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This study explored how secondary school EFL teachers engaged in professional learning opportunities when they participated in the development of ELT materials. While increasing research has examined language teaching materials and teacher learning, the two research fields have remained largely disconnected, hindering the potential of materials writing for professional learning. With eight teachers as focal participants, the data included in-depth interviews, written reflections, and official documents. Findings showed that the EFL teachers took advantage of materials writing for their professional learning in the areas of policy, theory, and practice. Their engagement with the national curriculum standards, language, and language learning theories, together with local classroom realities in relation to teaching materials, reciprocally interacted with their professional learning. Based on the findings, we recommend that professional development programs include materials writing by localizing the content, clarifying its objectives, teaming teachers with researchers, and creating feedback loops. [ABSTRACT FROM AUTHOR]

As a high-sensitivity and non-invasive technique, optical molecular tomography (OMT) can locate and visualize tissue quantitatively in three dimensions by collecting surface photons generated from luminescent biomarkers. It has great potential for tumor detection, surgery guidance, and pharmacokinetics research studies. However, due to the limited measurable surface photons and the highly scattered feature of photons, the reconstruction of OMT is highly ill-posed and ill-conditioned, which limits the performance in practice. To improve the accuracy of OMT, plenty of studies focus on precisely modeling photon propagation and accurately reconstructing light source. Since these methods are carried out based on different theories, we review famous solutions for the reconstruction in terms of the photon propagation models and inverse reconstruction algorithms to make an overall understanding for the methods of OMT reconstruction. Additionally, some prospects are listed to provide possible research orientation that may benefit future research. [ABSTRACT FROM AUTHOR]

Abnormal viscosity is closely related to the occurrence of many diseases, such as cancer. Therefore, real-time detection of changes in viscosity in living cells is of great importance. Fluorescent molecular rotors play a critical role in detecting changes in cellular viscosity. Developing red emission viscosity probes with large Stokes shifts and high sensitivity and specificity remains an urgent and important topic. Herein, a novel viscosity-sensitive fluorescent probe (TCF-VIS1) with a large stokes shift and red emission was prepared based on the 2-dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran (TCF) skeleton. Due to intramolecular rotation, the probe itself does not fluorescence at low viscosity. With the increase in viscosity, the rotation of TCF-VIS1 is limited, and its fluorescence is obviously enhanced. The probe has the advantages of simple preparation, large Stokes shift, good sensitivity and selectivity, and low cytotoxicity, which make it successfully used for viscosity detection in living cells. Moreover, TCF-VIS1 showed its potential for cancer diagnosis at the cell level and in tumor-bearing mice by detecting viscosity. Therefore, the probe is expected to enrich strategies for the detection of viscosity in biological systems and offer a potential tool for cancer diagnosis. [ABSTRACT FROM AUTHOR]

Dynamic fluorescence molecular tomography (DFMT), as a noninvasive optical imaging method, can quantify metabolic parameters of living animal organs and assist in the diagnosis of metabolic diseases. However, existing DFMT methods do not have a high capacity to reconstruct abnormal metabolic regions, and require additional prior information and complicated solution methods. This paper introduces a problem decomposition and prior refactor (PDPR) method. The PDPR decomposes the metabolic parameters into two kinds of problems depending on their temporal coupling, which are solved using regularization and parameter fitting. Moreover, PDPR introduces the idea of divide‐and‐conquer to refactor prior information to ensure discrimination between metabolic abnormal regions and normal tissues. Experimental results show that PDPR is capable of separating abnormal metabolic regions of the liver and has the potential to quantify metabolic parameters and diagnose liver metabolic diseases in small animals. [ABSTRACT FROM AUTHOR]

Lignin dissolution and the fluid behaviour of reaction systems play important roles in the conversion rate of lignin. This study investigated the solubility of enzymatic hydrolysis lignin (EHL) in 1-butyl-3-methylimidazole bisulphate ethanol solutions ([BMIM]HSO4/ethanol) and the dynamic shear rheological characterisation of EHL-[BMIM]HSO4/ethanol. Different with [BMIM]HSO4/water, [BMIM]HSO4/ethanol exhibited excellent abilities to dissolve EHL at [BMIM]HSO4% 20%–90%, with the maximum EHL solubility obtained at 40%–70%. The dynamic shear rheological characterisation strongly depended on temperatures, [BMIM]HSO4% and EHL%, exhibited as pseudoplastic fluid at higher [BMIM]HSO4% and EHL%, and Dilatant fluid at lower [BMIM]HSO4% and EHL%. Adjusting an appropriate [BMIM]HSO4% and EHL%, EHL-[BMIM]HSO4/ethanol was Newtonian fluid with the viscosity stable. EHL was regenerated from EHL-[BMIM]HSO4/ethanol without obvious changes in the chemical structure and thermal behaviour. This study provided ideas for the design of the [BMIM]HSO4/ethanol system and the optimisation of conversion processes for the economic utilisation of lignin. [ABSTRACT FROM AUTHOR]

Green navigation presents a challenge to sustainable mobility. Carbon emissions are a key indicator for evaluating the sustainability of a route. Some methods of green navigation consider the fastest and shortest route to be the least carbon-emitting option, solely from the driver's perspective. To address this issue, various studies have incorporated road factors into the sustainability evaluation model and designed static route planning algorithms to minimize carbon emissions. However, there has been no comprehensive analysis of carbon emissions from both the road and the driver perspectives, and the influence of a sustainability evaluation using dynamic traffic states has not been considered. In this paper, we propose a carbon emission evaluation model based on the life cycle assessment (LCA) and a dynamic route planning algorithm that focuses on near-real-time traffic states. First, we develop an evaluation model for carbon emissions from both the road and the driver perspectives using a carbon footprint measurement method. Next, we propose a route planning method with both a static calculation and near-real-time adjustment to minimize carbon emissions. Finally, we select three cases from South China with different characteristics to verify the effectiveness of our model and algorithm. This evaluation model calculates the carbon emissions caused by all parties involved, providing a comprehensive assessment of the total carbon emissions generated by traffic. This approach addresses the problem of traditional route planning, which often fails to account for the influences of variable traffic conditions on the greenest route. We verify the effectiveness of the greenest navigation algorithm and near-real-time green navigation and apply these two aspects to cases where the greenest route is compared with other common navigation results from different dimensions. We compare carbon emissions from vehicles and roads from electric vehicles and gasoline-powered vehicles. If an electric vehicle is equipped with a wind power generator, the proportion of the vehicle's carbon emissions will be very small. For other vehicle types, the carbon emissions will be more than 1000 times the road emissions. [ABSTRACT FROM AUTHOR]

