelligent technology, i.e., support vector machines (SVM), is firstly used to estimate initial values of the identified parameters with finite samples. As real measured motion data of the Mariner class ship always involve noise from sensors and external disturbances, the zigzag simulation test data include a substantial quantity of Gaussian white noise. Wavelet method and empirical mode decomposition (EMD) are used to filter the data corrupted by noise, respectively. The choice of the sample number for SVM to decide initial values of identified parameters is extensively discussed and analyzed. With de-noised motion data as input-output training samples, parameters of ship maneuvering models are estimated using RLS and SVM-RLS, respectively. The comparison between identification results and true values of parameters demonstrates that both the identified ship maneuvering models from RLS and SVM-RLS have reasonable agreements with simulated motions of the ship, and the increment of the sample for SVM positively affects the identification results. Furthermore, SVM-RLS using data de-noised by EMD shows the highest accuracy and best convergence.

Methylketones are broadly distributed in nature and perform a variety of functions. Most microorganisms are thought to produce methylketone by abortive β-oxidation of fatty acid catalytic metabolism. However, two methylketone synthetase genes in wild tomatoes are reported to synthesize methylketone using intermediates of the fatty acids biosynthetic pathway. In our previous study on Trojan horse-like interactions between the bacterium Bacillus nematocida B16 and its host worm, the chemical 2-heptanone was found to be an important attractant for the hosts. So here we used this model to investigate the genes involved in synthesizing 2-heptanone in microorganisms. We identified a novel methylketone synthase gene yneP in B. nematocida B16 and found enhancement of de novo fatty acid synthesis during 2-heptanone production. Interestingly, a homolog of yneP’ existed in the non-pathogenic species Bacillus subtilis 168, a close relative of B. nematocida B16 that was unable to lure worms, but GC-MS assay showed no 2-heptanone production. However, overexpression of yneP’ from B. subtilis in both heterologous and homologous systems demonstrated that it was not a pseudogene. The transcriptional analysis between those two genes had few differences under the same conditions. It was further shown that the failure to detect 2-heptanone in B. subtilis 168 was at least partly due to its conversion into 6-methyl-2-heptanone by methylation. Our study revealed methylketone biosynthesis of Bacillus species, and provided a co-evolution paradigm of second metabolites during the interactions between pathogenic/non-pathogenic bacteria and host.

According to the updated Roussel Uclaf Causality Assessment Method (RUCAM), drug-induced liver injury (DILI) is currently defined based on thresholds of alanine aminotransferase (ALT) levels above 5 × the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) levels greater than 2 × the ULN. However, many parameters with different thresholds are also currently used in the clinic. We therefore performed a comparative analysis to evaluate which set of criteria was the most appropriate to detect DILI. We enrolled hospitalized patients who received fluoroquinolones to treat or prevent infections. Three liver test criteria were used to diagnose DILI in these patients. RUCAM criteria were defined as the gold standard, and the other two criteria were as follows: 1) ALT or aspartate aminotransferase (AST) levels greater than 5 × the ULN on two consecutive occasions and/or ALP levels greater than 2 × the ULN on two consecutive occasions [issued by DILI Network (DILIN)]; 2) ALT levels greater than 1 × the ULN on two consecutive occasions or ALT levels greater than 2 × the ULN [issued by the National Medical Products Administration (NMPA) of China]. We found that the RUCAM criteria resulted in 657 warnings, DILIN criteria resulted in 358, NMPA criteria resulted in 1,377, and the positive predictive value (PPV) were 9.74%, 10.89%, and 9.73% (P = 0.80), respectively. The levels of agreement of the DILIN and NMPA criteria with the RUCAM criteria were moderate, but the agreement between the DILIN criteria and NMPA criteria was poor. In conclusion, the NMPA criteria with relatively lax thresholds for the parameters require much more labor to determine the diagnosis, making them unsuitable for clinical practice. Conversely, the DILIN criteria employing stricter thresholds for the parameters were more effective but would miss some positive cases, and the cases it identified were usually quite serious, which is not conductive to early intervention. Therefore, we still recommend the use of the RUCAM criteria in clinical practice.