The development of theranostic probes that integrate both diagnostic and therapeutic functions still remains an intractable challenge in precise cancer treatment. Herein, a novel bifunctional near-infrared (NIR) fluorescent probe (CEP1) for carboxylesterase (CE) imaging and photodynamic therapy (PDT) of hepatocellular carcinoma (HCC) has been firstly developed and successfully applied in vitro and in vivo. The probe was constructed by introducing carbamate as both the recognition unit and the fluorescence quenching unit into the fluorophore S-substituted Nile Blue (ENBS) via a self-eliminating spacer with substituted chloride. It can be activated by CE and hydrolyzed into fluorescent ENBS, which recover fluorescence at about 700 nm, and can generate superoxide radical anions under NIR irradiation. Additionally, the probe could effectively distinguish tumor cells from normal cells by CE imaging of live cells. Furthermore, it could achieve CE imaging in vivo and significantly inhibits tumor growth by imaging-guided PDT. Therefore, this study offers a promising and attractive platform for activatable imaging-guided PDT of HCC. [ABSTRACT FROM AUTHOR]

Background: Organophosphate (OP)-induced delayed neurological damage is attributed to permanent neuropathological lesions caused by irreversible OP-neurocyte interactions, without potent brain-targeted etiological antidotes to date. The development of alternative therapies to achieve intracerebral OP detoxification is urgently needed. Methods: We designed a brain-targeted nanoreactor by integrating enzyme immobilization and biomimetic membrane camouflaging protocols with careful characterization, and then examined its blood–brain barrier (BBB) permeability both in vitro and in vivo. Subsequently, the oxidative stress parameters, neuroinflammatory factors, apoptotic proteins and histopathological changes were measured and neurobehavioral tests were performed. Results: The well-characterized nanoreactors exerted favourable BBB penetration capability both in vitro and in vivo, significantly inhibiting OP-induced intracerebral damage. At the cellular and tissue levels, nanoreactors obviously blocked oxidative stress, cellular apoptosis, inflammatory reactions and brain histopathological damage. Furthermore, nanoreactors radically prevented the occurrence of OP-induced delayed cognitive deficits and psychiatric abnormality. Conclusion: The nanoreactors significantly prevented the development of OP-induced delayed neurological damage, suggesting a potential brain-targeted etiological strategy to attenuate OP-related delayed neurological and neurobehavioral disorders. [ABSTRACT FROM AUTHOR]

To alleviate the ill‐posed of the inverse problem in fluorescent molecular tomography (FMT), many regularization methods based on L2 or L1 norm have been proposed. Whereas, the quality of regularization parameters affects the performance of the reconstruction algorithm. Some classical parameter selection strategies usually need initialization of parameter range and high computing costs, which is not universal in the practical application of FMT. In this paper, an universally applicable adaptive parameter selection method based on maximizing the probability of data (MPD) strategy was proposed. This strategy used maximum a posteriori (MAP) estimation and maximum likelihood (ML) estimation to establish a regularization parameters model. The stable optimal regularization parameters can be determined by multiple iterative estimates. Numerical simulations and in vivo experiments show that MPD strategy can obtain stable regularization parameters for both regularization algorithms based on L2 or L1 norm and achieve good reconstruction performance. [ABSTRACT FROM AUTHOR]

With the enhanced interoperability of information among vehicles, the demand for collaborative sharing among vehicles increases. Based on blockchain, the classical consensus algorithms in collaborative IoV (Internet of Vehicle), such as PoW (Proof of Work), PoS (Proof of Stake), and DPoS (Delegated Proof of Stake), only consider the node features, which is hard to adapt to the immediacy and flexibility of vehicles. On the other hand, classical consensus algorithms often require mass computing, which undoubtedly increases the communication overhead, resulting in the inability to achieve collaborative IoV under asymmetric networks. Therefore, proposing a low failure rate consensus algorithm that takes into account running time and energy consumption becomes a major challenge in IoV applications. This paper proposes an AI-enabled consensus algorithm with vehicle features, combining vehicle-based metrics and neural networks. First, we introduce vehicle-based metrics such as vehicle online time, performance, and behavior. Then, we propose an integral model and a hierarchical classification method, which combine with a BP neural network to obtain the optimal solution for interconnection. Among them, we also use Informer to predict the future online duration of vehicles, which effectively solves the situation that the primary node vehicle drops off in collaborative IoV. Finally, the experimentations show that the vehicle-based metrics eliminate the problem of the primary node vehicle being offline, which realizes the collaborative IoV considering vehicle features. Meanwhile, it reduces the vehicle network system delay and energy consumption. [ABSTRACT FROM AUTHOR]

Despite immune checkpoint blockade (ICB) therapy has transformed cancer treatment, only 20.2% of these patients achieved a response. Understanding resistance mechanisms to ICB is important for the treatment of a wider population. In this work, we occasionally found that the silica nanoparticles (SiO2 NPs) accumulated in the liver can induce resistance to following ICB therapy to a subcutaneous tumor in mice. By analysis of T cells frequency, we uncovered that SiO2 NPs in the liver resulted in a siphoning of T cells from circulation to the liver by produced chemokines. In addition, liver immunosuppressive cells further inhibit the function and induce apoptosis of recruited T cells, leading to a systemic loss and reduced tumor infiltration of T cells, which contributes to poor responses to ICB therapy. However, such effect is not observed in poly(lactic-co-glycolic acid) (PLGA) NPs treated mice under the same conditions, likely due to their much lower immunogenicity in perturbing the liver immune microenvironment, indicating that cancer is not a local disease but an ecosystem that is linked to the distal environment. We further provide a new mechanism insight into ICB resistance induced by liver accumulation of nanoparticles. [ABSTRACT FROM AUTHOR]

The acidic tumor microenvironment (TME) is unfriendly to the activity and function of immune cells in the TME. Here, we report inorganic nanozymes (i.e., SnSe NSs) that mimic the catalytic activity of lactate dehydrogenase to degrade lactate to pyruvate, contributing to the metabolic treatment of tumors. As found in this study, SnSe NSs successfully decreased lactate levels in cells and tumors, as well as reduced tumor acidity. This is associated with activation of the immune response of T cells, thus alleviating the immunosuppressive environment of the TME. More importantly, the nanozyme successfully inhibited tumor growth in mutilate mouse tumor models. Thus, SnSe NSs show a promising result in lactate depletion and tumor suppression, which exemplifies its potential strategy in targeting lactate for metabolic therapy. [ABSTRACT FROM AUTHOR]

Owing to the immune microenvironment of bones and low selectivity of the drug, patients with bone metastases often respond poorly to immunotherapy. In this study, programmed cell death protein 1 (PD1)‐expressing hematopoietic stem cells (HSCs) are genetically engineered for bone‐targeted delivery of the transforming growth factor beta (TGF‐β) small‐molecule inhibitor SB‐505124 (SB@HSCs‐PD‐1). Intriguingly, compared to anti‐PD‐L1 monoclonal antibodies, as "living drugs", HSCs‐PD‐1 not only show great targeting ability to the bone marrow, but are also able to reduplicate themselves within the bone marrow niche and continuously express PD‐1 molecules. The SB released from HSCs‐PD‐1 competitively bound to TGF‐β receptors on CD4+ T cells and facilitate CD4+ T cell differentiation to helper T (TH)1 and TH2 cells, thereby reprogramming the local immunosuppressive milieu of the bone marrow. Additionally, HSCs‐PD‐1 can block programmed death‐ligand 1 on tumor and myeloid cells, resulting in reinvigorated anti‐tumor immunity of T cells. In conclusion, in the present study, an alternative cell engineering strategy is delineated for immune checkpoint blockade therapy, to target bone metastasis using HSCs as a platform, which shows great promise in the treatment of bone metastases. [ABSTRACT FROM AUTHOR]

The heat shock proteins (HSPs) are ubiquitous and conserved protein families in both prokaryotic and eukaryotic organisms, and they maintain cellular proteostasis and protect cells from stresses. HSP protein families are classified based on their molecular weights, mainly including large HSPs, HSP90, HSP70, HSP60, HSP40, and small HSPs. They function as molecular chaperons in cells and work as an integrated network, participating in the folding of newly synthesized polypeptides, refolding metastable proteins, protein complex assembly, dissociating protein aggregate dissociation, and the degradation of misfolded proteins. In addition to their chaperone functions, they also play important roles in cell signaling transduction, cell cycle, and apoptosis regulation. Therefore, malfunction of HSPs is related with many diseases, including cancers, neurodegeneration, and other diseases. In this review, we describe the current understandings about the molecular mechanisms of the major HSP families including HSP90/HSP70/HSP60/HSP110 and small HSPs, how the HSPs keep the protein proteostasis and response to stresses, and we also discuss their roles in diseases and the recent exploration of HSP related therapy and diagnosis to modulate diseases. These research advances offer new prospects of HSPs as potential targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Drug nanocrystals, one of most common drug delivery systems, enable the delivery of poorly water-soluble drugs with high drug loading and enhanced dissolution. The rapid clearance and uncontrolled drug release of drug nanocrystals limit their delivery efficiency and clinical application. Herein, an amphiphilic co-polymer, poly oligo(ethylene glycol) methacrylate-b-poly(styrene–co-4-formylphenyl methacrylate) (POEGMA-b-P (St-co-FPMA), PPP), characterized by a hydrophilic part with bottlebrush-like oligo(ethylene glycol) methacrylate (OEGMA) side chains, was synthesized as stabilizers to fabricate a high-drug-loading nanocrystal micelle (053-PPP NC micelle) using the chronic myeloid leukemia (CML) drug candidate N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053 or 053) as a model drug. The 053-PPP NC micelle was characterized and subjected to in vitro and in vivo studies. It featured a worm-like shape of small size, high drug loading (~50%), high colloidal stability, and controlled release in vitro. The presence of the 053-PPP NC micelle resulted in a long-circulation property and a much higher AUC. The 053-PPP NC micelle induced higher accumulation in the tumor tissues under multiple continuous administration. For in vivo efficacy, the 053-PPP NC micelle with a longer dosing interval (96 h), beneficial for improving patient adherence, demonstrated superiority to the 053-F127 NC. The proposed stabilizer PPP and the 053-PPP NC micelle with high drug loading enables drug delivery with long circulation and controlled release of drugs. It is also promising for the development of more efficient nanocrystal-based intravenous injection formulations for poorly water-soluble drugs. It might also offer new possibilities for potential clinical application of the CML candidate drug 053. [ABSTRACT FROM AUTHOR]

Vibrio vulnificus (V. vulnificus) infection-associated multiple antibiotic resistance has raised serious public health concerns. Recently, nanosponges (NSs) have been expected to provide innovative platforms for addressing antibacterial and drug-resistant challenges by targeting various pore-forming toxins (PFTs). In the present study, we constructed NSs to explore the effects and possible mechanism of recombinant V. vulnificus hemolysin (rVvhA)-induced injuries. In vitro, NSs significantly reversed rVvhA-induced apoptosis and necrosis, and improved toxin-induced intracellular reactive oxygen species (ROS) production, adenosine triphosphate (ATP) depletion, and apoptosis signaling pathway disruption. To explore the clinical translation potential of NSs, we established VvhA-induced septicemia and wound infection mouse models, respectively, and further found NSs could notably attenuate rVvhA-induced acute toxicity and septicemia-associated inflammation, as well as local tissue damage. In a conclusion, NSs showed excellent protective effects against rVvhA-induced toxicity, thus providing useful insights into addressing the rising threats of severe V. vulnificus infections. [ABSTRACT FROM AUTHOR]