Background: To survey the prevalence of potential drug-drug interactions (DDIs) between anticancer drugs and non-anticancer drugs and evaluate the risk factors associated with these drug-drug interactions in China. Methods: All discharged patients in the Department of Oncology were collected from Jun to Dec in 2016 with the Hospital Information System of the Chinese people’s Liberation Army General Hospital. Drugs were screened for interactions by Micromedex solutions database. Descriptive statistics were generated and logistic regression was used to identify the associated factors. Results: Among 6578 eligible patients, 1979 potential drug interactions were found in 1830 patients (27.82%). The most common drug-drug interaction was cisplatin and furosemide. Erlotinib was most likely to interact with various non-anticancer drugs. Most interactions were classified as pharmacodynamics (71.60%), major severity (97.02%) and were supported by fair documentation evidence (86.21%). In multivariate analysis, increasing number of medications, lung cancer and patients with stage IV had a higher risk for potential drug-drug interactions. Conclusion: Potential drug-drug interactions between antineoplastic drugs and non-antineoplastic drugs occur frequently in cancer patients of Chinese hospitals. Doctors should fully consider potential risk associated with DDIs. Further research should be performed to evaluate real clinical significance of these drug-drug interactions.

With the increasing application of unmanned surface vehicle-unmanned aerial vehicles (USV-UAVs) in maritime supervision, research on their deployment and control is becoming vitally important. We investigate the application of USV-UAVs for synergistic cruising and evaluate the effectiveness of the proposed collaborative model. First, we build a collaborative model consisting of the cruise vehicles and communication, detection, and command-and-control networks for the USV-UAV. Second, based on an analysis of the problems faced by collaborative USV-UAV systems, we establish a model to evaluate the effectiveness of such synergistic cruises. Third, we propose a weighting method for each evaluation factor. Finally, a model consisting of one UAV and four USVs is employed to validate our synergistic cruise model.

Autonomy is the core capability of future systems, and architecture design is one of the critical issues in system development and implementation. To discuss the architecture of autonomous systems in the future, this paper reviews the developing progress of architectures from automation systems to autonomous systems. Firstly, the autonomy and autonomous systems in different fields are summarized. The article classifies and summarizes the architecture of typical automated systems and infer three suggestions for building an autonomous system architecture: extensibility, evolvability, and collaborability. Accordingly, this paper builds an autonomous waterborne transportation system, and the architecture is composed of the object layer, cyberspace layer, cognition layer, and application layer, the proposed suggestions made in the construction of the architecture are reflected in the inter-relationships at all layers. Through the cooperation of four layers, the autonomous waterborne transportation system can autonomously complete the system functions, such as system control and transportation service. In the end, the characteristics of autonomous systems are concluded, from which the future primary research directions and the challenges of autonomous systems are provided.

In this study, a method for dynamically establishing ship domain in inland waters is proposed to help make decisions about ship collision avoidance. The surrounding waters of the target ship are divided to grids and then calculating the grid densities of ships in each moment to determine the shape and size of ship domain of different types of ships. At last, based on the spatiotemporal statistical method, the characteristics of ship domains of different types of ship in different navigational environments were analyzed. The proposed method is applied to establish ship domains of different types of ship in Wuhan section of the Yangtze River in January, February, July, and August in 2014. The results show that the size of ship domain increases as the ship size increases in each month. The domain size is significantly influenced by the water level, and the ship domain size in dry seasons is larger than in the wet seasons of inland waters.

Background: Ischemic stroke (IS) is an extremely heterogeneous disease with variable pathogenesis. Due to the lack of early diagnostic marker, the mortality rate of IS remains high worldwide. The family of Homer plays an important role in the pathology of atherosclerotic plaque. In this study, we have investigated its expression pattern and clinical significance in IS. Methods: RT-qPCR was performed to detect the expression of Homer1, Homer2, and Homer3. Results: We found that the mRNA levels of Homer1 (pConclusion: Our data suggested that Homer1 and Homer2 might be considered as novel diagnostic biomarkers for LAA stroke.