Existing target tracking algorithms are mainly divided into two categories: (1) deep learning-based approaches that have high accuracy and low speed; (2) correlation filtering-based approaches that have high speed and low accuracy. In order to balance the real-time performance and accuracy, this paper improves the KCF algorithm. The main innovation lies in the development of an adaptive dual feature model: the main feature model uses shallow texture features (Histogram of Oriented Gradients, HOG), and the auxiliary feature model uses features from convolutional neural networks (CNNs) that contain deep semantic information. These work together in an optimal manner to produce a more stable correlation filter. In order to improve the speed of the algorithm, we use principal component analysis to reduce the dimensionality of the high-dimensional CNN features. In addition, this paper also improves the accuracy of the tracking algorithm by means of scale optimization and optimization of the solution method. Our algorithm is compared with current advanced tracking algorithms with real-time speed, such as SiamFC, MEEM, SAMF, DSST, KCF, Struck, and TLD. The OPE result using the public data set OTB-2013 shows that the algorithm in this paper ranks first in the distance precision rate. Compared with the KCF algorithm, the distance precision rate and overlap success rate are improved by 25.9% and 23.2%, respectively, and the average speed of the proposed algorithm can reach 38 FPS. [ABSTRACT FROM AUTHOR]

A time-sensitive network (TSN) extends the conventional Ethernet to support time-sensitive data flow. Thus, it enables simultaneous transmission of high reliability (HR) flow, medium reliability (MR) flow, and low reliability (LR) flow on the same network, thereby improving the reliability of data transmission. A TSN is a symmetric network that connects sensors and other facilities. As a backbone network, it can efficiently connect the underlying sensors and other levels of facilities, as well as ensure the quality of service of the network. For modern supervisory control and data acquisition (SCADA) systems, several types of sensors are widely used. The acquisition cycle of sensors for different purposes varies significantly from milliseconds to seconds. Moreover, these data also have different real-time requirements. Based on satisfiability modulo theories (SMT), this study proposes a TSN routing and scheduling method by adding related scheduling constraints. Compared with other methods, the proposed method can realize the routing and scheduling of hybrid flow in a hyper period and consider MR flow and LR flow, which improves the feasibility and certainty of data flow interaction between substations. [ABSTRACT FROM AUTHOR]

Laboratory medicine plays an important role in clinical diagnosis. However, no laboratory‐based artificial intelligence (AI) diagnostic system has been applied in current clinical practice due to the lack of robustness and interpretability. Although many attempts have been made, it is still difficult for doctors to adopt the existing machine learning (ML) patterns in interpreting laboratory (lab) big data. Here, a knowledge‐and‐data‐driven laboratory diagnostic system is developed, termed AI‐based Lab tEst tO diagNosis (AI LEON), by integrating an innovative knowledge graph analysis framework and "mixed XGboost and Genetic Algorithm (MiXG)" technique to simulate the doctor's laboratory‐based diagnosis. To establish AI LEON, we included 89 116 949 laboratory data and 10 423 581 diagnosis data points from 730 113 participants. Among them, 686 626 participants were recruited for training and validating purposes with the remaining for testing purposes. AI LEON automatically identified and analyzed 2071 lab indexes, resulting in multiple disease recommendations that involved 441 common diseases in ten organ systems. AI LEON exhibited outstanding transparency and interpretability in three universal clinical application scenarios and outperformed human physicians in interpreting lab reports. AI LEON is an advanced intelligent system that enables a comprehensive interpretation of lab big data, which substantially improves the clinical diagnosis. [ABSTRACT FROM AUTHOR]

Increasing investigations have focused on long non-coding RNAs (lncRNAs) in various human diseases, including acute myocardial infarction (AMI). Although lncRNA HOTTIP has been identified to play an important role in coronary artery diseases, its role and specific mechanism in AMI remain unclear. To investigate the potential role of HOTTIP in MI, HOTTIP expression in hypoxia-treated cardiomyocytes and myocardial tissues of MI mice was evaluated. The potential targets of HOTTIP and miR-92a-2 were predicted using Starbase and Targetscan. To further determine the cardio-protective effects of HOTTIP in vivo, si-HOTTIP and miR-92a-2 mimics were individually or co-injected into mice through intramyocardial injection. Moreover, their roles were further confirmed in rescue experiments. HOTTIP was significantly upregulated in ischemic myocardium of MI mice and hypoxia-induced cardiomyocytes. Moreover, HOTTIP knockdown markedly promoted cardiomyocyte growth and inhibited cardiomyocyte apoptosis in vitro. Luciferase reporter assay showed that HOTTIP could directly sponge miR-92a-2 to negatively regulate miR-92a-2 expression. In addition, c-Met was identified as a direct target of miR-92a-2, and their correlation was confirmed by luciferase reporter assay. MiR-92a-2 overexpression significantly enhanced the protective effect of HOTTIP knockdown against AMI through partially inhibiting c-Met expression. Our results demonstrated that HOTTIP downregulation attenuated AMI progression via the targeting miR-92a-2/c-Met axis and suggested that HOTTIP might be a potential therapeutic target for AMI. [ABSTRACT FROM AUTHOR]

3-O-β-D-galactosylated resveratrol (Gal-Res) was synthesized from resveratrol (Res) and 3-O-β-D-galactose (Gal) in our previous study. In order to improve the pH sensitivity and bioavailability of Gal-Res, Gal-Res nanoparticles (Gal-Res NPs) were prepared using polydopamine (PDA) as a drug carrier. The drug loading (DL %) and entrapment efficiency (EE %) of Gal-Res NPs were 46.80% and 88.06%. The average particle size, polydispersity index (PDI), and Zeta potential of Gal-Res NPs were 179.38 ± 2.83 nm, 0.129 ± 0.013, and − 28.05 ± 0.36 mV, respectively. The transmission electron microscope (TEM) showed that Gal-Res NPs had uniform spherical morphology. Compared with the fast release of raw Gal-Res, the in vitro release of Gal-Res NPs was slow and pH-sensitive. The results of the blood vessel irritation and hemolysis test demonstrated that Gal-Res NPs had good hemocompatibility. The pharmacokinetics study in rats showed that area under the curve of plasma drug concentration time (AUC0→600) and half-life (t1/2) of Gal-Res NPs were enhanced 1.82-fold and 2.19-fold higher than those of raw Gal-Res. The in vivo biodistribution results showed that Gal-Res NPs were more distributed in liver tissue than Gal-Res. Gal-Res NPs with high bioavailability and liver accumulation were hopeful drug delivery systems (DDS) to treat liver diseases. [ABSTRACT FROM AUTHOR]

Early diagnosis and clear differentiation of pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) is clinically challenging. A machine learning model is developed for the diagnosis of PDAC. The model is induced using a dataset of 13 987 participants, of which 12 402 are used for training the model and the remaining 1585 for testing purposes. One thousand sixty‐six laboratory variables are reduced to 18 measures using standard filtering and feature importance methods. Then, five machine learning classifiers are evaluated for the study. Hyperparameter optimization for each classifier is carried out, and the optimal algorithm is established using a tenfold cross validation on the training data. Finally, gradient boosting decision tree‐based ternary classifier composed of 18 routine laboratory variables (GBDT‐TC18) is established. In the test cohort, GBDT‐TC18 differentiates PDAC from CP and healthy control (HC) with an accuracy better than carbohydrate antigen 19‐9 (CA19‐9)‐based diagnosis. It also maintains a high diagnostic accuracy for stages I, IIA, and IIB PDAC, small‐sized PDAC, body and tail adenocarcinoma, CA19‐9‐negative PDAC, and nonjaundice PDAC. What's more, GBDT‐TC18 shows a higher accuracy than CA19‐9 in distinguishing PDAC from CP. GBDT‐TC18 can be used to augment the capability of doctors for early and differential diagnosis of PDAC. [ABSTRACT FROM AUTHOR]

Summary: Acute myeloid leukemia (AML) is reported to be vulnerable to transcription disruption due to transcriptional addiction. Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, has attracted extensive attention as a drug target. Although several inhibitors, such as alvocidib and dinaciclib, have shown potent therapeutic effects in clinical trials on AML, the lack of high selectivity for CDK9 and other CDKs has limited their optimal clinical efficacy. Therefore, developing highly selective CDK9 inhibitors is still imperative for the efficacy and safety profile in treating AML. Here, we report a novel highly selective CDK9 inhibitor, JSH-009, which exhibited high potency against CDK9 and displayed great selectivity over 468 kinases/mutants. It also demonstrates impressive in vitro and in vivo antileukemic efficacy in preclinical models of AML, which makes JSH-009 a useful pharmacological tool for elucidating CDK9-mediated transcription and a novel therapeutic candidate for AML. [ABSTRACT FROM AUTHOR]

Polyploidy can cause variation in plant functional traits and thereby generate individuals that can adapt to fluctuating environments and exploit new environments. However, few empirical studies have tested for an association between ploidy level and climatic tolerance of invasive cytotypes relative to conspecific native‐range cytotypes. Here, we used an invasive plant Solidago canadensis to test whether invasive populations had a higher proportion of polyploids, greater height and stem‐base diameter, and occupied a wider range of climatic conditions than conspecific native‐range populations. We also tested whether the invasive populations had overcome genetic founder effects. We sampled a total of 80 populations in parts of the invaded range in China and native range in North America for in situ measurements of plant height and stem‐base diameter in the field and for population genetic and cytotype analyses. To examine climatic correlates, we augmented our field‐sampled data with occurrence records obtained from Global Biodiversity Information Facility. All, except one, of the populations that we sampled in China occurred in a humid subtropical climate. In contrast, the North American populations occurred in humid continental, humid subtropical, and semi‐arid climatic zones. All populations of S. canadensis in China were purely hexaploid, while the North American populations were diploid, tetraploid, and hexaploid. The invasive hexaploids were significantly taller and had a larger stem‐base diameter than native hexaploids. Native hexaploids were significantly taller and had larger stem‐base diameter than native diploids. Climatic correlate assessment found that invasive and native populations occupied different climatic envelopes, with invasive populations occurring in warmer and less seasonal climates than native populations. However, there was no significant correlation between ploidy level and climatic envelope of S. canadensis. Molecular phylogeography data suggest reduced genetic founder effects in the invaded range. Overall, these results suggest that polyploidy does not influence S. canadensis climatic tolerance. [ABSTRACT FROM AUTHOR]

Objectives: Zein nanoparticles (Zein NPs) were used as a hydroxyapatite (HA) biomineralization template to generate HA/Zein NPs. Doxorubicin hydrochloride (DOX) was loaded on HA/Zein NPs (HA/Zein‐DOX NPs) to improve its pH‐sensitive release, bioavailability and decrease cardiotoxicity. Methods: HA/Zein‐DOX NPs were prepared by phase separation and biomimetic mineralization method. Particle size, polydispersity index (PDI), Zeta potential, transmission electron microscope, X‐ray diffraction and Fourier‐transform infrared spectroscopy of HA/Zein‐DOX NPs were characterized. The nanoparticles were then evaluated in vitro and in vivo. Key findings: The small PDI and high Zeta potential demonstrated that HA/Zein‐DOX NPs were a stable and homogeneous dispersed system and that HA was mineralized on Zein‐DOX NPs. HA/Zein‐DOX NPs showed pH‐sensitive release. Compared with free DOX, HA/Zein‐DOX NPs increased cellular uptake which caused 7 times higher in‐vitro cytotoxicity in 4T1 cells. Pharmacokinetic experiments indicated the t1/2β and AUC0–t of HA/Zein‐DOX NPs were 2.73‐ and 3.12‐fold higher than those of DOX solution, respectively. Tissue distribution exhibited HA/Zein‐DOX NPs reduced heart toxicity with lower heart targeting efficiency (18.58%) than that of DOX solution (37.62%). Conclusion: In this study, HA/Zein‐DOX NPs represented an antitumour drug delivery system for DOX in clinical tumour therapy with improved bioavailability and decreased cardiotoxicity. [ABSTRACT FROM AUTHOR]

Cell membranes have been continuously imitated and used for the modification of nanoparticles (NPs) to improve NP biological properties. Cell membrane-coated NPs, where core NPs are wrapped with plasma membrane vesicles, show high biocompatibility, targeting specificity and low side effects. Compared with conventional strategies, this novel approach directly leverages intact and natural functions of cell membranes, instead of replicating these features via synthetic techniques. This top-down technique bestows NPs with enhanced biointerfacing capabilities with potential in the diagnosis and treatment of cancer, infection and other diseases. Herein, we report on the advances in cell membrane-coated NPs, including the preparation process, source cell membranes for wrapping and potential applications of these cell membrane-coated NPs. [ABSTRACT FROM AUTHOR]