Background: Hepatocellular carcinoma (HCC) is a malignant tumor worldwide. Due to the lack of early prediction marker, numerous patients were diagnosed in their late stage. The family of cavins plays important roles in caveolae formation and cellular processes. Cavin-2, one of the members of cavins, has been reported as a suppresser in cancers. In this study, we have investigated its expression pattern and clinical significance in HCC. Methods: RT‑qPCR was performed to detect the expression of cavin-2. Results: Cavin-2 was down-regulated in HCC and associated with tumor differentiation (r=-0.275, P=0.013) and tumor-node-metastasis (TNM) stage (r=-0.216, P=0.035). The Overall survival analysis showed that patients with lower cavin-2 expression had a relatively poor prognosis. Meanwhile, the multivariate analysis revealed that cavin-2 was an independent prognostic factor. The receiver operating characteristic curve analyses indicated that plasma cavin-2 presented a high accuracy (AUC=0.727, 0.865, 0.901) for diagnosing HCC cases from controls, hepatitis B and cirrhosis patients, respectively. Meanwhile, plasma cavin-2 showed a high sensitivity (88.4%, 89.9%) for detecting HCC with the serum α‑fetoprotein (AFP) levels below 200 ng/ml from those hepatitis B and cirrhosis cases. Conclusion: Our data suggested that cavin-2 might be considered as a potential prognostic and diagnostic indicator in HCC.

Purpose: This study explores how search motivation and context influence mobile Web search behaviors. Design/methodology/approach: We studied 30 experienced mobile Web users via questionnaires, semi-structured interviews, and an online diary tool that participants used to record their daily search activities. SQLite Developer was used to extract data from the users' phone logs for correlation analysis in Statistical Product and Service Solutions (SPSS). Findings: One quarter of mobile search sessions were driven by two or more search motivations. It was especially difficult to distinguish curiosity from time killing in particular user reporting. Multi-dimensional contexts and motivations influenced mobile search behaviors, and among the context dimensions, gender, place, activities they engaged in while searching, task importance, portal, and interpersonal relations (whether accompanied or alone when searching) correlated with each other. Research limitations: The sample was comprised entirely of college students, so our findings may not generalize to other populations. More participants and longer experimental duration will improve the accuracy and objectivity of the research. Practical implications: Motivation analysis and search context recognition can help mobile service providers design applications and services for particular mobile contexts and usages. Originality/value: Most current research focuses on specific contexts, such as studies on place, or other contextual influences on mobile search, and lacks a systematic analysis of mobile search context. Based on analysis of the impact of mobile search motivations and search context on search behaviors, we built a multi-dimensional model of mobile search behaviors.

In this paper, using cloud model and Delphi, we build a comprehensive evaluation cloud model to solve the problems of qualitative description and quantitative transformation in ship navigation adaptability comprehensive evaluation. In the model, the normal cloud generator is used to find optimal cloud models of reviews and evaluation factors. The weight of each evaluation factor is determined by cloud model and Delphi. The floating cloud algorithm is applied to aggregate the bottom level’s evaluation factors, and comprehensive cloud algorithm is used to aggregate the highest level’s evaluation factors to get comprehensive evaluation cloud model. Finally, evaluation result is got by matching comprehensive evaluation cloud model and optimal cloud model of reviews. As case study, the model is applied to the small LNG ship’s navigation adaptability in Southeast Asia. Compared with the fuzzy comprehensive evaluation method, the model proposed in this paper is more intuitive and reliable in comprehensive evaluation of the small LNG ship’s navigation adaptability.

Background: To evaluate off-label and off-NCCN guidelines uses of antineoplastic drugs in a major Chinese hospital.Methods: Totally 1122 patients were selected from July to December 2011. Then, the off-label and off-NCCN guidelines uses of antineoplastic drugs were analyzed.Results: In 798 of 1122 patients (71.12%), drugs were used for off-label. In 317 of 1122 patients (28.25%), the drugs were prescribed for off-label and off-NCCN guidelines. 2591 medical orders for 1122 patients, 1051/2591 (40.56%) medical orders were off-label; 445/2591(17.17%) medical orders were off-label and off-NCCN guidelines. In 445 off-label and off-NCCN medical orders, 399 (89.66%) were unapproved indications, 38 (8.54%) were unapproved drug concentration and 12 (2.70%) were unapproved route of administration. Percentage of off-label and off-NCCN guidelines drug uses in male was higher than that in female (21.92% vs. 11.39%, P

A Digital Image Correlation (DIC) based method is proposed to characterize Mode I fatigue delamination onset and propagation in laminated composites. With the help of DIC, the displacement field around a delamination crack is obtained and further processed to determine the position of the crack tip. With this method the delamination length can be measured automatically in each cycle with a precision on the order of few hundreds of micrometers. The fatigue delamination onset life is then determined by detecting the increase of the delamination length, and the fatigue delamination propagation rate is calculated. The proposed method produces more conservative fatigue life measurements in comparison with the compliance increase method in ASTM D6115.