Objective: Tanshinone IIA (TSN) and Tetramethylpyrazine (TMP) were combined in a composite, oil-in-water nanoemulsions (TSN/TMP O/W NEs) was prepared to prolong in vitro and vivo circulation time, and enhance the bioavailability of TSN. Material and methods: Physicochemical characterization of TSN/TMP O/W NEs was characterized systematically. The in vitro dissolution and in vivo pharmacokinetic experiments of TSN/TMP O/W NEs were also evaluated. Result: A formulation was optimized, yielding a 32.5 nm average particle size, an encapsulation efficiency of over 95 %, and were spherical in shape as shown by TEM. TSN/TMP O/W NEs were shown to extend the release and availability in vitro compared to raw compounds. In pharmacokinetic study, the AUC0→∞ and t1/2 of the TSN/TMP O/W NEs were 481.50 mg/L*min and 346.39 min higher than TSN solution, respectively. Brain tissue concentration of TSN was enhanced with TSN/TMP O/W NEs over raw TSN and even TSN O/W NEs. Conclusions: Therefore, nanoemulsions are an effective carrier to increase encapsulation efficiency of drugs, improve bioavailability and brain penetration for TSN – which is further enhanced by pairing with the co-delivery of TMP, providing a promising drug delivery. [ABSTRACT FROM AUTHOR]

Objectives: Gambogenic acid (GNA), one of the main active ingredients isolated from Garcinia cambogia, has shown diverse antitumour activities. However, short biological half‐life and low oral bioavailability severely limit its clinical application. Here, we developed GNA‐loaded zein nanoparticles (GNA‐ZN‐NPs) based on phospholipid complex and zein nanoparticles to prolong the circulation time and enhance oral bioavailability of GNA. Methods: The physicochemical properties of GNA‐ZN‐NP were characterized in details. The in vitro release profile, in vivo pharmacokinetic experiments and tissue distribution of GNA‐ZN‐NPs were also evaluated. Key findings: The particle size, PDI and encapsulation efficiency of GNA‐ZN‐NPs were 102.90 nm, 0.027 and 76.35 ± 0.64%, respectively. The results of SEM, FTIR, DSC and XRD demonstrated that GNA‐ZN‐NPs were prepared successfully. The in vitro dissolution of GNA‐ZN‐NPs exhibited controlled release compared with raw GNA solution. The pharmacokinetic study showed that the AUC of GNA‐ZN‐NPs was significantly increased, and the t1/2 and MRT values of GNA‐ZN‐NPs were 3.21‐fold and 2.19‐fold higher than that of GNA solution. Tissue distribution results illustrated that GNA‐ZN‐NPs showed hepatic‐targeting properties. Conclusion: GNA‐ZN‐NPs significantly enhanced the oral bioavailability and prolonged half‐life of GNA, providing a promising oral drug delivery system to improve in vivo pharmacokinetic behaviour of GNA. [ABSTRACT FROM AUTHOR]

Advances in the development of therapeutic extracellular vesicles (EVs) for cancer immunotherapy have allowed them to emerge as an alternative to cell therapy. In this proof-of-concept work, we develop bispecific EVs (BsEVs) by genetically engineering EV-producing dendritic cells (DCs) with aCD19 scFv and PD1 for targeting tumor antigens and blocking immune checkpoint proteins simultaneously. We find that these bispecific EVs (EVs-PD1-aCD19) have an impressive ability to accumulate in huCD19-expressing solid tumors following intravenous injection. In addition, EVs-PD1-aCD19 can remarkably reverse the immune landscape of the solid tumor by blocking PD-L1. Furthermore, EVs-PD1-aCD19 can also target tumor-derived EVs in circulation, which prevents the formation of a premetastatic niche in other tissues. Our technology is a demonstration of bispecific EV-based cancer immunotherapy, which may inspire treatments against various types of tumors with different surface antigens and even a patient-tailored therapy. [Display omitted] • Bispecific EVs expressing aCD19 and PD1 are developed by genetic engineering • Bispecific EVs target tumor antigen huCD19 and bind PD-L1 within solid tumors • Bispecific EVs also target tumor-derived EVs to prevent the formation of premetastatic niche Xu et al. develop therapeutic dendritic cell-derived bispecific EVs with aCD19 scFv and PD1 expression for targeting tumor antigens and binding immune checkpoint proteins simultaneously. The bispecific EVs accumulate in solid tumor and rebuild the immunosuppressive microenvironment, showing significant primary tumor regression and metastasis inhibition in a mouse model. [ABSTRACT FROM AUTHOR]

Objective: To improve the water solubility and enhance the oral bioavailability of gambogenic acid (GNA). Methods: GNA-phospholipid complex (GNA-PLC) micelles were successfully prepared by anti-solvent method. Results: The encapsulation efficiency of GNA-PLC micelles can reach 99.33 % (w/w). The average particle size of the GNA-PLC micelles was 291.23 nm which was approximate agreed with the transmission electron microscopy (TEM). In vitro release profile showed the GNA-PLC and GNA-PLC micelles have significant sustained-release of GNA compared with crude GNA. Pharmacokinetic parameters indicated that the area under concentration–time curve (AUC0→t) of GNA in cases of GNA-PLC and GNA-PLC micelles are 2.04- and 3.92-fold higher than crude GNA, respectively. Conclusions: The better water solubility and higher bioavailability of GNA in GNA-PLC micelles with significant sustained-release of GNA endow the nanoparticle with great potential in GNA delivery system. [ABSTRACT FROM AUTHOR]

Objectives: Resveratrol (Res), a naturally occurring polyphenol, has shown pharmacological activities in treatment of liver diseases. However, the application of Res was limited by its poor bioavailability and liver targeting. Herein, 3‐O‐β‐D‐Galactosylated Resveratrol (Gal‐Res) was synthesized by structural modification of Res to enhance bioavailability and liver targeting. Methods: The Gal‐Res was characterized by IR, 1H‐NMR spectra and MS. The in vitro antitumour experiments, in vivo pharmacokinetics and biodistribution studies were evaluated. Results: Gal‐Res was successfully synthesized in our study. Compared to Res, Gal‐Res resulted in enhanced cytotoxicity in HepG2 cells. After intravenous injection of normal SD rats, Gal‐Res significantly improved the bioavailability of Res and the Cmax and AUC0–t of Gal‐Res were 3.186 and 3.929 time than that of Res. In addition, in the study of liver targeting, the relative uptake rate (Re) of Gal‐Res in the liver (2.006) is the largest. The drug targeting efficiency (Te; 38.924%) of Gal‐Res was greater than that of Res. These showed that Gal‐Res could significantly improve the distribution ability of Res in liver. Conclusions: On the whole, Gal‐Res increased cellular uptake to HepG2 cells, bioavailability and liver targeting, providing its future clinical application in the treatment of liver diseases. [ABSTRACT FROM AUTHOR]

BCR fused ABL kinase is the critical driving oncogene for chronic myeloid leukemia (CML) and has been extensively studied as the drug discovery target in the past decade. The successful introduction of tyrosine kinase inhibitors (TKI) such as Imatinib, Dasatinib and Bosutinib has greatly improved the CML patient survival rate. However, upon the chronic treatment, a variety of TKI resistant mutants, such as the V299L mutant which has been found in more and more patients with the high-throughput sequencing technology, are observed, although the incidence is still considered rare compared to the more prevalent gatekeeper T315I mutant. However, with the progress of the precision medicine concept, the rare mutation (or the orphan drug target) has attracted more and more attention. Here we report a novel type II BCR-ABL kinase inhibitor, CHMFL-ABL-039, which not only displayed great potency (IC50: 7.9 nM) and selectivity (S score (1) = 0.02) against native ABL kinase among other kinases in the kinome, but also exhibited great potency (IC50: 27.9 nM) and selectivity against Imatinib-resistant V299L mutant among other frequently observed ABL kinase mutants. CHMFL-ABL-039 has demonstrated greater efficacies than Imatinib regarding to the anti-proliferation, inhibition of the signaling pathway, arrest of cell cycle progression, induction of apoptosis in vitro and suppression of the tumor progression in vivo in the native and V299L mutated BCR-ABL kinase-driven cells/xenograft models. It would be a useful pharmacological tool to study the TKI resistant ABL V299L mutant-mediated pathology and provide a potential precise treatment approach for this orphan CML subtype in the precision medicine era. [ABSTRACT FROM AUTHOR]

This article reports on a large-scale survey study investigating EFL learners' beliefs about oral corrective feedback (CF). A 44-item questionnaire tapping into learners' beliefs about corrective feedback was administered to 2670 Chinese EFL learners. These learners were from 15 Chinese universities in 14 provinces and municipalities across the country, which were stratified in accordance with per capita GDP values. An exploratory factor analysis generated seven factors: general attitude toward CF, CF timing, output-prompting CF, uptake, input-providing CF, peer CF, and gravity of errors. The results indicate that participants had an overall positive attitude toward CF, and they showed more preferences for immediate CF over delayed CF, and output-prompting CF over input-providing CF. Additionally, learners were slightly positive about the efficacy of uptake and peer correction. Findings also suggest some consistency between the Chinese learners' CF beliefs and empirical SLA research about the effectiveness of error correction, as well as the variance of CF-related beliefs across educational contexts. [ABSTRACT FROM AUTHOR]

As developing science and technology, traditional two-dimensional computer vision cannot meet the people's needs for the three-dimensional recognition, and the depth information of objects are required by more and more applications. Recently, structured light has become one of the core techniques of depth acquisition. The main idea of the approach is first projecting pre-designed pattern onto objects, then capturing an image and processing further. In a structured light system, the phase-shifting algorithm, which is a depth acquiring algorithm for sinusoidal pattern, is discussed in this paper, and is argued that its performance weakness for applying in the real time environments. Then we propose the performance optimization on its phase wrapping step and phase unwrapping step, respectively. Finally, we compare acquiring results and advantages as well as disadvantages of them by experiments results. Experiments show that the optimized phase-shifting algorithm is 4.6× faster than the original one with the ignorable errors. [ABSTRACT FROM AUTHOR]

Traditional saliency detection methods are designed only for a single salient object and cannot detect multiple salient objects in the image. This paper proposes a novel method for detecting multiple salient objects in the image, which is based on both objectness estimation method and superpixel segmentation method. The present study shows that the proposed method can correctly detect the salient regions for multiple objects and outperforms the other three state-of-the-art saliency detection methods. [ABSTRACT FROM AUTHOR]

Wound healing is a complex biological process, and current research finds that jellyfish have a great capacity for promoting growth and healing. However, the underlying mechanisms remain unclear. Thus, this study was conducted to investigate the molecular mechanisms and effects of a tentacle extract (TE) from the jellyfish Cyanea capillata (C. capillata) on cell proliferation and migration in human umbilical vein endothelial cells (HUVECs). First, our results showed that TE at the concentration of 1 μg/ml could promote cell proliferation over various durations, induce a transition of the cells from the G1-phase to the S/G2-phase of the cell cycle, and increase the expression of cell cycle proteins (CyclinB1 and CyclinD1). Second, we found that TE could activate the PI3K/Akt, ERK1/2 and JNK MAPK signaling pathways but not the NF-κB signaling pathway or the apoptosis signaling cascade. Finally, we demonstrated that the TE-induced expression of cell cycle proteins was decreased by ERK1/2 inhibitor PD98059 but not by PI3K inhibitor LY294002 or JNK inhibitor SP600125. Similarly, the TE-enhanced migration ability of HUVECs was also markedly attenuated by PD98059. Taken together, our findings indicate that TE-induced proliferation and migration in HUVECs mainly occurred through the ERK1/2 MAPK signaling pathway. These results are instructively important for further research on the isolation and purification of growth-promoting factors from C. capillata and are hopeful as a means to improve human wound repair in unfavorable conditions. [ABSTRACT FROM AUTHOR]

Nanoplastics (NPs) as contaminants in food and water have drawn increasing public attention. However, little is known about how NPs shape the gut immune landscape after injection. In this study, we fabricate NPs (∼500 nm) and microplastics (MPs) (∼2 μm) and evaluate their in vivo effects by feeding them to mice. The results suggest that NPs show a better ability to induce gut macrophage activation than MPs. In addition, NPs trigger gut interleukin-1 (IL-1)-producing macrophage reprogramming via inducing lysosomal damage. More importantly, IL-1 signaling from the intestine can affect brain immunity, leading to microglial activation and Th17 differentiation, all of which correlates with a decline in cognitive and short-term memory in NP-fed mice. Thus, this study provides insight into the mechanism of action of the gut-brain axis, delineates the way NPs reduce brain function, and highlights the importance of fixing the plastic pollution problem worldwide. [Display omitted] • Gut immune response is inversely correlated with the size of ingested nanoplastics • Nanoplastics trigger intestinal IL-1-producing macrophages by inducing lysosomal damage • IL-1 released from the intestine affects brain immunity • Halting nanoplastics feeding or blocking IL-1 signaling alleviates behavioral disorder Yang et al. report that nanoplastics induce a reduction in cognitive and memory abilities after oral administration in mice, provide insight into the mechanism of the gut-brain axis in this context, and highlight the importance of resolving the plastic pollution problem worldwide. [ABSTRACT FROM AUTHOR]

ABSTRACT The major toxic mechanism of Microcystin-LR is inhibition of the activity of protein phosphatase 2A (PP2A), resulting in a series of cytotoxic effects. Our previous studies have demonstrated that microcystin-LR (MCLR) induced very different molecular effects in normal cells and the tumor cell line SMMC7721. To further explore the MCLR toxicity mechanism in tumor cells, human laryngeal epithelial cells (Hep-2) was examined in this study. Western blot, immunofluorescence, immunoprecipitation, and transwell migration assay were used to detect the effects of MCLR on PP2A activity, PP2A substrates, cytoskeleton, and cell migration. The results showed that the protein level of PP2A subunits and the posttranslational modification of the catalytic subunit were altered and that the binding of the AC core enzyme as well as the binding of PP2A/C and α4, was also affected. As PP2A substrates, the phosphorylation of MAPK pathway members, p38, ERK1/2, and the cytoskeleton-associated proteins, Hsp27, VASP, Tau, and Ezrin were increased. Furthermore, MCLR induced reorganization of the cytoskeleton and promoted cell migration. Taken together, direct covalent binding to PP2A/C, alteration of the protein levels and posttranslational modification, as well as the binding of subunits, are the main pattern for the effects of MCLR on PP2A in Hep-2. A dose-dependent change in p-Tau and p-Ezrin due to PP2A inhibition may contribute to the changes in the cytoskeleton and be related to the cell migration in Hep-2. Our data provide a comprehensive exposition of the MCLR mechanism on tumor cells. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 890-903, 2017. [ABSTRACT FROM AUTHOR]

Our previous studies have described the toxic effects of microcystin-LR (MC-LR) in various normal cell lines and human hepatoma SMMC-7721 cells, but the specific effects of MC-LR in other types of cancer cells with respect to protein phosphatase 2A (PP2A) have not been fully elaborated. A549 human lung adenocarcinoma cells have been identified to express organic anion-transporting polypeptides (OATP) involved in cellular uptake of MC-LR, and thus probably make an appropriate in vitro model to assess MC-LR's cytotoxicity. Hence, in our present study, A549 cells were treated with various concentrations of MC-LR for 24 h. The presence of MC-LR in A549 cells was confirmed, and PP2A activity, PP2A substrates, cytoskeleton, apoptosis, and proliferation were subsequently explored. The results showed that 5-10 μM MC-LR inhibited PP2A activity significantly but 0.5-1 μM MC-LR did not change PP2A activity dramatically. The inhibition could result from the hyperphosphorylation of PP2A/C at Tyr307, an elevation in the total PP2A/C expression and the dissociation of α4/PP2A/C complexes. Moreover, MC-LR led to rearrangements of filamentous actin and microtubules, which might be correlated with the hyperphosphorylation of Ezrin, VASP and HSP27 due to PP2A inhibition and mitogen-activated protein kinase (MAPK) activation. However, exposure to MC-LR for 24 h failed to trigger either apoptosis or proliferation, which might be related to PP2A-inhibition-induced hyperphosphorylation of Bcl-2 and Bad and the activation status of Akt. In conclusion, our data indicated that MC-LR induced extensive molecular and cellular alterations in A549 cells through a PP2A-centered pathway, which differed in some respects from our previous study in SMMC-7721 cells. To our knowledge, this is the first report comprehensively demonstrating the effects of MC-LR in A549 cells, and our findings provide insights into the mechanism of MC-LR toxicity in cancer cells. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1065-1078, 2017. [ABSTRACT FROM AUTHOR]

ABSTRACT Microcystin-LR (MC-LR) is one of the most toxic members of microcystins released by freshwater cyanobacterial. The major mechanism of MC-LR toxicity has been attributed to its inhibition of protein phosphatases 1 (PP1) and 2A (PP2A). In our prior research, α4 protein, a regulator of PP2A, was found not only crucial for PP2A regulation but also for the overall response of HEK 293 cells encountering MC-LR. To explore the role of α4 in MC-LR toxicity via PP2A regulation, here, HEK 293 cells overexpressing α4 protein were exposed to MC-LR and PP2A, cytoskeletal organization, and cytoskeleton-related proteins were investigated. The results showed that PP2A activity decreased and PP2A/C subunit expression and phosphorylation at Tyr307 increased significantly in the group exposed to high MC-LR. Vimentin IF became concentrated and formed perinuclear bundles. However, the assembly of actin filament and microtubules remained unchanged and the expression and phosphorylation of the cytoskeleton-related proteins HSP27 and VASP did not increase significantly. Some of these results differ from those of our previous study in which normal HEK293 cells were exposed to MC-LR. Our results indicate that elevated α4 expression confers some resistance to MC-LR-induced cytoskeletal change These new findings provide helpful insights into the mechanism of MC-LR toxicity and the role of α4 in regulating PP2A function. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 255-264, 2017. [ABSTRACT FROM AUTHOR]